Rainer Rompel

Phase II DeCOG-Study of Ipilimumab in Pretreated and Treatment-Naïve Patients with Metastatic Uveal Melanoma

Purpose Up to 50% of patients with uveal melanoma (UM) develop metastatic disease with limited treatment options. The immunomodulating agent ipilimumab has shown an overall survival (OS) benefit in patients with cutaneous metastatic melanoma in two phase III trials. As patients with UM were excluded in these studies, the Dermatologic Cooperative Oncology Group (DeCOG) conducted a phase II to assess the efficacy and safety of ipilimumab in patients with metastatic UM. Patients and Methods We undertook a multicenter phase II study in patients with different subtypes of metastatic melanoma. Here we present data on patients with metastatic UM (pretreated and treatment-naïve) who received up to four cycles of ipilimumab administered at a dose of 3 mg/kg in 3 week intervals. Tumor assessments were conducted at baseline, weeks 12, 24, 36 and 48 according to RECIST 1.1 criteria. Adverse events (AEs), including immune-related AEs were graded according to National Cancer Institute Common Toxicity Criteria (CTC) v.4.0. Primary endpoint was the OS rate at 12 months. Results Forty five pretreated (85%) and eight treatment-naïve (15%) patients received at least one dose of ipilimumab. 1-year and 2-year OS rates were 22% and 7%, respectively. Median OS was 6.8 months (95% CI 3.7–8.1), median progression-free survival 2.8 months (95% CI 2.5–2.9). The disease control rate at weeks 12 and 24 was 47% and 21%, respectively. Sixteen patients had stable disease (47%), none experienced partial or complete response. Treatment-related AEs were observed in 35 patients (66%), including 19 grade 3–4 events (36%). One drug-related death due to pancytopenia was observed. Conclusions Ipilimumab has very limited clinical activity in patients with metastatic UM. Toxicity was manageable when treated as per protocol-specific guidelines. Trial Registration ClinicalTrials.gov NCT01355120

A first prospective population-based analysis investigating the actual practice of melanoma diagnosis, treatment and follow-up

AIM OF THE STUDY To describe the current management of patients diagnosed with cutaneous melanoma and melanoma in situ in Germany and assess for adherence with the existing German guideline in a first prospective population-based analysis. METHODS Prospective and longitudinal population-based study using online questionnaires. Registration by practitioners and hospitals was open for all patients diagnosed with melanoma between April and June 2008 in Germany. For data analysis, patients with melanoma stages 0-III (AJCC 2002) were included. RESULTS Data from 1081 patients registered by 106 different centres were available for analysis. Male patients were significantly older than female patients (61.4 years versus 55.8years, p<0.0001) and presented with thicker primary tumours (1.62 mm [median 0.9 mm] versus 1.48 mm [median 0.8 mm], p=0.01). Excessive safety margin excisions were most often applied in melanoma in situ and in small centres. Insufficient excision margins (6.9%) were associated with head and neck localisation, geographical region and implementation of further staging procedures. Decision on sentinel lymph node biopsy complied with the German guideline in >85% of cases and was dependent on age and tumour localisation. Only 60% of patients received a complete lymph node dissection (CLND) after a positive SLNB, the rate of CLND was lowest in older patients. Adjuvant treatments were initiated in only 34% of patients formally qualifying for adjuvant treatment based on guideline recommendations. Approximately half of all staging procedures were done in no-risk/low-risk tumour patients. CONCLUSIONS Management of melanoma in Germany did not show great dependency on centre size, geographical area or treating physician but rather on patient and tumour characteristics. The low rate of adjuvant treatment initiations reflects the need of treatment options in this patient group. Excessive initial staging procedures generate significant costs.

Short German guidelines: Squamous cell carcinoma

Squamous cell carcinoma (SCC) of the skin is a malignant locally destructive epithelial tumor which uncommonly metastasizes. SCC is the second most common skin tumor following basal cell carcinoma. It has shown a rapid increase in increase in the white population. The most important etiologic factor is chronic UV exposure, especially in individuals sensitive to UV light. Risk factors for developing SCC include actinic keratoses, advanced age, high cumulative sun exposure, and lightly pigmented skin. The most important risk factor is the presence of actinic keratoses In Great Britain, the age-dependent prevalence of actinic keratoses is estimated at 15% for men and 7% for women. Transition from actinic keratosis to SCC occurs in about 5% of lesions. In addition to the malignant transformation induced by UV irradiation, other etiologic factors include chronic wounds and inflammatory lesions such as leg ulcers, burns, and other scars, as well as lichen planus and bullous dermatoses. Both arsenic exposure and ionizing radiation can also induce SCC. The incidence of SCC is markedly increased in immunosup-pressed individuals, and the tumors are more aggressive in this population. This is true for patients with iatrogenic immunosuppression after organ transplantation, hematologic malignancies, chemotherapy and HIV infection. The malignant transformation of keratinocytes is triggered by carcinogenic human papilloma viruses which are more common in immunosuppressed patients. Genetic syndromes with increased incidence of SCC include albinism, xeroderma pigmentosum and Muir-Torre syndrome. In central Europe the incidence of SCC was estimated at 20-30 / 100,000 yearly during the 1990s. About 90% of the tumors are on the face. The average age at presentation is 70 years; men are more often affected than women. Metastasis occurs in around 5% of patients and almost always involves the regional lymph nodes. The 5-year survival with metastases is 25-50%. The clinical presentation of SCC is heterogenous, although not as varied as basal cell carcinoma. Invasive SCC can arise from erythematous patches or hyperkeratotic plaques (actinic keratosis, Bowen disease). Most SCC are nodular with crusting and often ulceration. They grow

Prospective Randomized Multicenter Adjuvant Dermatologic Cooperative Oncology Group Trial of Low-Dose Interferon Alfa-2b With or Without a Modified High-Dose Interferon Alfa-2b Induction Phase in Patients With Lymph Node–Negative Melanoma

PURPOSE Interferon alfa (IFN-alpha) has shown clinical efficacy in the adjuvant treatment of patients with high-risk melanoma in several clinical trials, but optimal dosing and duration of treatment are still under discussion. It has been argued that in high-dose IFN-alpha (HDI), the intravenous (IV) induction phase might be critical for the clinical benefit of the regimen. PATIENTS AND METHODS In an attempt to investigate the potential role of a modified high-dose induction phase, lymph node-negative patients with resected primary malignant melanoma of more than 1.5-mm tumor thickness were included in this prospective randomized multicenter Dermatologic Cooperative Oncology Group trial. Six hundred seventy-four patients were randomly assigned to receive 4 weeks of a modified HDI scheme. This schedule consisted of 5 times weekly 10 MU/m(2) IFN-alpha-2b IV for 2 weeks and 5 times weekly 10 MU/m(2) IFN-alpha-2b administered subcutaneously (SC) for another 2 weeks followed by 23 months of low-dose IFN-alpha-2b (LDI) 3 MU SC three times a week (arm A). LDI 3 MU three times a week was given for 24 months in arm B. Results Of 650 assessable patients, there were 92 relapses among the 321 patients receiving high-dose induction as compared with 95 relapses among the 329 patients receiving LDI only. Five-year relapse-free survival rates were 68.0% (arm A) and 67.1% (arm B), respectively. Likewise, melanoma-related fatalities were similar between both groups, resulting in 5-year overall survival rates of 80.2% (arm A) and 82.9% (arm B). CONCLUSION The addition of a 4-week modified HDI induction phase to a 2-year low-dose adjuvant IFN-alpha-2b treatment schedule did not improve the clinical outcome.

Brief S2k guidelines – Cutaneous squamous cell carcinoma

Helmut Breuninger, Thomas Eigentler, Friedrich Bootz, Axel Hauschild, Rolf-Dieter Kortmann, Klaus Wolff, Eggert Stockfleth, Rolf-Markus Szeimies, Rainer Rompel, Claus Garbe, Stephan Grabbe (1) Department of Dermatology, Tübingen University Hospital, Germany (2) Clinic and Polyclinic for Otolaryngology/Surgery, Bonn University Hospital, Germany (3) Department of Dermatology, Kiel University Hospital, Germany (4) Leipzig University Clinic for Radiotherapy and Radiooncology, Germany (5) Clinic and Polyclinic for Oral and Maxillofacial Surgery, Klinikum rechts der Isar, Munich, Germany (6) Department of Dermatology, Venereology, and Allergology, Charité – Universitätsmedizin, Berlin, Germany (7) Department of Dermatology and Allergology, Knappschaftskrankenhaus Recklinghausen, Germany (8) Department of Dermatology, Klinikum Kassel, Germany (9) Department of Dermatology, Mainz University Hospital, Germany

Prospective evaluation of follow-up in melanoma patients in Germany – Results of a multicentre and longitudinal study

BACKGROUND Patient numbers requiring long-term melanoma surveillance are constantly rising. Surveillance is costly and guideline recommendations vary substantially. METHODS In this German nationwide study, information on surveillance and treatment of patients diagnosed with melanoma and melanoma in situ (MMis) between April and June 2008 was prospectively collected over four years. Additionally, patient self-report questionnaires were evaluated to assess anxiety, depression, health-related quality of life, socio-demographic information and use of disease specific health information sources at year 4 after primary diagnosis. RESULTS Complete data was available for 668 patients from 67 centres, of whom 96.0% were in regular melanoma surveillance. In year 3-4 of surveillance, only 55.6% of locoregionary metastases were detected during surveillance visits. Only 33.3% were self-detected by the patient even though 69.4% were documented as being clinically visible or palpable. Costs of 4year surveillance of 550 patients without tumour recurrence (stage I-IIC and MMis) accumulated to 228,155.75 €. Guideline-adherence for follow-up frequency, lymph node ultrasound, S100 serum level tests and diagnostic imaging recommendations was approximately 60% in year 3-4 of surveillance. Multivariate regression analysis showed that certain patient/tumour characteristics and regional differences were significantly associated with guideline deviations. The percentage of patients who exceeded published cut-off scores indicating clinically relevant symptoms of anxiety and depression were significantly increased. Patients frequently reported lack of psychosocial support and education but ascribed great importance to these. CONCLUSIONS We recommend further reduction of melanoma follow-up in low-risk melanoma patients and improvement of psycho-social support and patient education for all melanoma patients.

DRGs in der Dermatologie: Ergebnisse des DRG‐Evaluationsprojektes der Deutschen Dermatologischen Gesellschaft

Hintergrund: Die Einführung des DRG‐Systems in Deutschland optional ab dem 1. 1. 2003 und für alle Krankenhäuser verpflichtend ab dem 1. 1. 2004 hat zu einer großen Verunsicherung v. a. auf der Krankenhausseite geführt, da befürchtet wird, daß die in Deutschland praktizierten diagnostischen und therapeutischen Maßnahmen sich nicht sachgerecht mit einem DRG‐System abbilden und vergüten lassen. Daher hat die Deutsche Dermatologische Gesellschaft ein DRG‐Evaluationsprojekt in Zusammenarbeit mit der DRG‐Research‐Group des Universitätsklinikums Münster und der Bundesärztekammer mit dem Ziel durchgeführt, die medizinische und ökonomische Homogenität der Fallgruppen zu überprüfen.

G‐DRG Version 2004: Veränderungen aus Sicht der Dermatologie

Die Finanzierung der stationären Krankenhausleistungen über ein DRG‐basiertes Vergütungssystem wird ab 2004 für alle Krankenhäuser verpflichtend eingeführt. Nachdem mit der Krankenhausfallpauschalenverordnung 2004 (KFPV 2004) die zentralen Punkte der G‐DRG‐Systemversion bekannt geworden sind, stellt sich die Frage nach den Konsequenzen. Festzustellen ist, daß der erste deutsche DRG‐Fallpauschalenkatalog sich sehr deutlich von dem bisherigen Optionskatalog unterscheidet, so daß eine intensive Auseinandersetzung mit den neuen Bedingungen erforderlich wird. Medizinökonomisches Handeln wird stärker als bisher den Krankenhausalltag prägen und Einfluß nehmen auf sich verändernde Versorgungsstrukturen. Die wesentlichen Grundlagen und die Anwendung der neuen Bestimmungen müssen deshalb bekannt sein. Neben den allgemeinen Abrechnungsregeln werden vor allem die Veränderungen im neuen Fallpauschalenkatalog erläutert und Auswirkungen für die Dermatologie beispielhaft beleuchtet. Weiterhin müssen die Klassifikationssysteme in den Versionen OPS‐301 SGB V und ICD‐10‐GM 2004 sowie die Deutschen Kodierrichtlinien Version 2004 Berücksichtigung finden. Daher werden ebenso die wesentlichen Neuerungen im Verwendungszusammenhang für die Dermatologie vorgestellt.

OP-Hospitationsprogramm der VOD und DDG

Über viele Jahre hinweg wurden Kolleginnen und Kollegen in den operativen Abteilungen einiger ausgewiesener dermatologischer Kliniken gastfreundlich aufgenommen, um ihre operative Qualifikation zu erweitern, neue Techniken zu erlernen und die Kenntnisse in der eigenen Klinik weiterzugeben. Aus der positiven Resonanz entstand die Idee zu einem strukturierten Austausch unter den dermatologischen Kliniken. Da wechselseitige Rotationen über längere Zeiträume aus formalen Gründen kaum realisierbar sind, hat die Vereinigung für operative und onkologische Dermatologie (VOD) in Abstimmung mit dem Präsidium der Deutschen Dermatologischen Gesellschaft (DDG) ein praxisnahes Ausbildungskonzept zur Qualitätssicherung in der Dermatochirurgie entwickelt. Aufgrund der hohen Bedeutung der operativen Dermatologie in der Versorgung von Menschen mit Hauttumoren, mit gutartigen Fehlund Neubildungen, mit venösen Erkrankungen u. v. a. m. werden auszubildende Kolleginnen und Kollegen in den Hautkliniken und Fachärztinnen und Fachärzte in der Niederlassung gleichermaßen angesprochen. Das OPHospitationsprogramm ist primär an den Inhalten der Weiterbildungsordnung (OPKatalog des Fachgebietes) orientiert. Weiterhin werden innovative Methoden und minimal invasive Techniken vermittelt, die im aktuellen Interesse wissenschaftlicher Prüfung durch die Arbeitsgemeinschaften/Arbeitskreise der DDG stehen. Nachfolgend werden die Inhalte des Hospitationsprogramms und der strukturelle Ablauf vorgestellt. Spezielle Zertifizierungen durch die DDG bzw. DDA werden kurzfristig angestrebt.

Actual practice of melanoma follow-up and treatment in Germany: results of a prospective, longitudinal cohort study.

DEAR EDITOR, Approximately 17 800 cutaneous invasive melanomas and 5000 melanomas in situ were detected in 2008 in Germany, and incidence trends show a threefold increase over the last 30 years, while mortality remained at a constant level. Unlike in many other countries, melanoma treatment in Germany (including surgical and systemic procedures) is primarily in the hands of dermatologists specialized in dermato-oncology. The extent of melanoma surveillance, especially with regard to imaging studies and the frequency of follow-up visits, remains an issue of controversy, and recommendations vary from country to country. Due to the increasing incidence and decreasing mortality rates, the number of patients in long-term melanoma surveillance will rise continuously. Sufficient management of this number of patients will be possible only if follow-up is both costand time-effective. It is also uncertain to what degree guideline recommendations are being (or can be) followed in actual clinical practice. The currently available research on melanoma follow-up is based mostly on studies of a monocentric and/or retrospective nature. The aims of this study were therefore (i) to describe prospectively the current practice of melanoma follow-up and treatment in Germany in the first 2 years after melanoma diagnosis in a large and representative cohort of patients with melanoma from various centres around Germany; and (ii) to assess guideline adherence regarding followup frequency in stage I melanoma and adjuvant therapy in stage III disease. The study was initiated in Germany in April 2008 as a nationwide project. Ethical approval was attained from the ethics committee of the medical faculty at Mannheim, University of Heidelberg, Germany. All patients diagnosed with melanoma and melanoma in situ between 1 April and 30 June 2008 in Germany were eligible for study participation. Patients were registered online by physicians from hospitals and doctors’ offices after the patient had signed informed consent for study participation. Between 1 April and 30 September 2010, follow-up data were gathered by the registering centre using extensive online questionnaires (Data S1; see Supporting Information). The centres received a reimbursement of €20 for each completed set of follow-up documentation. As patients were not randomly selected, all data should be considered exploratory. Missing data were not substituted; implausible data were recorded as ‘missing’. The v-test was used to test for differences between groups for categorical variables, and the Wilcoxon test for continuous variables. Multivariate logistic regression analyses were performed to investigate factors associated with the surveillance frequency of patients with stage I disease. Factors significant at the P < 0 05 level in univariate analyses were included in a stepwise multivariate regression analysis. All analyses were performed using SAS statistical software v.9.2 (SAS Inc, Cary, NC, U.S.A.). Follow-up data were available for 1006 patients (Table 1). Overall 948 (94 2%) were documented as being in regular surveillance, generally by their recruiting centre (72 3%) (Table 1). Few patients had been referred to a general practitioner (1 5%) or oncologist (0 3%). In the no-risk/low-risk patients (melanoma in situ and stage I), 575 of 671 patients (85 7%) in regular surveillance underwent staging procedures (Table S1; see Supporting Information). The majority of stage I patients (70 0%) were seen at the correct follow-up intervals. In 20 8% the interval between visits was too short, and in 9 2% too long. Multivariate analysis showed that having shorter intervals than recommended between follow-up visits was significantly associated with younger age; female sex; location of the primary (head/neck vs. lower extremity; trunk vs. lower extremity); region (central Germany vs. southern Germany); implementation of diagnostic procedures and centre size (small vs. large) (Table S2; see Supporting Information). The majority of first recurrences were detected by dermatologists in hospitals (74 1%), who were heavily involved in follow-up of patients with high-risk melanoma (Table S3; see Supporting Information). Only five patients self-detected the recurrence, even though 20 metastases were documented as being clinically visible, 12 as palpable. Forty-nine (60 5%) of the first recurrences were detected by diagnostic imaging. Overall, 56 8% of patients with stage III disease at diagnosis (n = 95) received adjuvant treatment within the first 6 months after melanoma diagnosis (Table 2). Low-dose interferon was the most commonly administered treatment (56%). Eighteen patients advanced to stage III disease during follow-up (Table 3). Only seven of these patients (39%) received systemic treatment after progression, mainly lowdose interferon (57%). Patients’ age was the main reason why they did not undergo systemic treatment after disease progression.