Daniela Göppner

The price of tumor control: an analysis of rare side effects of anti-CTLA-4 therapy in metastatic melanoma from the ipilimumab network

Background Ipilimumab, a cytotoxic T-lymphocyte antigen-4 (CTLA-4) blocking antibody, has been approved for the treatment of metastatic melanoma and induces adverse events (AE) in up to 64% of patients. Treatment algorithms for the management of common ipilimumab-induced AEs have lead to a reduction of morbidity, e.g. due to bowel perforations. However, the spectrum of less common AEs is expanding as ipilimumab is increasingly applied. Stringent recognition and management of AEs will reduce drug-induced morbidity and costs, and thus, positively impact the cost-benefit ratio of the drug. To facilitate timely identification and adequate management data on rare AEs were analyzed at 19 skin cancer centers. Methods and Findings Patient files (n = 752) were screened for rare ipilimumab-associated AEs. A total of 120 AEs, some of which were life-threatening or even fatal, were reported and summarized by organ system describing the most instructive cases in detail. Previously unreported AEs like drug rash with eosinophilia and systemic symptoms (DRESS), granulomatous inflammation of the central nervous system, and aseptic meningitis, were documented. Obstacles included patientś delay in reporting symptoms and the differentiation of steroid-induced from ipilimumab-induced AEs under steroid treatment. Importantly, response rate was high in this patient population with tumor regression in 30.9% and a tumor control rate of 61.8% in stage IV melanoma patients despite the fact that some patients received only two of four recommended ipilimumab infusions. This suggests that ipilimumab-induced antitumor responses can have an early onset and that severe autoimmune reactions may reflect overtreatment. Conclusion The wide spectrum of ipilimumab-induced AEs demands doctor and patient awareness to reduce morbidity and treatment costs and true ipilimumab success is dictated by both objective tumor responses and controlling severe side effects.

Cutaneous, gastrointestinal, hepatic, endocrine, and renal side-effects of anti-PD-1 therapy

BACKGROUND Anti-programmed cell death receptor-1 (PD-1) antibodies represent an effective treatment option for metastatic melanoma as well as for other cancer entities. They act via blockade of the PD-1 receptor, an inhibitor of the T-cell effector mechanisms that limit immune responses against tumours. As reported for ipilimumab, the anti-PD-1 antibodies pembrolizumab and nivolumab can induce immune-related adverse events (irAEs). These side-effects affect skin, gastrointestinal tract, liver, endocrine system and other organ systems. Since life-threatening and fatal irAEs have been reported, adequate diagnosis and management are essential. METHODS AND FINDINGS In total, 496 patients with metastatic melanoma from 15 skin cancer centers were treated with pembrolizumab or nivolumab; 242 side-effects were described in 138 patients. In 116 of the 138 patients, side-effects affected the skin, gastrointestinal tract, liver, endocrine, and renal system. Rare side-effects included diabetes mellitus, lichen planus, and pancreas insufficiency due to pancreatitis. CONCLUSION Anti-PD1 antibodies can induce a plethora of irAEs. The knowledge of them will allow prompt diagnosis and improve the management resulting in decreased morbidity.

Neurological, respiratory, musculoskeletal, cardiac and ocular side-effects of anti-PD-1 therapy

BACKGROUND Anti-programmed cell death 1 (PD-1) antibodies represent an effective treatment option for metastatic melanoma and other cancer entities. They act via blockade of the PD-1 receptor, an inhibitor of the T-cell effector mechanisms that limit immune responses against tumours. As reported for ipilimumab, the anti-PD-1 antibodies pembrolizumab and nivolumab can induce immune-related adverse events (irAEs). These side-effects can involve skin, gastrointestinal tract, liver, the endocrine system and other organ systems. Since life-threatening and fatal irAEs have been reported, adequate diagnosis and management are essential. METHODS AND FINDINGS In total, 496 patients with metastatic melanoma from 15 skin cancer centres were treated with pembrolizumab or nivolumab. Two hundred forty two side-effects in 138 patients have been analysed. In 77 of the 138 patients side-effects affected the nervous system, respiratory tract, musculoskeletal system, heart, blood and eyes. Not yet reported side-effects such as meningo-(radiculitis), polyradiculitis, cardiac arrhythmia, asystolia, and paresis have been observed. Rare and difficult to manage side-effects such as myasthenia gravis are described in detail. CONCLUSION Anti-PD-1 antibodies can induce a plethora of irAEs. The knowledge of them will allow prompt diagnosis and improve the management resulting in decreased morbidity.

Sentinel Lymph Node Biopsy Status Is a Key Parameter to Stratify the Prognostic Heterogeneity of Malignant Melanoma in High-Risk Tumors >4.0 mm

Background: The value of sentinel lymph node biopsy (SLNB) as a useful strategy to assess the risk of future metastasis in high-risk melanomas (>4.0 mm) is controversially discussed. Objectives: In a single-center retrospective study, the prognostic relevance of SLNB and other risk factors in the subgroup of melanomas >4.0 mm was investigated and compared to previously published results. Methods: Using Kaplan-Meier estimates and Cox regressions, we assessed the prognostic relevance of SLNB in our subcohort of 87 patients with thick melanomas >4.0 mm (T4). The mean follow-up for this subgroup was 51 months. We compared SLN value as compared to ulceration. Results: SLN and ulceration, analyzed as separate risk factors as well as their combination, predicted a highly reduced life expectancy in terms of recurrence-free survival (RFS) in our cohort of patients. SLN, but not ulceration, also predicted overall survival (OS). Conclusions: Positive SLNB is an essential predictor of RFS and OS in T4 melanoma patients, whereas ulceration lacked significance with respect to OS in our cohort. Our data thus suggest the routine use of SLNB also for T4 melanoma and may therefore allow to optimize risk-stratified therapeutic regimens.

High incidence of naevi-associated BRAF wild-type melanoma and dysplastic naevi under treatment with the class I BRAF inhibitor vemurafenib.

There is growing evidence that not only malign keratinocytic but also melanocytic tumours can arise during treatment with vemurafenib. During an on-going early access trial, 13 patients harbouring a BRAF-V600E mutation received vemurafenib (Zelboraf®) 960 mg twice daily to test the safety, tolerability, efficacy and response rate for advanced melanoma. Clinically or dermatoscopically suspicious cutaneous tumours under treatment with vemurafenib were excised. The BRAF-V600E status of confirmed new primary melanoma and dysplastic naevi was tested using a genetic mutation assay and immunohistochemistry. Four of the 13 patients (31%) developed 4 new naevi-associated malignant melanomas and 5 dysplastic naevi between 6 weeks and 6 months after the start of treatment. With the exception of one in situ melanoma, all tumours were BRAF wild-type. Immunohistochemistry revealed increased expression of ERK, pERK and active Rac1-GTP in the naevi-associated melanoma and dysplastic naevi. Careful and continuous skin examination, including dermoscopy, appears to be required during treatment with vemurafenib.

Successful combination therapy of a locally advanced squamous cell carcinoma of the skin with cetuximab and γ-irradiation

Squamous cell carcinoma (SCC) as predominantly UV-induced skin cancer occurs particularly in advanced age. Even though rare on the whole with about 1 % the risk of metastasis increases significantly in dependence on tumor thickness, the degree of differentiation and histological criteria, but also on the horizontal extension of the tumor [1]. Especially in elderly patients cutaneous SCC represents a therapeutic challenge, as due to increased comorbidities larger surgical procedures are associated with considerable risk [2]. An 85-year-old woman presented in our clinic with a 10 12 cm large ulcerated tumor on the Successful combination therapy of a locally advanced squamous cell carcinoma of the skin with cetuximab and -irradiation

Intermittent High-Dose Intravenous Interferon Alfa-2b for Adjuvant Treatment of Stage III Melanoma: Final Analysis of a Randomized Phase III Dermatologic Cooperative Oncology Group Trial

PURPOSE To evaluate the efficacy, safety, tolerability, and quality of life (QoL) in patients receiving intravenous, intermittent high-dose interferon alfa-2b (IFN-α-2b [iHDI]) compared with standard high-dose IFN-α-2b (HDI). PATIENT AND METHODS Patients with stage III resected lymph node or in-transit metastasis from cutaneous malignant melanoma were randomly assigned to receive either a standard HDI regimen or three courses of IFN-α-2b 20 MIU/m(2) administered intravenously 5 days a week for 4 weeks then repeated every 4 months. Distant metastasis-free survival was the primary end point for efficacy analysis. In addition, relapse-free survival, overall survival, safety as determined by Common Terminology Criteria for Adverse Events criteria, and QoL were secondary end points. RESULTS Of 649 patients enrolled, 22 patients were excluded from the intent-to-treat analysis. The remaining 627 patients were well balanced between the arms according to sex, age, and stage. After a median follow-up of 55 months, a multivariable Cox model revealed no significant differences for distant metastasis-free survival (hazard ratio [HR], 1.21; P = .12) or overall survival (HR, 1.01; P = .85). In contrast, the difference for relapse-free survival was significant (HR, 1.27; P = .03), favoring standard HDI. Early termination of treatment because of adverse events or QoL occurred significantly more often with HDI than with iHDI (26.0% v 14.8%; P < .001). CONCLUSION Although the safety and QoL profiles for the intermittent regimen were favorable, no significant difference was observed for survival while the HR for relapse with iHDI was increased. Therefore, an iHDI regimen, as tested here, cannot be recommended as adjuvant treatment for high-risk melanoma.

A multicenter DeCOG study on predictors of vemurafenib therapy outcome in melanoma: pretreatment impacts survival

BACKGROUND Kinase inhibitors targeting the BRAF V600 mutation have become standard in the treatment of metastatic melanoma. Albeit in wide clinical use, the patterns associated with therapy outcome are not fully elucidated. The present study was aimed to identify predictive factors of therapy response and survival under the BRAF inhibitor vemurafenib. PATIENTS AND METHODS This multicenter retrospective study analyzed patient, tumor, and pretreatment characteristics collected in BRAF V600-mutated stage IV melanoma patients before single-agent therapy with the BRAF inhibitor vemurafenib. RESULTS A total of 300 patients from 14 centers were included into this study with a median follow-up time of 13.0 months. Median progression-free survival (PFS) was 5.1 months; median overall survival (OS) was 7.6 months. Best response under vemurafenib was associated with serum lactate dehydrogenase (LDH; ≤ versus >upper normal limit; P = 0.0000001), Eastern Cooperative Oncology Group (ECOG) overall performance status (OPS) (0 versus ≥ 1; P = 0.00089), and BRAF mutation subtype (V600E versus V600K; P = 0.016). Multivariate analysis identified ECOG OPS ≥ 1 [hazard ratio (HR) = 1.88; P = 0.00005], immunotherapy pretreatment (HR = 0.53; P = 0.0067), elevated serum LDH (HR = 1.45; P = 0.012), age >55 years (HR = 0.72; P = 0.019), and chemotherapy pretreatment (HR = 1.39; P = 0.036) as independent predictors of PFS. For OS, elevated serum LDH (HR = 1.99; P = 0.00012), ECOG OPS ≥ 1 (HR = 1.90; P = 0.00063), age >55 years (HR = 0.65; P = 0.011), kinase inhibitor pretreatment (HR = 1.86; P = 0.014), immunotherapy pretreatment (HR = 0.57; P = 0.025), chemotherapy pretreatment (HR = 2.17; P = 0.039), and male gender (HR = 0.70; 95% confidence interval 0.50-0.98; P = 0.039) were found as predictors. CONCLUSION Our data demonstrate that the type of pretreatment strongly influences the outcome of vemurafenib therapy, with a precedent immunotherapy showing a positive, and a prior chemotherapy and kinase inhibitors showing a negative impact on survival, respectively. Moreover, we show that the patients OPS, serum LDH, age, and gender independently impact vemurafenib therapy outcome. These findings should be taken into account for the future design of therapy sequencing in BRAF V600 mutation-positive melanoma patients.

Technical parameters of vertical in vivo multiphoton microscopy: a critical evaluation of the flyscanning method

The optical biopsy could be a quick and painless support or alternative to a punch biopsy. In this letter the first in vivo vertical wide field two photon microscopy (2PM) images of healthy volunteers are shown. The 2PM images are fused images of two photon excited auto fluorescence (AF) and second harmonic generation (SHG) signals given as false-color images of 200 μm × 7 mm in size. By using these two nonlinear effects, the epidermis can be easily distinguished from the dermis at a glance. The auto fluorescence provides cellular resolution of the epidermal cells, and elastin fibers are partly visible in the dermis. Collagen, visible by SHG signal, is the dominant structure in the dermis. As contact agent water was evaluated to increase the AF signal, especially in the deeper layers of epidermis and dermis. For further improvement any terminal hairs should be removed by shaving and by taking tape strips of the first five layers of the stratum corneum. The first images illustrated that young skin compared to aged skin shows remarkably different dermal elastin and collagen signals in the dermis.

High-resolution two-photon imaging of HE-stained samples in dermatohistopathology – A pilot study on skin tumours

Abstract Non-invasive two-photon microscopy (TPM) provides a new technique which could become in the future a substitute for hematoxylin and eosin (HE) staining of tissue sections of the epidermis and upper and middle dermis as well. High-resolution imaging, in combination with false-colour representation, allows an accurate reproduction of standard microscopy. The vertical skin viewing of epidermis and upper dermis by means of TPM allows for a new histopathological supportive technique, especially in non-melanoma skin cancer such as squamous cell carcinoma and basal cell carcinoma. If it could be used on fresh tissue samples, it could provide an alternative method to Mohs 3D histology, even though the definitive criteria for melanocytic tumours have not yet been sufficiently evaluated. Zusammenfassung Die neue, nicht-invasive Zwei-Photonen-Mikroskopie (two-photon microscopy, TPM) ermöglicht eine qualitativ hohe Reproduktion fast gleichwertig zu histologischen Präparaten exzidierter Tumoren, die die Epidermis und obere und mittlere Dermis erfassen. Mit Hilfe der durch die Scanner-Technik erzeugten hochaufgelösten Bilder in Kombination mit einer zusätzlichen Falschfarbendarstellung können relevante diagnostische wie prognostische Kriterien akkurat beurteilt werden. Die vertikale Bildgebung von Dermis und Epidermis durch die TPM ermöglicht eine ergänzende histopathologische Beurteilung vor allem bei weißem Hautkrebs wie dem Plattenepithel- oder Basalzellkarzinom. Ihr zukünftiger Einsatz an Frischpräparaten verspricht daher eine Alternative zu Mohs 3D-Histologie zu sein, auch wenn entscheidende Diagnosekriterien bei melanozytären Tumoren bislang noch nicht hinreichend beurteilbar sind.