Melanoma: Garbe C

Garbe C, Hauschild A, Volkenandt M, Schadendorf D, Stolz W, Reinhold U, Kortmann RD, Kettelhack C, Frerich B, Keilholz U, Dummer R, Sebastian G, Tilgen W, Schuler G, Mackensen A, Kaufmann R. · University Department of Dermatology, Tübingen, Germany. · Melanoma Res. · Pubmed #18337653 No free full text.

Abstract: Systemic medical treatment of melanoma is administered in the adjuvant and palliative setting. Adjuvant therapy may be considered in patients with primary melanoma with more than 1.5 mm tumor thickness and with regional node metastasis. Presently no indication for systemic adjuvant chemotherapy or for adjuvant therapy with nonspecific immune-stimulatory agents outside controlled studies is seen. Interferon-alpha is the first substance in the adjuvant therapy of melanoma, which has shown to present a significant advantage to the patients in some prospective randomized studies. Good arguments for using adjuvant interferon-alpha therapy in high-risk melanoma patients exist. Both high-dose and low-dose interferon-alpha show promise. The major indications for systemic chemotherapy and chemoimmunotherapy are inoperable recurrent tumors, inoperable regional metastases and distant metastases (stage IV). As treatment in such situations is primarily palliative, the effect of any regimen on the quality of life must be carefully weighed. As a first line treatment, single agent therapy is recommended, as polychemotherapy or biochemotherapy did not show significant advantages for prolongation of survival; hence they are more toxic. An urgent need for development of new treatment modalities is necessary and general principles of experimental immunotherapy are outlined.

Garbe C, Hauschild A, Volkenandt M, Schadendorf D, Stolz W, Reinhold U, Kortmann RD, Kettelhack C, Frerich B, Keilholz U, Dummer R, Sebastian G, Tilgen W, Schuler G, Mackensen A, Kaufmann R. · University Department of Dermatology, Tübingen, Germany. · Melanoma Res. · Pubmed #18227710 No free full text.

Abstract: The primary treatment of a melanoma is surgical excision. An excisional biopsy is preferred, and safety margins of 1 cm for tumor thickness up to 2 mm and 2 cm for higher tumor thickness should be applied either at primary excision or in a two-step procedure. When dealing with facial, acral or anogenital melanomas, micrographic control of the surgical margins may be preferable to allow reduced safety margins and conservation of tissue. The sentinel lymph node biopsy should be performed in patients whose primary melanoma is thicker than 1.0 mm and this operation should be performed in centers where both the operative and nuclear medicine teams are experienced. In clinically identified lymph node metastases, radical lymph node dissection is considered standard therapy. If distant metastases involve just one internal organ and operative removal is feasible, then surgery should be seen as therapy of choice. Radiation therapy for the primary treatment of melanoma is indicated only in those cases in which surgery is impossible or not reasonable. In regional lymph nodes, radiation therapy is usually recommended when excision is not complete (R1 resection) or if the nodes are inoperable. In distant metastases, radiation therapy is particularly indicated in bone metastases, brain metastases and soft tissue metastases.

Leiter U, Garbe C. · Division of Dermatoloncology, Department of Dermatology, University Medical Center, University of Tuebingen, Liebermeisterstr, 25, 72076 Tuebingen, Germany. · Adv Exp Med Biol. · Pubmed #18348450 No free full text.

Abstract: Melanoma and nonmelanoma skin cancer (NMSC) are now the most common types of cancer in white populations. Both tumor entities show an increasing incidence rate worldwide but a stable or decreasing mortality rate. The rising incidence rates of NMSC are probably caused by a combination of increased sun exposure or exposure to ultraviolet (UV) light, increased outdoor activities, changes in clothing style, increased longevity, ozone depletion, genetics and in some cases, immune suppression. A dose-dependent increase in the risk of squamous cell carcinoma (SCC) of the skin was found associated with exposure to Psoralen and UVA irradiation. An intensive UV exposure in childhood and adolescence was causative for the development of basal cell carcinoma (BCC) whereas for the aetiology of SCC a chronic UV exposure in the earlier decades was accused. Cutaneous malignant melanoma is the most rapidly increasing cancer in white populations. The frequency of its occurrence is closely associated with the constitutive colour of the skin and depends on the geographical zone. The highest incidence rates have been reported from Queensland, Australia with 56 new cases per year per 100,000 for men and 43 for women. Mortality rates of melanoma show a stabilisation in the USA, Australia and also in European countries. The tumor thickness is the most important prognostic factor in primary melanoma. There is an ongoing trend towards thin melanoma since the last two decades. Epidemiological studies have confirmed the hypothesis that the majority of all melanoma cases are caused, at least in part, by excessive exposure to sunlight. In contrast to squamous cell carcinoma, melanoma risk seems not to be associated with cumulative, but intermittent exposure to sunlight. Therefore campaigns for prevention and early detection are necessary.

Hauschild A, Schadendorf D, Garbe C, Ugurel S, Kähler KC. · Department of Dermatology, University of Kiel, Kiel, Germany. · Cancer Treat Res. · Pubmed #17953423 No free full text.

This publication has no abstract.

Garbe C, Eigentler TK. · Division of Dermatooncology, Department of Dermatology, Eberhard Karls University, Tübingen, Germany. · Melanoma Res. · Pubmed #17496787 No free full text.

Abstract: Although the incidence of melanoma is still rising in Caucasian populations, the increase in mortality has leveled off. Improvements in early diagnosis, with more frequent diagnosis of low-risk patients (i.e. those with <1 mm of tumor thickness), is the main reason for these divergent developments. Primary prevention has not yet been successful and recent studies have demonstrated the lack of effectiveness of sunscreen in preventing nevi in children. Progress was made in early melanoma diagnosis when dermoscopy and digital dermoscopy were introduced, and computer algorithms have proved to be highly efficacious for automated melanoma diagnosis. Primary melanomas are now excised with narrower surgical margins of 1-2 cm. Sentinel-node biopsy is recommended as a nodal staging procedure in patients with tumor thickness of 1 mm and more, but the prognostic impact of this procedure has not yet been demonstrated. New imaging techniques, e.g. whole-body MRI and PET-CT, provide more accurate staging, particularly in patients with apparent metastasis, and facilitate decisions on surgical treatment strategies. Staging is now based on the 2001 TNM classification including tumor thickness and histopathologic ulceration in stages I and II and lymph node micro and macro-metastasis in stage III. A stage- and risk-adopted follow-up schedule is proposed for melanoma surveillance. Adjuvant therapy with interferon-alpha in high-risk patients offers a small benefit in terms of recurrence-free and overall survival; the optimal dosage and duration of this treatment are still to be defined. Almost no progress has been made in the medical treatment of disseminated metastasis of melanoma. Therapy with dacarbazine and a few other single agents remains the first-line treatment approach of choice. A number of new treatment modalities, including targeted molecules and immunologic approaches with monoclonal antibodies, are under development; hopefully, new treatment modalities will be available in the near future.

Garbe C, Hauschild A, Volkenandt M, Schadendorf D, Stolz W, Kortmann RD, Kettelhack C, Frerich B, Keilholz U, Dummer R, Sebastian G, Tilgen W, Schuler G, Mackensen A, Kaufmann R. · Universitäts-Hautklinik Tübingen. · J Dtsch Dermatol Ges. · Pubmed #16638065 No free full text.

This publication has no abstract.

Eigentler TK, Garbe C. · Skin Cancer Program, Department of Dermatology, EberhardKarl University, Tübingen, Germany. · Front Radiat Ther Oncol. · Pubmed #16394678 No free full text.

This publication has no abstract.

Garbe C. · Division of Dermato-Oncology, Department of Dermatology, University of Tübingen, Germany. · Dermatol Ther. · Pubmed #16297017 No free full text.

Abstract: Numerous laboratory tests and imaging methods are available that can be used in patients who are diagnosed with cutaneous melanoma. The downside risks related to testing are cost and patient anxiety. Therefore, it must be critically considered which examinations are useful and feasible. After a diagnosis of primary cutaneous melanoma, many physicians in Germany perform lymph node ultrasound to detect occult regional metastasis. Whole-body imaging techniques, except the physical examination, are unlikely to detect distant occult metastasis. In tumors that have an intermediate or high risk of recurrence (> 1 mm tumor thickness), baseline whole-body imaging may serve as a reference for ongoing evaluation. During follow-up care, physical examination alone is appropriate when there is a low risk for recurrence (up to 1-mm tumor thickness). In patients whose tumors are > 1 mm thickness, regular lymph node ultrasound examinations and determination of serum tumor marker S-100beta protein are commonly used by physicians in Germany. Whole-body imaging techniques are useful in patients who have locoregional and/or distant metastasis. For consideration of surgical resections in stage IV disease, more advanced examinations techniques such as positron emission tomography-computed tomography or whole body magnetic resonance imaging may be used. Early detection of limited disease using these methods may be helpful for patients who have locoregional metastases and for 10-20% of patients who have distant metastases and whose limited disease may be amenable to surgical resection.

Eigentler TK, Radny P, Kamin A, Weide B, Caroli UM, Garbe C. · Sektion Dermatologische Onkologie, Universitätshautklinik der Eberhard-Karls-Universität Tübingen. · J Dtsch Dermatol Ges. · Pubmed #16033477 No free full text.

Abstract: A new AJCC/UICC staging classification of malignant melanoma was published in 2001 and has been in use since then. Compared to the TNM classification used for the previous 15 years, the new classification contains fundamental changes. The classification of the primary tumor is now based on newly defined classes for Breslow's tumor thickness (0 - 1.0 mm; 1.01 - 2.0 mm, 2.01 - 4.0 mm; > 4.0 mm). Histopathologically diagnosed ulceration is the second prognostic factor in primary melanoma and its presence leads to upstaging into the next higher T category. Clark level of invasion is now only relevant for tumors up to 1 mm thick; levels IV and V are also reasons for upstaging. Classification of regional lymph node metastasis distinguishes between microscopic metastasis only as detected with sentinel lymph node biopsy and clinically detectable macroscopic metastasis. Additionally, the number of metastatic nodes and the presence of satellite and in-transit metastasis are prognostic factors for classification of regional lymph node metastasis. In distant metastasis, the kind of organ involvement has a role for classification (only skin and lymph nodes vs. lung vs. other organs) and an elevated LDH value leads to upstaging. A critical analysis of data of the German Central Malignant Melanoma Registry did not confirm the strong role of histopathological ulceration of the primary tumor in all T- and N-stages. Furthermore, there is an inconsistency of the classification as stage IIC displays a significantly worse prognosis as compared to stage IIIA. In spite of these drawbacks the new staging classification should used particularly in clinical trials in order to make data internationally comparable.

Meier F, Schittek B, Busch S, Garbe C, Smalley K, Satyamoorthy K, Li G, Herlyn M. · Department of Dermatology, University of Tuebingen, Tuebingen, Germany. · Front Biosci. · Pubmed #15970553 No free full text.

Abstract: Malignant melanoma is a highly aggressive tumor of the pigment-producing cells in the skin with a rapidly increasing incidence and a poor prognosis for patients with advanced disease that is resistant to current therapeutic concepts. Therefore, the development of novel strategies for treating melanoma are of utmost importance. In melanoma, both the Ras-Raf-MEK-ERK (MAPK) and the PI3K-AKT (AKT) signaling pathways are constitutively activated through multiple mechanisms, and thus exert several key functions in melanoma development and progression. Conversely, several molecules known to play key roles in melanoma development and progression such as the adhesion molecules E-/N-cadherin, MelCAM and alphavbeta3 integrin are regulated by these pathways and/or activate the same. The results of the research to date indicate that in melanoma both the MAPK and the AKT signaling pathways may represent promising therapeutic targets.

Bauer J, Blum A, Strohhäcker U, Garbe C. · Department of Dermatology, Eberhard-Karls-University, Liebermeisterstr. 25, 72076 Tübingen, Germany. · Br J Dermatol. · Pubmed #15656806 No free full text.

Abstract: BACKGROUND: Dermoscopy has improved the sensitivity and specificity of clinical diagnosis of melanoma from 60% to over 90%. However, in order not to miss melanoma a certain percentage of suspicious but benign lesions has to be excised. OBJECTIVES: To evaluate the dermoscopic changes and the rates of excision in benign melanocytic naevi and cutaneous malignant melanoma in long-term follow-up of high-risk patients using digital dermoscopy. METHODS: Digital dermoscopic images of 2015 atypical melanocytic naevi in 196 high-risk patients were analysed retrospectively. Among others, the following data were collected for each naevus: changes in surface area, overall architecture, dermoscopic patterns and distribution of pigmentation. All tumours suspicious for melanoma or showing asymmetrical changes were excised. RESULTS: During a median follow-up time of 25 months 128 (6.4%) of all naevi showed changes in size or architecture. Eighty-six per cent of all changes in patients who attended more than one visit were observed at the first follow-up visit. Thirty-three lesions showing changes were excised and two melanomas in situ and 31 melanocytic naevi were diagnosed. CONCLUSIONS: Follow-up examinations using digital dermoscopy revealed unchanged morphology in the large majority of melanocytic naevi. Excisions were only performed in cases of asymmetrical growth, asymmetrical changes of pigmentation, or development of dermoscopic features indicative of melanoma. The ratio of 33 lesions excised in order to identify two melanomas in situ seems reasonable and may be further reduced in future.

Blum A, Luedtke H, Ellwanger U, Schwabe R, Rassner G, Garbe C. · Department of Dermatology, Eberhard-Karls-University, Liebermeisterstrasse 25, 72076 Tuebingen, Germany. · Br J Dermatol. · Pubmed #15541081 No free full text.

Abstract: BACKGROUND: Digital image analysis has been introduced into the diagnosis of skin lesions based on dermoscopic pictures. OBJECTIVES: To develop a computer algorithm for the diagnosis of melanocytic lesions and to compare its diagnostic accuracy with the results of established dermoscopic classification rules. METHODS: In the Department of Dermatology, University of Tuebingen, Germany, 837 melanocytic skin lesions were prospectively imaged by a dermoscopy video system in consecutive patients. Of these lesions, 269 were excised and examined by histopathology: 84 were classified as cutaneous melanomas and 185 as benign melanocytic naevi. The remaining 568 lesions were diagnosed by dermoscopy as benign. Digital image analysis was performed in all 837 benign and malignant melanocytic lesions using 64 different analytical parameters. RESULTS: For lesions imaged completely (diameter < or = 12 mm), three analytical parameters were found to distinguish clearly between benign and malignant lesions, while in incompletely imaged lesions six parameters enabled differentiation. Based on the respective parameters and logistic regression analysis, a diagnostic computer algorithm for melanocytic lesions was developed. Its diagnostic accuracy was 82% for completely imaged and 84% for partially imaged lesions. All 837 melanocytic lesions were classified by established dermoscopic algorithms and the diagnostic accuracy was found to be in the same range (ABCD rule 78%, Menzies' score 83%, seven-point checklist 88%, and seven features for melanoma 81%). CONCLUSIONS: A diagnostic algorithm for digital image analysis of melanocytic lesions can achieve the same range of diagnostic accuracy as the application of dermoscopic classification rules by experts. The present diagnostic algorithm, however, still requires a medical expert who is qualified to recognize cutaneous lesions as being of melanocytic origin.

Leiter U, Meier F, Schittek B, Garbe C. · Department of Dermatology, Division of Dermatologic Oncology, Eberhard-Karls-University, Tuebingen, Germany. · J Surg Oncol. · Pubmed #15221923 No free full text.

Abstract: The natural course of cutaneous melanoma (CM) is determined by its metastatic spread and depends on tumor thickness, ulceration, gender, localization, and the histologic subtype of the primary tumor. CM metastasis develops via three main metastatic pathways and occurs as satellite or in-transit metastasis, as regional lymph node metastasis or as distant metastasis at the time of primary recurrence. About 50% of all CM patients with tumor progression firstly develop regional lymph node metastases. In the other 50% the first metastases are satellite or in-transit metastases (about 20%), or immediately distant metastases (about 30%). Development of distant metastasis appears to be an early event in metastatic spread and may in the majority of cases originate from the primary tumor, only few cases may develop secondarily to locoregional metastasis. Reporting of organ involvement in distant metastasis greatly differs between the results of imaging techniques and autopsy results in respect to the metastatic patterns detected, pointing out that there is a need of improved imaging systems. Proliferation, neovascularization, lymphangiogenesis, invasion, circulation, and embolism are important steps in the pathogenesis of CM metastasis, with tumor vascularity as an important independent significant prognostic factor. The expression of chemokine receptors in cancer cells associated with the expression of the respective chemokine receptor ligands in the target sites of the metastasis is an interesting observation which may stimulate the development of new therapeutic strategies.

Garbe C, Eigentler TK. · Sektion Dermatologische Onkologie, Universitäts-Hautklinik, Eberhard-Karls-Universität, Tübingen. · Hautarzt. · Pubmed #15043023 No free full text.

Abstract: Treatment of melanoma in the stage of distant metastasis aims on palliation and achievement of durable tumor remission with prolongation of survival. As long as metastasis is confined to one organ system and is removable, surgery remains the treatment of first choice. In limited metastasis radiotherapy may likewise be indicated, particularly in bone and brain metastasis. More extensive metastasis should be treated by chemotherapy or chemoimmunotherapy. Monochemotherapy with dacarbazine, temozolomide, fotemustine and vindesine or its combinations with interferon-alpha are currently preferred. Polychemotherapy or its combinations with interferon-alpha and interleukin-2 are suitable to produce higher response rates but failed to prolong survival. As these treatments are associated with substantially higher toxicity they have been widely abandoned. Combined treatment with dacarbazine and interferon-alpha obtain tumor responses or stable disease in 40-50% and objective tumor remissions in 15-20% of patients. Effective cancer vaccination strategies and blockade of melanoma specific target molecules are currently developed as new treatment options.

Eigentler TK, Caroli UM, Radny P, Garbe C. · Department of Dermatology, Eberhard-Karls-University, Tübingen, Germany. · Lancet Oncol. · Pubmed #14662431 No free full text.

Abstract: We undertook a systematic review of 41 randomised studies in disseminated melanoma, identified by a comprehensive search. We aimed to investigate rates of response to various treatment modalities and the outcome for the patients. We analysed seven studies that compared polychemotherapy with single-agent dacarbazine, six that compared different chemotherapeutic schedules with each other, five on the addition of tamoxifen to a reference therapy, and six that included non-specific immunostimulators. In 17 studies, the addition of interferon alfa, interleukin 2, or both, to a reference therapy was investigated, including trials with biochemotherapy. Many trials had small sample sizes and did not report a power analysis; not all were analysed by intention to treat. Although some treatment regimens, especially polychemotherapeutic schedules, seem to increase response rates, none of the treatment schedules was proven to prolong overall survival. Patients with disseminated melanoma should be treated with well-tolerated drug regimens, such as single-agent treatments or in combination with interferon alfa. Systemic treatments should preferably be investigated in randomised trials so that the potential benefits of new treatment concepts can be thoroughly examined.

Garbe C, Schadendorf D. · Section Dermatological Oncology, Dermatology Department, University Hospital Tübingen, Germany. · Onkologie. · Pubmed #12845208 No free full text.

Abstract: The main goal of follow-up examinations of patients with cutaneous melanomas is early diagnosis of developing recurrent or second tumors. Timely recognition of recurrence has a relevant effect on the prognosis. In 80% of the cases recurrences are diagnosed for the first time in the course of follow-up when follow-up procedures are carried out systematically. Most recurrences are discovered during a physical examination. Sonographic examination of the lymph nodes is also a very sensitive method which can lead to the diagnosis of locoregional recurrences before they are palpable. Further image-producing techniques are not necessary for surveillance of primary tumors. In contrast to former recommendations, new research indicates that less extensive diagnostic procedures are sufficient in primary tumor stages, especially when the tumor thickness of the melanoma is less than 1 mm. Consequently, costs can be reduced considerably without additional risk to the patient.

Bauer J, Garbe C. · Department of Dermatology, Eberhard Karls University, Tübingen, Germany. · Pigment Cell Res. · Pubmed #12753404 No free full text.

Abstract: Acquired melanocytic nevi (MN) in Caucasian populations are important markers for the risk of melanoma development. The total number of MN on the whole body is the most important independent risk factor for melanoma and the risk of melanoma development increases almost linearly with rising numbers of MN. Additionally, the presence of atypical MN and of actinic lentigines are likewise independent risk factors for melanoma. Atypical mole syndrome should be defined by the presence of many acquired MN and a threshold number of atypical MN. Acquired MN develops mainly during childhood and adolescence in the first two decades of life. The number of acquired nevi seems to be related to hereditary factors and nevus-prone families exist. The amount of sun exposure is the most important environmental risk factor for nevus development, particularly in early childhood. Interestingly, sunburns may play a role in nevus development, but seem not to be required, and even moderate sun exposure promotes the process. Therefore, preventive measures for nevus and melanoma development should target young children and adolescents.

Garbe C, Blum A. · Department of Dermatology, University of Tübingen, Germany. · Skin Pharmacol Appl Skin Physiol. · Pubmed #11586069 No free full text.

Abstract: Rising incidence rates of cutaneous melanoma have been observed during the last three decades. At the beginning of the 1970s 3 cases and in the 1990s 9 cases per 100,000 inhabitants and year were reported by the Saarland Cancer Registry in Germany. Other incidence studies from Germany in the 1990s even reported 10-12 cases per 100,000 inhabitants and year, which is more likely to be the representative melanoma incidence in Western Germany. In a worldwide comparison this is a medium incidence rate as compared to clearly higher incidence rates in the United States (10-20 cases per 100,000 inhabitants and year) and in Australia (40-60 cases per 100,000 inhabitants and year). In Europe the highest incidence rates have been reported from Scandinavia (about 15 cases per 100,000 inhabitants and year) and the lowest from the Mediterranean countries (about 5-7 cases per 100,000 inhabitants and year). Mortality rates likewise increased in Germany between 1970 and 1995 in males from 1.7 to 3.2 cases and in females from 1.6 to 2.0 cases per 100,000 inhabitants and year. In the 1990s, in Germany and in many other countries a leveling off of mortality rates was observed. 48,928 melanoma patients have been recorded by the Central Malignant Melanoma Registry from the German-speaking countries in the time period from 1983 to September 2000, and clinico-epidemiological analysis of cutaneous melanoma is based on this data material. While 2/3 of all melanoma patients in Germany were females in the 1970s, there is now a more balanced gender distribution with more than 45% of patients being males. Age distribution does not significantly change during the last three decades. Most melanomas are diagnosed in the age group between 50 and 60 years, 22% of all melanomas are diagnosed before the 40th year of age. A clear decrease of Breslow's tumor thickness was found from the beginning of the 1980s to the mid-1990s with the median thickness decreasing from 1.3 to 0.8 mm. Lower Breslow's tumor thickness at first diagnosis of cutaneous melanoma has only been reported from Australia. This development indicates improved early recognition of cutaneous melanoma which is presently the main factor for a more favorable prognosis.

Hauschild A, Volkenandt M, Garbe C. · Klinik für Dermatologie, Venerologie und Allergologie, der Christian-Albrechts-Universität Kiel. · Dtsch Med Wochenschr. · Pubmed #11098240 No free full text.

This publication has no abstract.

Blaheta HJ, Schittek B, Breuninger H, Garbe C. · Department of Dermatology, Eberhard-Karls-University, Tübingen, Germany. · Recent Results Cancer Res. · Pubmed #11092041 No free full text.

Abstract: The technique of sentinel lymph node (SLN) biopsy has been demonstrated to be highly predictive for the detection of melanoma micrometastases in the regional lymph node basin. Therefore, the SLN was proposed to accurately reflect the lymph node status of patients with primary cutaneous melanoma. As the regional lymph node status is one of the most powerful predictors of survival in patients with primary melanoma, the histopathologic assessment is critically important for accurate staging. In approximately 20% (ranging from 9% to 42%) of patients with primary melanoma, the SLN was found to be tumor-positive by histopathology or immunohistochemistry. However, the true incidence of metastatic melanoma cells in (sentinel) lymph nodes is underestimated by histopathologic examination. Recently, the method of reverse transcription-polymerase chain reaction (RT-PCR) for tyrosinase mRNA has been used as a molecular marker for the presence of melanoma cells. Tyrosinase RT-PCR was demonstrated to significantly increase the detection of melanoma cells in SLNs as compared to histopathology. All lymph nodes positive by histopathology were shown to express tyrosinase by RT-PCR. Furthermore, tyrosinase transcripts were also detected in 36-52% of stage I and II melanoma patients with SLNs negative by histopathology. Importantly, the recurrence rate was significantly higher in patients with histologically negative SLNs who were found to be positive by RT-PCR than in patients with negative results by both techniques. These findings indicate that RT-PCR status of the SLN is more sensitive for detection of minimal melanoma disease than histopathology. Therefore, the RT-PCR status of the SLN may be suitable to improve melanoma staging and may serve as a prognostic factor in patients with primary cutaneous melanoma.

Schittek B, Blaheta HJ, Ellwanger U, Garbe C. · Department of Dermatology, Eberhard Karls University, Tübingen, Germany. · Recent Results Cancer Res. · Pubmed #11092036 No free full text.

Abstract: Conflicting results were obtained by various research groups using the tyrosinase reverse transcription polymerase chain reaction (RT-PCR) for detecting melanoma cells circulating in peripheral blood. Whereas 100% positivity was initially reported for stage IV patients, more recent investigations reported positive detection rates between 30% and 50% in patients with disseminated melanoma. While the high detection rate initially reported in metastatic melanoma may be explained by contamination problems, methodological differences in different steps of the technical procedure of RT-PCR may account for the differences reported in more recent examinations. Major differences may result from the kind of blood preparation, the RNA isolation method, the kind of RT enzyme used, and the gene targeted by PCR primers. In our experience, blood purification by a Ficoll gradient increased melanoma cell detection rates compared to RNA extraction from total blood or after erythrocyte lysis. Amplification of MelanA in addition to tyrosinase resulted in a 30% enhanced sensitivity of melanoma cell detection compared to amplification to tyrosinase alone, whereas gp100/pMel17 and MUC18 gene products were already detected in blood from nonmelanoma patients. These findings are in agreement with those of other groups. Currently, an increase in the sensitivity for detection of circulating tumour cells to more than 50% of patients with disseminated melanoma seems to be unlikely. It is interesting that between 15% and 30% positive results and sometimes more have already been obtained from patients with primary melanoma. So far, there is no data for judging the prognostic significance of the detection of circulating tumour cells in patients without clinically recognisable metastases. Our limited experience shows that staging examinations in these patients reveal no proof of macrometastasis. Therefore, it is presently unclear whether these positive findings are associated with long-term prognosis or if they merely reflect false positive findings in this highly sensitive RT-PCR technique.

Hauschild A, Agarwala SS, Trefzer U, Hogg D, Robert C, Hersey P, Eggermont A, Grabbe S, Gonzalez R, Gille J, Peschel C, Schadendorf D, Garbe C, O'Day S, Daud A, White JM, Xia C, Patel K, Kirkwood JM, Keilholz U. · University of Kiel, Kiel, Charité Berlin. · J Clin Oncol. · Pubmed #19349552 No free full text.

Abstract: PURPOSE: This phase III, randomized, double-blind, placebo-controlled study was conducted to evaluate the efficacy and safety of sorafenib with carboplatin and paclitaxel (CP) in patients with advanced melanoma who had progressed on a dacarbazine- or temozolomide-containing regimen. PATIENTS AND METHODS: A total of 270 patients were randomly assigned to receive intravenous paclitaxel 225 mg/m2 plus intravenous carboplatin at area under curve 6 (AUC 6) on day 1 of a 21-day cycle followed by either placebo (n = 135) or oral sorafenib 400 mg (n = 135) twice daily on days 2 to 19. The primary efficacy end point was progression-free survival (PFS); secondary and tertiary end points included overall survival and incidence of best response, respectively. RESULTS: The median PFS was 17.9 weeks for the placebo plus CP arm and 17.4 weeks for the sorafenib plus CP arm (hazard ratio, 0.91; 99% CI, 0.63 to 1.31; two-sided log-rank test P = .49). Response rate was 11% with placebo versus 12% with sorafenib. Dermatologic events, grade 3 thrombocytopenia, diarrhea, and fatigue were more common in patients treated with sorafenib plus CP versus placebo plus CP. CONCLUSION: In this study, the addition of sorafenib to CP did not improve any of the end points over placebo plus CP and cannot be recommended in the second-line setting for patients with advanced melanoma. Both regimens had clinically acceptable toxicity profiles with no unexpected adverse events. A trial of similar design for the first-line treatment of patients with advanced melanoma (intergroup trial E2603) is currently ongoing.

Hauschild A, Trefzer U, Garbe C, Kaehler KC, Ugurel S, Kiecker F, Eigentler T, Krissel H, Schott A, Schadendorf D. · Department of Dermatology, University of Kiel bCharité-University Medicine Berlin, Germany. · Melanoma Res. · Pubmed #18626312 No free full text.

Abstract: Systemic treatment of metastatic melanoma is of low efficacy, and new therapeutic strategies are needed. Histone deacetylase inhibitors are supposed to restore the expression of tumor suppressor genes and induce tumor cell differentiation, growth arrest, and apoptosis. This study was aimed to evaluate the efficacy, safety, and pharmacokinetics of the histone deacetylase inhibitor pyridylmethyl-N-{4-[(2-aminophenyl)-carbamoyl]-benzyl}-carbamate (MS-275) in patients with pretreated metastatic melanoma. Patients with unresectable AJCC stage IV melanoma refractory to at least one earlier systemic therapy were randomized to receive MS-275 3 mg biweekly (days 1+15, arm A) or 7 mg weekly (days 1+8+15, arm B), in 4-week cycles. The primary study endpoint was objective tumor response, secondary endpoints were safety and time-to-progression. On the basis of Simon's two-stage design, the study initially allowed an entry of 14 patients per arm; if there was at least one responder, additional 33 patients were to be enrolled. Among 28 patients enrolled, no objective response was detected. Four (29%) patients in arm A and three (21%) patients in arm B showed disease stabilizations. Median time-to-progression was comparable in both arms with 55.5 versus 51.5 days, respectively; median overall survival was 8.84 months. Toxicity was mild to moderate with nausea (39%) and hypophosphatemia (29%) as the most frequently reported events. No treatment-related serious adverse events occurred. Single-agent treatment with MS-275 was well-tolerated and showed long-term tumor stabilizations, but no objective responses in pretreated metastatic melanoma. Further evaluation of MS-275 in combination schedules is warranted.

Weide B, Carralot JP, Reese A, Scheel B, Eigentler TK, Hoerr I, Rammensee HG, Garbe C, Pascolo S. · Department of Dermatology, Institute for Cell Biology, University of Tübingen, Germany. · J Immunother. · Pubmed #18481387 No free full text.

Abstract: Vaccination against tumor antigens has been shown to be a safe and efficacious prophylactic and therapeutic antitumor treatment in many animal models. Clinical studies in humans indicate that specific immunotherapy can also result in clinical benefits. The active pharmaceutical ingredient in such vaccines can be DNA, RNA, protein, or peptide and can be administered naked, encapsulated, or after delivery in vitro into cells that are then adoptively transferred. One of the easiest, most versatile and theoretically safest technologies relies on the direct injection of naked messenger RNA (mRNA) that code for tumor antigens. We and others have shown in mice that intradermal application of naked mRNA results in protein expression and the development of an immune response. We used this protocol to vaccinate 15 melanoma patients. For each patient a growing metastasis was removed, total RNA was extracted, reverse-transcribed, amplified, and cloned. Libraries of cDNA were transcribed to produce unlimited amounts of copy mRNA. Autologous preparations were applied intradermally in combination with granulocyte macrophage colony-stimulating factor as adjuvant. We demonstrate here that such treatment is feasible and safe (phase 1 criteria). Furthermore, an increase in antitumor humoral immune response was seen in some patients. However, a demonstration of clinical effectiveness of direct injection of copy mRNA for antitumor immunotherapy was not shown in this study and must be evaluated in subsequent trials.

Garbe C, Radny P, Linse R, Dummer R, Gutzmer R, Ulrich J, Stadler R, Weichenthal M, Eigentler T, Ellwanger U, Hauschild A. · Division of Dermatologic Oncology, Department of Dermatology, Eberhard-Karls-University of Tübingen, Tübingen, Germany. · Ann Oncol. · Pubmed #18281266 links to  free full text

Abstract: BACKGROUND: More than half of patients with melanoma that has spread to regional lymph nodes develop recurrent disease within the first 3 years after surgery. The aim of the study was to improve disease-free survival (DFS) and overall survival (OS) with interferon (IFN) alpha2a with or without dacarbazine (DTIC) compared with observation alone. PATIENTS AND METHODS: A total of 444 patients from 42 centers of the German Dermatologic Cooperative Oncology Group who had received a complete lymph node dissection for pathologically proven regional node involvement were randomized to receive either 3 MU s.c. of IFNalpha2a three times a week for 2 years (Arm A) or combined treatment with same doses of IFNalpha2a plus DTIC 850 mg/m(2) every 4-8 weeks for 2 years (Arm B) or to observation alone (Arm C). Treatment was discontinued at first sign of relapse. RESULTS: A total of 441 patients were eligible for intention-to-treat analysis. Kaplan-Meier 4-year OS rate of those who had received IFNalpha2a was 59%. For those with surgery alone, survival was 42% (A versus C, P = 0.0045). No improvement of survival was found for the combined treatment Arm B with 45% survival rate (B versus C, P = 0.76). Similarly, DFS rates showed significant benefit for Arm A, and not for Arm B. Multivariate Cox model confirmed that Arm A has an impact on OS (P = 0.005) but not Arm B (P = 0.34). CONCLUSIONS: 3 MU interferon alpha2a given s.c. three times a week for 2 years significantly improved OS and DFS in patients with melanoma that had spread to the regional lymph nodes. Interestingly, the addition of DTIC reversed the beneficial effect of adjuvant interferon alpha2a therapy.