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This study analysed the changes of excision margins in correlation with tumour thickness as recorded over the last three decades in Germany. The study also evaluated surgical management in different geographical regions and treatment options for metastasized melanoma. A total of 42 625 patients with invasive primary cutaneous melanoma, recorded by the German Central Malignant Melanoma Registry between 1976 and 2005 were included. Multiple linear regression analysis was used to investigate time trends of excision margins adjusted for tumour thickness. Excision margins of 5.0 cm were widely used in the late 1970s but since then have been replaced by smaller margins that are dependent on tumour thickness. In the case of primary melanoma, one-step surgery dominated until 1985 and was mostly replaced by two-step excisions since the early 1990s. In eastern Germany, one-step management remained common until the late 1990s. During the last three decades loco-regional metastases were predominantly treated by surgery (up to 80%), whereas systemic therapy decreased. The primary treatment of distant metastases has consistently been systemic chemotherapy. This descriptive retrospective study revealed a significant decrease in excision margins to a maximum of 2.00 cm. A significant trend towards two-step excisions in primary cutaneous melanoma was observed throughout Germany. Management of metastasized melanoma showed a tendency towards surgical procedures in limited disease and an ongoing trend to systemic treatment in advanced disease.

Local therapies have been highly effective in the treatment of melanoma. The objective of this study was to evaluate the use of a novel intralesional chemotherapy - cisplatin/adrenaline injectable gel - for the treatment of refractory or recurrent cutaneous and soft tissue melanoma metastases. The gel is injected directly into the lesion and delivers high concentrations of cisplatin at the injection site, where it is retained for extended periods, with little systemic exposure. A total of 28 patients with refractory or recurrent melanoma were enrolled in this open-label, multicentre study. Of these, 25 patients with 244 lesions were evaluable for efficacy. Lesions were injected with 0.5 ml (2 mg cisplatin + 0.05 mg adrenaline) of gel/cm(3) of tumour. Patients received up to six weekly treatments within an 8 week period. The objective response rate (complete responses [CRs] plus partial responses [PRs]) for all the tumours treated (1-72 per patient) was 53% (130 out of 244; 114 CRs, 16 PRs). The response rate for the target tumours (i.e. each patient's single, most symptomatic, largest or most threatening tumour) was 44%. The median response duration for all tumours was 347 days (range 30-783 days) and median number of treatments per tumour was five (range one to twelve). Systemic toxicity was negligible; local adverse reactions such as erythema, necrosis or pain occurred frequently, but were easily managed in most cases. In conclusion, cisplatin/adrenaline injectable gel was well tolerated, easy to administer, and effective in treating metastatic melanoma confined to the skin or soft tissues.

An empirically established chemoimmunotherapy that combines the epifocal application of the contact sensitizer dinitrochlorobenzene (DNCB) to cutaneous metastases with the systemic administration of dacarbazine (DTIC) yields high response rates and results in prolonged survival. However, despite the fact that this therapy has been in clinical use for several years, the mode of action still remains elusive. In order to overcome this limitation we established a murine model system. B16 melanoma cells were implanted subcutaneously in syngeneic C57BL/6 mice and treatment was started 7 days after. In a first set of experiments mice received intraperitoneal injections of DTIC followed by epifocal applications of DNCB 24 h later. Treatment significantly decreased tumour growth. In contrast, no significant effect was induced by DTIC or DNCB alone. Using this regimen, with varying doses of either DTIC or DNCB, we demonstrated that the therapeutic effect is dose dependent. Furthermore, the treatment of subcutaneous tumours with DTIC and DNCB influenced the course of visceral metastases: the growth of pulmonary metastases was significantly inhibited if subcutaneous tumours were treated as described. In conclusion, we have established a model system that seems to be appropriate for both the optimization of this therapeutic regimen and the characterization of effector mechanisms.

The aim of this study was the evaluation of both the antitumour activity and toxicity of an immunochemotherapeutic regimen consisting of interferon-alpha2b and interleukin-2 in combination with fotemustine for patients with metastatic melanoma. To improve the penetration of fotemustine into the brain, it was given immediately after immunotherapy, when the blood-brain barrier is still disturbed. Of the 19 patients treated, three complete remissions (CRs) and one partial remission (PR) were induced, giving an objective response rate of 21% (95% confidence interval 6-46%). The durations of the CRs were 9, 19 and 44 months; the PR lasted for 59+ months. The overall survival times for the patients with CR were 21, 25 and 70+ months, and 59+ months for the PR. For nine patients (47%, 95% confidence interval 24-71%) disease was stabilized for a median period of 8 months (range 2-18 months), resulting in a median survival of 18 months (range 10-41+ months). No haematological toxicity of World Health Organization grade 3 or more was observed and in general toxicity was low. In summary, this immunochemotherapy regimen led to long-term survival in occasional patients, and about half of the patients achieved stable disease, with prolonged treatment- and progression-free survival compared with nonresponding patients. The occurrence of brain metastases, however, was not prevented, and in fact was the site of recurrence in those patients achieving a CR. Due to its low toxicity, this protocol can be applied at a community hospital level.

To examine the intra-individual heterogeneity of the local inflammatory infiltrate in metastases of untreated melanoma patients we analysed 42 skin and subcutaneous metastases from 11 patients. Metastases were excised on the same date (10 patients) or consecutively (six patients), and processed in a two-step immunoperoxidase technique using monoclonal antibodies directed against T-cells (CD3, CD25) and two macrophage subpopulations (RM 3/1, 27E10). The number of positively stained T-cells and macrophages were counted for each lesion in representative high power fields. The mean values were calculated. We observed limited heterogeneity among T-cells (CD3+) and activated T-cells (CD25+) in simultaneously excised metastases. Contrary to this, markedly heterogeneous CD3+ infiltrates were found in metastases taken on different dates, even if there was a time difference of only 1 day between excisions, suggesting spontaneous variations. However, activated T-cells in follow-up biopsies showed only limited heterogeneity. In spite of inter-individual variations, metastases taken simultaneously, as well as consecutively, showed little intra-individual heterogeneity with respect to macrophages. Our findings should be taken into account for comparative studies of the infiltrate in metastatic melanoma during immunotherapy.

In order to investigate the effects of in vivo treatment with interferon-alpha (IFN-alpha) on melanoma antigens, a clinical EORTC trial (No. 18852) was accompanied by an immunohistological study. Twenty patients with melanoma metastases of skin and soft tissues, eventually also of the lung, who were treated with systemic IFN-alpha, were evaluated for a comparison of metastases before (40) and during (42) treatment. Representative cryostat sections were studied immunohistologically with a panel of monoclonal antibodies against differentiation antigens (HMW-MAA, K-1-2, NKI-beteb, M-2-10-15), progression markers (transferrin receptor, ICAM-1, VLA-2), histocompatibility antigens (HLA-A, B, C, HLA-DR) and the proliferation-associated nuclear antigen Ki67. We found an overall reduction of the proliferation-associated antigen Ki-67 (p < 0.01), and an increase in expression of HLA-DR (p < 0.05) and ICAM-1 (trend) during treatment. The intensity of expression of HLA-A, B and C antigens as well as pigmentation (p < 0.01) was found to be increased. Early progression (< or = 8 weeks after onset of treatment) was associated with a lack of phenotypic changes. The data suggest an independent modulation of proliferation, pigmentation, and antigen expression by systemic treatment of metastatic melanoma with IFN-alpha.

An angiostatic approach was used to assess the impact of anti-inflammatory therapy in combination with metronomic low-dose chemotherapy. A randomized multi-institutional phase II trial was designed to select metronomic chemotherapy (arm A: trofosfamide 50 mg orally three times daily, day 1+) or combined anti-inflammatory/angiostatic treatment (arm B: trofosfamide as above mentioned plus rofecoxib 25 mg orally, day 1+, and pioglitazone 60 mg orally, day 1+) for further evaluation. A total of 76 patients, mostly (60%) refractory to at least one previous chemotherapy with maximum tolerated doses, and progression of metastatic melanoma were included. The estimated progression-free survival (PFS) rates at one year were 0% for metronomic chemotherapy (A), but 9% for additional anti-inflammatory therapy (B). Vice versa the hazard ratio for the intent-to-treat analysis of A versus B was 1.9 (P=0.008). By Cox analysis, the impact of anti-inflammatory therapy on PFS achieved significance (P=0.016) as well as C-reactive protein response on overall survival (P=0.045). WHO grade 3 (no grade 4) toxicities were reported in arm A/B in 19 and 28%, respectively. In conclusion, control of tumour-associated inflammatory processes (C-reactive protein response) is associated with longer PFS than achieved with metronomic chemotherapy alone in metastatic melanoma.

Melanoma patients with multiple brain metastases not amenable to surgery or stereotactic radiotherapy were treated with total brain irradiation in fractions of 2.5 Gy four times weekly, up to 40 Gy. At days 1, 8, and 25 100 mg/m2 fotemustine was infused 4 h before Irradiation. Of 12 evaluable patients, four showed partial remission and three stabilization in the brain. The median survival in these two groups of patients was 6 months; the survival of the other patients was 2 months. Severe haematological side effects were observed in 6/13 patients. In conclusion, the combination of fotemustine and total brain Irradiation seems to be more effective than either treatment alone, but bears the risk of additional bone-marrow toxicity.

Between 1983 and 1989 a phase II study was carried out by the EORTC Malignant Melanoma Cooperative Group in which postmenopausal women with advanced melanoma but a good performance status received tamoxifen, 40 mg per day, as a single agent. From 12 centres, 114 patients were registered of whom 107 appeared to be eligible and 102 evaluable. Seven died of progressive disease within 4 weeks, eight others had early progressive disease (of whom seven died within 7 weeks). The response rate was 4.9%, the complete response rate 1%. Without prior chemotherapy three of 58 responded, with prior chemotherapy two of 44. Except for one of 46 patients with lung metastases who experienced a PR of these metastases, all responders were patients with slowly growing small soft tissue metastases. We conclude that, because of the few side effects, tamoxifen can be recommended for (postmenopausal) patients who have only a small number of slowly growing metastases and who are not yet candidates for treatment with toxic drugs.

Interleukin-10 (IL-10), originally described as a product of TH2 cell clones, has been recognized as a potential immunosuppressive cytokine. To investigate the relevance of IL-10 in melanoma patients in vivo, we studied IL-10 serum levels in 104 untreated patients in different stages of the disease; 20 healthy subjects and 22 patients with inflammatory dermatoses served as controls. Serum levels were measured by ELISA. Only one of 31 patients with stage I melanoma (3%) and one of 16 stage II patients (6%) showed detectable IL-10 levels. Interestingly, six of 17 patients with lymph node metastases (stage III, 35%) and 29 of 40 patients with widespread disease (stage IV, 73%) revealed IL-10 levels of 15-480 pg/ml. No healthy person and only one control patient had a detectable IL-10 serum level. The data suggest that IL-10 in melanoma patients may contribute to down-modulation of anti-tumour responses in vivo.

Human melanoma is an immunogenic tumour which is characterized by a number of defined tumour-associated antigens and a specific T-cell-mediated immune response. Nevertheless, there is only limited evidence for an effective antitumour immune response able to eradicate established melanoma. Thus, the existence of an immunologically suppressed state in the tumour-bearing host has become an axiom in tumour immunology. There is increasing evidence that abnormalities in signal transduction events involved in cell activation are the molecular basis for the observed T-cell dysfunction. These abnormalities include altered patterns of protein tyrosin phosphorylation, decreased protein levels of the Src-family kinases p56(lck) and p59(lyn), and of the CD3zeta chain. Furthermore, differences in the expression of transcription factors of the nuclear factor NF-kappaB/Rel family have been described.

Fotemustine (FM) is a new chloronitrosurea (CNU), chemically characterized by the graft of an aminophosphonic acid on the CNU radical, which makes it highly lipophilic. Following single-institution phase I and II studies with remarkably high response rates of some 40%, including brain metastases of 25% and more, the EORTC-MCG started a multicentre phase II trial to confirm these results according to EORTC guidelines. Treatment consisted of an induction cycle of FM (100 mg/m2 on days 1 + 8 + 15), followed by maintenance courses (q3w). Fifty-four patients were entered by 11 institutions. General interest in this promising new agent, however, led clinicians of six additional institutions to join the EORTC trial and 90 more patients were included in only 4 months. This rapidly rising accrual rate became inversely related to the physicians' adherence to the eligibility criteria: palliation of symptoms rather than clinical research was the dominant reason to start treatment. Clinical characteristics and results in the eligible vs non-eligible patient group (in parentheses) were as follows: male/female 29/26 (68/65), mean age 54 years (53), ECOG-PS 0-1 (0-4), CR 2 (0), PR 10 (2), NC 17 (5) and for brain metastases: PR 4 (1), NC 2 (1), for an ORR of 12% (5%). Median duration of response was 6 months (range 4-16). The clinically relevant toxicity was limited to the haematopoiesis with delayed platelet nadirs (30% grade III+IV), granulocyte (25% grade III + IV) and the gastrointestinal tract: nausea and vomiting (26% grade II, 18% III, 1% IV). This study confirms that FM is active in melanoma including brain metastases.(ABSTRACT TRUNCATED AT 250 WORDS)