Quality of life and comorbidity in localized malignant melanoma: results of a German population-based cohort study.

BACKGROUND: Incidences of malignant melanoma continue to increase in fair-skinned populations. At least 80% of patients are diagnosed with localized disease and can expect a 5-year relative survival rate of >90%. Given that the median age at diagnosis of malignant melanoma is 59 years, many patients already suffer chronic diseases when they are confronted with cancer. OBJECTIVES: The aim of this study was to analyze the effect of additional chronic diseases on health-related quality of life (QoL) in a population-based cohort of melanoma patients two years after presumably curative treatment. METHODS: In 2003-2004, 1085 patients with localized malignant melanoma were recruited from the population-based Munich Cancer Registry to answer validated QoL questionnaires. Information about comorbidities was also obtained. Factors predicting QoL were analyzed using multivariate logistic regression models. RESULTS: A total of 781 patients (72%) returned completed questionnaires, of which 664 (61%) could be included in the analyses. Quality of life scores and differences in subgroups (e.g., sex and age) were essentially similar to those in the general population. Age, number of comorbidities, and several chronic diseases (e.g. heart and kidney disease, diabetes, former depression) were the strongest predicting factors and influenced almost every aspect of QoL. CONCLUSIONS: Localized malignant melanoma does not worsen QoL per se, compared with QoL in the general population. Comorbidities have similar effects on QoL in malignant melanoma patients as they do in the general population. Therefore, cohorts of patients with localized malignant melanoma can represent a basis for comparisons with other cohorts of cancer patients to determine the respective impacts of cancer-related and non-cancer-related factors on QoL.

No association of vitamin D metabolism-related polymorphisms and melanoma risk as well as melanoma prognosis: a case-control study.

Melanoma is one of the most aggressive human cancers. The vitamin D system contributes to the pathogenesis and prognosis of malignancies including cutaneous melanoma. An expression of the vitamin D receptor (VDR) and an anti-proliferative effect of vitamin D in melanocytes and melanoma cells have been shown in vitro. Studies examining associations of polymorphisms in genes coding for vitamin D metabolism-related proteins (1α-hydroxylase [CYP27B1], 1,25(OH)(2)D-24hydroxylase [CYP24A1], vitamin D-binding protein [VDBP]) and cancer risk are scarce, especially with respect to melanoma. Mainly VDR polymorphisms regarding melanoma risk and prognosis were examined although other vitamin D metabolism-related genes may also be crucial. In our hospital-based case-control study including 305 melanoma patients and 370 healthy controls single nucleotide polymorphisms in the genes CYP27B1 (rs4646536), CYP24A1 (rs927650), VDBP (rs1155563, rs7041), and VDR (rs757343, rs731236, rs2107301, rs7975232) were analyzed for their association with melanoma risk and prognosis. Except VDR rs731236 and VDR rs2107301, the other six polymorphisms have not been analyzed regarding melanoma before. To further improve the prevention as well as the treatment of melanoma, it is important to identify further genetic markers for melanoma risk as well as prognosis in addition to the crude phenotypic, demographic, and environmental markers used in the clinic today. A panel of genetic risk markers could help to better identify individuals at risk for melanoma development or worse prognosis. We, however, found that none of the polymorphisms tested was associated with melanoma risk as well as prognosis in logistic and linear regression models in our study population.

Health-related quality of life before and during adjuvant interferon-α treatment for patients with malignant melanoma (DeCOG-trial).

Adjuvant treatment with interferon-α (IFN-α) for patients with malignant melanoma can improve relapse-free and overall survival, but IFN-associated side effects may reduce patient's quality of life. The aim of the study was to prospectively evaluate health-related quality of life (HRQoL) in patients with melanoma before and during Low-Dose IFN-α therapy. In a prospective multicenter trial conducted by the Dermatologic Cooperative Oncology Group, 850 patients with cutaneous stage II malignant melanoma received a standard Low-Dose of IFN-α-2a. We evaluated HRQoL using the European Organization for Research and Treatment of Cancer Quality of Life Core 30 questionnaire at baseline and after 3, 6, and 12 months of IFN-α treatment in 282 patients. Nine of 15 subscales showed significant poorer results after 3 months of adjuvant IFN treatment. Symptoms included reduced physical functioning, reduced cognitive functioning, fatigue, nausea, pain, dyspnea, insomnia, diarrhea, and loss of appetite. We did not find a significant change over time for role, emotional, or social functioning. Only cognitive functioning and dyspnea continuously worsened through the twelfth month. At baseline women had significantly lower scores for physical and emotional functioning and for fatigue compared with men. During treatment, women scored significantly poorer on physical functioning, emotional functioning, fatigue, pain, and constipation subscales. Patients who reported having a bad or very bad QoL before treatment were 5.8 times more likely to discontinue treatment early because of psychiatric problems. We conclude that adjuvant low-dose IFN treatment is associated with significant deterioration of HRQoL. Specific psychosocial care should be offered especially for patients who report lower HRQoL and emotional problems before treatment to prevent early discontinuation.

Analysis of predictive factors for the outcome of complete lymph node dissection in melanoma patients with metastatic sentinel lymph nodes.

BACKGROUND: Sentinel lymph node biopsy (SLNB) is a widely accepted procedure to accurately stage patients with melanoma. However, there is no consensus concerning the practical consequences of a positive SLN, since a survival benefit of a complete lymph node dissection (CLND) has not yet been demonstrated. OBJECTIVE: We wondered whether we could identify a subgroup of patients with metastatic involvement of the SLN who could be excluded from the recommendation to undergo CLND. METHODS: At the Department of Dermatology at the University of Munich, a total of 213 patients with metastatic SLNs (24.9%) were identified among 854 patients who had undergone SLNB between 1996 and 2007. All SLN-positive patients had been advised to have CLND. Survival analyses were performed by using the Kaplan-Meier approach. RESULTS: A total of 176 (82.6%) of 213 SLN-positive patients underwent CLND. In this group, 26 patients (14.8%) showed metastatic disease in non-sentinel lymph nodes (NSLN). The 5-year overall survival (OS) was 26.1% in NSLN-positive patients and 74% in NSLN-negative patients. SLN-positive patients who refused CLND had a better prognosis than patients with CLND. Breslow tumor thickness was significantly associated with positive CLND status with higher median values in CLND-positive than CLND-negative patients (3.03 vs 2.22 mm). LIMITATIONS: The subgroup of patients with metastatic disease in CLND may have been too small to reach statistical significance for other tumor- or patient-related parameters. Mitotic indices of the primary melanomas had not been determined in this retrospective study; thus a possible correlation with lymph node status could not be tested. CONCLUSION: Among SLN-positive patients, the presence of metastatic NSLN is a highly significant poor prognostic factor. Tumor thickness is a significant prognostic parameter for positive CLND status and might be considered in the decision to perform CLND in case of metastatic SLN.

Dose-dependent development of depressive symptoms during adjuvant interferon-{alpha} treatment of patients with malignant melanoma.

BACKGROUND: Adjuvant IFN-α treatment for patients with malignant melanoma is often complicated by depression. The influence of dosage, however, is unknown. OBJECTIVE: The authors sought to elucidate this dosage effect. METHOD: Using the Zung Self-Rating Depression Scale and the German Bf-S Self-Rating (Affectivity) Scale, the authors prospectively compared the frequency and severity of IFN-α-induced depressive symptoms between a group of 29 patients receiving low-dose and 17 patients getting high-dose induction therapy for 4 weeks. RESULTS: Patients receiving high-dose induction treatment had significantly higher depression scores after 4 weeks, and significantly more patients in the high-dose group developed depression. CONCLUSION: The authors concluded that frequency and severity of IFN-α-associated depression during melanoma treatment are dose-dependent.

Prognostic factors associated with sentinel lymph node positivity and effect of sentinel status on survival: an analysis of 1049 patients with cutaneous melanoma.

Sentinel lymph node biopsy (SLNB) is a widely accepted staging procedure in patients with melanoma. However, it is unclear which factors predict the occurrence of micrometastasis and overall prognosis and whether SLNB should also be performed in patients with thin primary tumors. At our Department of Dermatology, University of Munich (Germany), 1049 consecutive melanoma patients were identified for SLNB between 1996 and 2007, and were followed-up to assess disease-free and overall survival. Of those, a total of 854 patients were analyzed prospectively. Patients with positive SLN were subjected to selective lymphadenectomy. The association of patient characteristics with SLN was assessed by multivariate logistic regression. Survival curves were performed using the Kaplan-Meier method. Cox proportional hazard regression with different adjustments was used to estimate the effect of SLN on survival. The detection rate of SLN was 97.24%, of which 24.9% were metastatic. Significant parameters upon SLN positivity were tumor thickness and nodular type of melanoma. The 5-year overall survival was 90.1 and 58.1% in SLN-negative and SLN-positive patients, respectively. Upon multivariate analysis tumor thickness and SLN status were significant factors influencing both disease-free survival and overall survival. In conclusion, our data confirm that SLNB is relevant as a diagnostic and staging procedure and that tumor thickness is of predictive importance. SLN status should be taken into account when designing clinical trials and informing patients about the probable course of their disease. Our data suggest that in case of a nodular melanoma subtype SLNB should also be considered at a tumor thickness below 1 mm.

[A rare case of local relapsing oral melanoma]. / Ein seltener Fall eines lokal rezidivierenden oralen Melanoms.

Melanoma of the oral mucosa is an extremely rare tumor. At the time of diagnosis most melanomas are in an advanced stage because of few clinical signs. Therefore the prognosis of melanoma of the oral mucosa is often very poor. We present a 48-year-old patient with melanoma of the oral mucosa first diagnosed 22 years ago. Over 20 years several wide excisions were necessary because of multiple local relapses. Eventually, the patient died from brain metastases.

Depressive mood changes and psychiatric symptoms during 12-month low-dose interferon-alpha treatment in patients with malignant melanoma: results from the multicenter DeCOG trial.

The purpose of the present study was to evaluate the incidence, spectrum and extent of psychiatric symptoms in patients with malignant melanoma (MM) before and during adjuvant treatment with interferon-alpha (IFN-alpha). 850 patients with cutaneous MM of > or =1.5 mm tumor thickness received standard low-dose IFN-alpha 2a in this prospective multicenter trial of the Dermatologic Cooperative Oncology Group (DeCOG). Psychiatric symptoms were evaluated at baseline and after 3, 6, and 12 months with the Beck Depression Inventory (BDI) and the Symptom Check List 90-Revised (SCL 90-R). In all, 282 patients completed all questionnaires. Mean BDI depression scores increased significantly during the first 6 months of IFN-alpha treatment (P < or =0.001), followed by a mild but not significant decrease. Also mean SCL 90-R scores increased significantly during the first 3 months of adjuvant treatment with IFN-alpha (P< or =0.001) and remained elevated until month 12 (P< or =0.001). Only 5% developed BDI scores >10, indicating a clinically significant depressive syndrome and only 1.4% reached a BDI score > or =18, indicating a moderate to severe depressive syndrome. Patients, who dropped-out early from psychiatric reasons, had significantly increased BDI and SCL-90R scores at baseline. Women scored higher in both scales before and during treatment if compared with men. In conclusion, adjuvant treatment with IFN-alpha was associated with a significant increase of BDI- and SCL 90-R scores. A higher pretreatment depression score was found to be a risk factor for an early drop-out during therapy. Pretreatment screening and an interdisciplinary care of the patients is recommended.

The use of high-resolution ultrasonography for preoperative detection of metastases in sentinel lymph nodes of patients with cutaneous melanoma.

BACKGROUND: Sentinel lymph node biopsy (SLNB) reliably assesses the status of the regional lymph node basins and provides prognostic information in patients with cutaneous melanoma, but is logistically demanding and expensive. OBJECTIVE: The aim of this study was to evaluate the ability of high resolution B-mode ultrasonography (US) for pre-operative identification and characterization of sentinel lymph nodes (SLN) in patients with cutaneous melanoma. PATIENTS AND METHODS: In a prospective trial, the use of high resolution US was assessed in 25 consecutive patients with cutaneous melanoma identified for SLNB, first, for its value in primary detection of SLN, and, second, for its value in the correct assessment of SLN after lymphoscintigraphic mapping. RESULTS: High resolution B-mode US correctly identified two of 6 positive SLN. The sensitivity, specificity, positive predictive value, and negative predictive value of US were 33.3% (95% CI 43.3-77.7), 100.0% (95% CI 88.1-100.0), 100.0% (95%CI 15.8-100.0) and 87.9% (95% CI 71.8-96.6), respectively. CONCLUSION: High resolution B-mode US cannot replace SLNB, especially in the detection of micrometastases, but it remains the most important method to assess the lymph node status for macrometastases presurgically.

Time trends in tumour thickness vary in subgroups: analysis of 6475 patients by age, tumour site and melanoma subtype.

An elevated tumour thickness is strongly associated with an increased risk of mortality in melanoma patients. In the last few decades, an overall decrease of the tumour thickness to prognostically more favourable levels has been observed in several countries. Nevertheless, it is not clear whether this positive time trend occurred uniformly in specific subgroups of melanoma patients. Therefore, we aimed to assess time trends of tumour thickness by age group, tumour site and melanoma subtype. The study population consisted of 6475 patients with histologically proven primary invasive cutaneous melanomas seen at the Department of Dermatology and Allergology at the Ludwig-Maximilian-University Munich between 1977 and 2000. Age-adjusted time trends were assessed using linear and logistic regression analysis. Overall, a positive time trend with a decreasing tumour thickness was observed during the observation period in most subgroups. However, no significant time trend was observed in patients with a melanoma on the feet or with a nodular or acrolentiginous melanoma. The almost constant high tumour thickness of these patients might be caused by underaddressing the specific traits of these melanomas in earlier prevention campaigns. An important goal for the upcoming years should consist of a positive time trend with a decreasing tumour thickness in these subgroups.

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.

Evidence-based and interdisciplinary consensus-based German guidelines: systemic medical treatment of melanoma in the adjuvant and palliative setting.

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.

Evidence and interdisciplinary consensus-based German guidelines: surgical treatment and radiotherapy of melanoma.

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.

Evidence and interdisciplinary consense-based German guidelines: diagnosis and surveillance of melanoma.

Melanoma is a malignant tumor that arises from melanocytic cells and primarily involves the skin. The most important exogenous etiological factor is exposure to ultraviolet irradiation. Diagnosis of melanoma is based primarily on its clinical features, and the A-B-C-D rule is useful in identifying pigmented lesions, which are suspicious for melanoma (Asymmetry, Border irregular, Color inhomogeneous and Diameter more than 5 mm). Dermoscopy is very helpful in clarifying the differential diagnosis of pigmented lesions. About 90% of melanomas are diagnosed as primary tumors without any evidence for metastasis. The tumor-specific 10-year survival for all such tumors is about 75-85%. The most important prognostic factors for primary melanoma without metastases are vertical tumor thickness (Breslow depth) as measured on the histological specimen, presence of histopathologically recognized ulceration, invasion level (Clark level) and identification of micrometastases in the regional lymph nodes via sentinel lymph node biopsy. The current tumor node metastasis classification for the staging of primary melanoma is based on these factors. Melanomas can metastasize either by the lymphatic or by the hematogenous route. About two-thirds of metastases are originally confined to the drainage area of regional lymph nodes. A regional metastasis can appear as satellite metastases up to 2 cm from the primary tumor, as intransit metastases in the skin between the site of the primary tumor and the first lymph node and as regional lymph node metastases. In the stage of regional metastasis, the differentiation between micrometastasis and macrometastasis and the number of lymph nodes involved are crucial. As soon as distant metastasis develops, prognosis depends on the site of the metastasis and on the lactate dehydrogenase levels in the blood. The frequency and extent of follow-up examinations is based on the initial tumor parameters. In thin primary melanomas up to 1-mm tumor thickness, clinical examinations at 6-month intervals are sufficient and in thicker primary melanomas, at 3-month intervals. Lymph node sonography as well as determination of the tumor marker protein S100beta are recommended. Additionally, in the stage of regional metastasis, whole body imaging should be performed every 6 months; in the stage of distant metastasis, surveillance has to be scheduled individually.

Pretreatment levels of sTNF-R1 and sIL-6R are associated with a higher vulnerability for IFN-alpha-induced depressive symptoms in patients with malignant melanoma.

Immunomodulatory therapy with interferon-alpha (IFN-alpha) often leads to neuropsychiatric side effects, especially depression. An activation of the immune system is discussed to trigger neurotransmitter changes and depressive illness. So far, few data are available about biologic markers, who may predict the individual risk for developing depressive symptoms during IFN-alpha therapy. The aim of the present study was to investigate the predictive role of certain immunologic markers for the development of IFN-alpha-induced depression. We hypothesized that patients characterized by a proinflammatory and TH1-accentuated immune response before treatment might have an increased risk for developing depressive mood changes. Thirty-three melanoma patients were prospectively investigated during adjuvant treatment with IFN-alpha-2a/2b (3 x 3 Mio units/wk). Depressive mood changes were assessed with the self-rating depression scale (SDS, Zung-scale) before and during IFN-alpha treatment. Serum concentrations of soluble tumor necrosis factor-R1 (sTNF-R1), soluble interleukin-6R (sIL-6R), sIL-4R, and neopterin were measured before and after 3 months of treatment. sIL-6R, which was negatively associated with SDS scores, significantly predicted higher depression scores in the first 3 months of IFN-alpha treatment. sTNF-R1, which was positively associated with SDS scores, significantly predicted the development of late depressive symptoms after 6 months of therapy. In contrast to the initial hypothesis, patients characterized by high sTNF-R1 and low sIL-6R baseline levels, indicating an anti-inflammatory condition before therapy, had a higher vulnerability for depression during IFN-alpha therapy.