Cutaneous melanoma: interferon alpha adjuvant therapy for patients at high risk for recurrent disease

Systemic adjuvant therapy in melanoma patients is the systemic treatment that is administered with the goal of eradicating micrometastatic deposits in patients who are clinically free of disease after surgical removal of the primary melanoma, but with a high risk of systemic recurrence. Interferon-alpha (IFN-alpha) is one of the most frequently used adjuvant therapies. Several randomized trials evaluated the efficacy of IFN-alpha in melanoma patients. However, results from conducted trials are controversial. Twelve randomized IFN-alpha trials are discussed in detail. All trials, including meta-analysis, failed to demonstrate a clear impact of IFN-alpha therapy on overall survival in melanoma patients. Based on currently available evidence, IFN-alpha therapy in the adjuvant setting should not be considered standard of care for patients who have melanoma. Results from ongoing studies are awaited. Further research for this therapy is required.     

Interferon-alpha therapy for melanoma

Although surgery may be curative in early malignant melanoma, its effect on survival lessens with each succeeding stage of the disease. A wide variety of immunological strategies have therefore been used to improve the prognosis of patients with malignant melanoma, but adjuvant therapy with interferon (IFN)-alpha is the only treatment to show a therapeutic benefit in randomized controlled studies. The current data indicates that where IFN-alpha is used at low dose, its main effect is on disease-free survival, whereas high-dose regimens may improve overall survival as well. This paper will review the published data on IFN-alpha therapy in patients with intermediate and high-risk melanoma and explore future avenues for managing patients with this difficult disease.     

Phase I study of pegylated interferon‐alpha‐2b as an adjuvant therapy in Japanese patients with malignant melanoma

In the adjuvant setting for malignant melanoma, interferon (IFN)‐α‐2b and pegylated (PEG) IFN‐α‐2b were approved in several countries including the USA before these were approved in Japan. To resolve the “drug‐lag” issue, this phase I study was designed to evaluate the safety and tolerability in Japanese patients with stage II or III malignant melanoma who had undergone surgery, by treating with PEG IFN‐α‐2b. As with a previously reported phase III study, patients were to receive PEG IFN‐α‐2b 6 μg/kg per week s.c. during an 8‐week induction phase, followed by a maintenance phase at a dose of 3 μg/kg per week up to 5 years. Dose‐limiting toxicity and pharmacokinetics were assessed during the initial 8 weeks. Of the nine patients enrolled, two patients had dose‐limiting toxicities that resolved after discontinuation of treatment. The most frequently reported drug‐related adverse events (DRAE) included pyrexia, decreased neutrophil and white blood cell counts, and arthralgia. Grade 3 DRAE included decreased neutrophil count. No deaths, serious adverse events and grade 4 adverse events were reported. Distant metastasis occurred in one patient. No apparent differences in area under the concentration–time curve and maximum observed serum concentration were observed between Japanese and historical non‐Japanese pharmacokinetic data, suggesting no marked racial differences. No neutralizing antibody was detected in these patient samples. PEG IFN‐α‐2b was tolerated in Japanese patients, and eventually approved in Japan in May 2015 for adjuvant therapy in patients with stage III malignant melanoma. Because the number of patients was limited, further investigation would be crucial.     

Übersicht zu Interferon-Nebenwirkungen am Auge bei adjuvanter Melanomtherapie

BACKGROUND AND OBJECTIVE: In dermatology, interferon Alfa 2 is used in adjuvant therapy of melanoma (stage IIa/b) as well as in treatment of cutaneous lymphoma or melanoma (stage III or higher). In the past 2 years, several case reports have described interferon-induced ocular side effects, including sudden loss of vision and ischemic retinopathy. We wondered if incidence and prognosis of ocular complications were elevated in patients receiving an adjuvant treatment of melanoma with interferons. PATIENTS/METHODS: We analyzed 1334 reports of adverse effects of interferons, which had been spontaneously reported in Germany since 1990. RESULTS. 8.4% of all reported adverse effects of interferons were ocular. More than the half of these patients developed significant visual loss including retinal ischemia. CONCLUSIONS: These data underscore the importance to inform patients concerning ocular adverse effects and emphasize the need to monitor the retina during adjuvant interferon therapy.     

Interferon alpha as adjuvant postsurgical treatment of melanoma: a meta-analysis

BACKGROUND: The literature on the benefit of alpha-interferon (IFN-alpha) as adjuvant postsurgical treatment of melanoma reports discordant results. OBJECTIVE: With the published data so far, we performed a meta-analysis in order to evaluate the effect of IFN-alpha on the relapse rate (RR) and the overall survival (OS). METHODS: Published randomised trials were identified by Medline search. Stage IV melanoma was not considered. RESULTS: Nine published studies were included, with a total of 2,880 patients. Both the per protocol and the intention-to-treat analysis show that IFN-alpha significantly decreased the RR (OR = 0.74; 95% CI = 0.64-0.86). Subgroup analyses show that, for all stages, high and low doses decreased the RR (OR = 0.71, 95% CI = 0.54-0.92, and OR = 0.76, 95% CI = 0.63-0.91, respectively). No difference has been evidenced on OS. CONCLUSIONS: High and low doses of IFN-alpha significantly decrease the RR, but the OS does not seem to be improved.     

A costly revolution for a subgroup of patients with metastatic melanoma

ORIGINAL ARTICLE: Hauschild A, Grob JJ, Demidov LV et al. Dabrafenib in BRAF‐mutated metastatic melanoma: a multicentre, open‐label, phase 3 randomised controlled trial. Lancet 2012; 380: 358–65. Background Dabrafenib, an inhibitor of mutated BRAF, has clinical activity with a manageable safety profile in phase I and II studies in patients with BRAF (V600)‐mutated metastatic melanoma. Hauschild et al. aimed to assess the efficacy of dabrafenib in a phase III trial of patients with BRAF (V600)‐mutated metastatic melanoma. Methods Patients were enrolled into a phase III trial between December 2010 and September 2011. This report is based on the cut‐off date of 19 December 2011. Patients with previously untreated stage IV or unresectable stage III BRAF (V600)‐mutated melanoma were randomly assigned (3:1) to receive dabrafenib (150 mg twice daily, orally) or dacarbazine (1000 mg m^?2 intravenously every 3 weeks). Patients were stratified according to American Joint Committee on Cancer stage. The primary endpoint was investigator‐assessed progression‐free survival (PFS) and was analysed by intention to treat. Safety was assessed per protocol. Findings Of the 733 patients screened, 250 were randomly assigned to receive either dabrafenib (187 patients) or dacarbazine (63 patients). Median PFS was 5·1 months for dabrafenib and 2·7 months for dacarbazine, with a hazard ratio of 0·30 (95% confidence interval 0·18–0·51, P < 0·0001). At cut‐off, 107 (57%) patients in the dabrafenib group and 14 (22%) in the dacarbazine group remained on randomized treatment. Treatment‐related adverse events (grade 2 or higher) occurred in 100 (53%) of the 187 patients who received dabrafenib and in 26 (44%) of the 59 patients who received dacarbazine. The most common adverse events with dabrafenib were skin‐related toxic effects, fever, fatigue, arthralgia and headache. The most common adverse events with dacarbazine were nausea, vomiting, neutropenia, fatigue and asthenia. Grade 3–4 adverse effects were uncommon in both groups. Interpretation Dabrafenib significantly improved PFS compared with dacarbazine.     

Which adjuvant treatment for patients with BRAFV600-mutant cutaneous melanoma?

Treatment of patients with melanoma has considerably improved over the past decade and more recently with adjuvant therapies for patients with American Joint Committee on Cancer (AJCC) stage III (loco-regional metastases) or IV (distant metastases) totally resected melanoma, in order to prevent recurrence. In the adjuvant setting, two options are available to patients with BRAF^V600-mutant AJCC stage III totally resected melanoma: anti-PD-1 blockers (nivolumab or pembrolizumab) or BRAF plus MEK inhibitors (dabrafenib plus trametinib). In the absence of comparative studies, it is difficult to determine which of these options is best. Our aim was to review published studies focusing on the management of patients with BRAF^V600-mutant melanoma in the adjuvant setting. We also reviewed the main clinical trials of BRAF plus MEK inhibitors and immunotherapy in advanced (i.e. unresectable metastatic) BRAF-mutant melanoma in an attempt to identify results potentially affecting the management of patients on adjuvants. More adverse events are observed with targeted therapy, but all resolve rapidly upon drug discontinuation, whereas with immune checkpoint blockers some adverse events may persist. New therapeutic strategies are emerging, notably neoadjuvant therapies for stage III patients and adjuvant therapies for stage II patients; the place of the adjuvant strategy amidst all these options will soon be re-evaluated. The choice of adjuvant treatment could influence the choice of subsequent treatments in neo-adjuvant or metastatic settings. This review will lead clinicians to a better understanding of the different adjuvant treatments available for patients with totally resected AJCC stage III and IV BRAF^V600-mutant melanoma before considering subsequent treatment strategies.     

Influence of various cytokines on the interleukin-2-dependent lysis of melanoma cells in vitro

To obtain information about useful combinations of various cytokines in melanoma therapy, we studied the influence of interleukin-2 (IL-2) in combination with interferon-alpha (IFN-alpha), IFN-gamma and tumour necrosis factor-alpha (TNF-alpha) on the lytic activity of IL-2-stimulated cells in vitro. Peripheral mononuclear cells (PMC) were incubated for 4 days with various combinations of cytokines and used as effector cells. Two different melanoma cell lines (M19 and M26) were used as target cells. The lytic activity of stimulated PMC was determined using a modified hexosaminidase assay. IL-2 was mainly responsible for the lytic activity of the effector cells in a dose-dependent manner. IFN-alpha, IFN-gamma and TNF-alpha did not enhance lytic activity with an optimal IL-2 dose (50 IU/ml IL-2). Using a suboptimal IL-2 dose (5 IU/ml), they increased cytotoxicity. The specific lysis of M19 cells was significantly increased by pretreatment of the cells with 5 IU/ml IFN-alpha together with 50 IU/ml TNF-alpha (t-test, P0.001), while the specific lysis of M26 cells was increased by pretreatment with 5 IU/ml IFN-gamma. We conclude that the lysis of melanoma cells by cytotoxic cells in vitro can be enhanced by various cytokines. The optimal cytokine combination differed for the two melanoma cell lines tested.     

The expression of cytotoxic mediators is altered in mononuclear cells of patients with melanoma and increased by interferon-alpha treatment

BACKGROUND: The role of cytotoxic cells in the control of cancer is now well established. OBJECTIVES: To evaluate the expression of perforin and granzyme A in cytotoxic cells of patients with melanoma and to look for a link between this expression and natural tumour progression; to check if interferon (IFN)-alpha administration increased expression of cytotoxic mediators; and to evaluate if this increase was correlated with the antitumoral effect of IFN-alpha. METHODS: To determine in patients with melanoma the expression of the cytotoxic mediators perforin and granzyme A in peripheral blood natural killer (NK) and T cells, we used flow cytometry before and after IFN-alpha administration. RESULTS: Compared with healthy volunteers, we observed in 82 patients a low percentage of NK cells harbouring perforin [75% (95% confidence interval (CI) 70-79) vs. 92% (95% CI 89-95), P < 0.001] and granzyme A [48% (95% CI 41-55) vs. 73% (95% CI 66-81), P < 0.001]. By contrast, a high percentage of T cells, and particularly of CD56+ T cells, expressed perforin [56% (95% CI 41-71) vs. 28% (95% CI 18-38), P < 0.001], whereas a low percentage of CD56+ T cells expressed granzyme A [30% (95% CI 24-36) vs. 54% (95% CI 43-65), P < 0.001]. In untreated patients, the percentage of CD56+ T cells expressing granzyme A was higher in progressors than in nonprogressors [49% (95% CI 39-58) vs. 16% (95% CI 0-33), P = 0.003]. We followed cytotoxic mediator expression in 17 patients treated with IFN-alpha. IFN-alpha administration increased granzyme A expression in NK cells [44% (95% CI 27-61) and 65% (95% CI 54-76) before and after treatment, respectively, P = 0.010], rather than perforin expression, whereas expression of both perforin [46% (95% CI 30-62), and 58% (95% CI 44-73), P = 0.112] and especially granzyme A [27% (95% CI 14-40) vs. 45% (95% CI 26-64), P = 0.016] was increased in CD56+ T cells after IFN-alpha administration. Yet, this effect was not correlated with the clinical response to IFN-alpha. CONCLUSIONS: Thus, the expression of cytotoxic mediators is altered in cytotoxic cells of patients with melanoma, and increased under IFN-alpha administration.     

Adverse effects of isotretinoin: A retrospective review of 1743 patients started on isotretinoin

Background/Objectives: Isotretinoin has revolutionized the management of acne vulgaris. However, concerns continue regarding the adverse effect profile of isotretinoin. This study aims to review the adverse effects experienced by patients started on isotretinoin by a single dermatologist. Methods: Retrospective chart review of 1743 patients started on isotretinoin for various dermatological conditions over a 6‐year period. Details of the dose of isotretinoin used, concomitant medications, adverse effects and outcome were recorded. Results: One‐fifth (18.5%) of patients reported no adverse effects during the study period. Cheilitis was the most commonly reported adverse effect, affecting 78% of users, followed by eczema and tiredness, seen in 12% each. However, these were clearly dose‐dependent, as the group treated with doses of isotretinoin under 0.25 mg/kg/day only reported cheilitis in 47%, eczema in 7% and tiredness in 5%, compared with 96%, 16% and 18%, respectively, in those treated with more than 0.75 mg/gm/day. Twenty‐four patients (1.4%) stopped isotretinoin because of adverse effects; a further three patients complained of severe adverse effects on at least one occasion, but continued taking the medication. The adverse effect(s) that led to patients stopping isotretinoin were cheilitis (22 patients), mood change (13), tiredness (12), eczema (6) and pregnancy (2). There were no reported instances of suicidal ideation or attempted suicide. Conclusions: Other than the two oral contraceptive failures, there were no serious adverse events recorded during this review period. Isotretinoin is a very effective medication with a low adverse‐effect profile when used at lower doses.     

Cohort study of metastatic melanoma patients in the Dermatology Institute of Florence 1990/1997

BACKGROUND: Chemotherapy and immunotherapy are treatments currently employed in advanced melanoma, but responses obtained are poor, and metastatic melanoma patients with visceral localization rarely survive for more than 6 months. Thus, different therapeutic regimens are used in metastatic melanoma and no standardized therapy exists so far. METHODS: We report a retrospective survival study involving 80 patients with metastatic melanoma who were treated either with chemotherapy [dacarbazine (DTIC) alone or DTIC in monotherapeutic or polychemotherapeutic regimen] or immunochemotherapy [interferon (IFN)-alpha at low doses added to chemotherapy]. Survival of patients was statistically evaluated in an actuarial curve taking into account as predictive variables sex, age, marital status, site of primary tumour, histological type, Clark level, sites of metastases, and the different therapeutic regimens (i.e. DTIC alone, DTIC plus IFN-alpha, or others, with or without IFN-alpha). RESULTS: Site of primary melanoma, histological type, Clark level and therapy regimen appeared to exhibit a prognostic significance in survival; when a multivariate analysis was performed to obtain a mutual adjustment of survival values for each variable, only the therapeutic regimen was found to be significant as an independent prognostic variable. Patients treated with immunochemotherapy, i.e. DTIC plus IFN-alpha, showed a probability of dying of 0.41 (95% confidence interval 0.2-0.8) compared with patients treated with DTIC alone. CONCLUSIONS: In our study immunochemotherapy, comprised of DTIC plus IFN-alpha at low doses, was associated with a significantly longer survival of patients, in comparison with chemotherapy comprised of only DTIC.     

Necrotizing cutaneous lesions complicating treatment with pegylated-interferon alfa in an HIV-infected patient.

Pegylated interferon alfa is a pegylated formulation of recombinant human interferon (IFN) conjugated with polyethylene-glycol (PEG). The major advantages of this formulation, compared to standard IFN, is a prolonged half-life which allows for once-weekly injection. Its antiviral efficacy in association with ribavirin as a new standard treatment of chronic hepatitis C has been recently documented. Efficacy of PEG-IFN in the therapy of HIV infection is currently being evaluated in prospective pilot studies. We describe herein the first observation of cutaneous necrosis at the sites of PEG-IFN injection in an HIV-infected patient. A 50-year-old man, HIV infected, was treated with antiretroviral bitherapy combining zidovudine and didanosine for 30 months. Weekly subcutaneous injections of PEG-IFN-alpha-2b were started at a dose of 1.5 microg/kg. Nine months later, two successive necrotizing cutaneous lesions developed at the site of injection. The cutaneous ulcerations slowly healed under local therapy without interruption or dose modification of the PEG-IFN. We review the literature on previously reported cases of cutaneous necrosis following standard or pegylated IFN-alpha injection and discuss the different pathophysiological mechanisms that might be involved.     

Changes in Immunological Parameters after Combination Adjuvant Therapy with Intravenous DTIC,ACNU, and VCR,and Local Injection of IFN-β (DAV + IFN-β Therapy) into Malignant Melanoma

Combination adjuvant therapy with intravenous dimethyl triazeno imidazole carboxamide (DTIC), 1-[4-amino-2-methyl-5-pyrimidinyl]-methyl-3-[2-chloroethyl]-3-nitrosourea hydrochloride (ACNU) and vincristine (VCR) and local injection of interferon-β (IFN-β) (DAV + IFN-β therapy) has been widely applied to treat malignant melanoma, and its therapeutic effect is accepted in Japan. Natural killer (NK) activity, CD4+ and CD8+ T cell counts, CD4/CD8 ratio, and white blood cell counts were analyzed before and after DAV + IFN-β therapy in order to validate its efficacy. After DAV + IFN-β therapy, the CD4/CD8 ratio was elevated; however, numbers of both CD4+ and CD8+ T cells and NK activity were consecutively depressed. Peripheral lymphocytes were also decreased, possibly by myelosuppression due to the DAV therapy. The posttreatment suppression of NK activity appeared in spite of the administration of IFN-β. It is suggested that a more effective adjuvant immunomodulator should be introduced to improve the therapeutic effect of the combination adjuvant chemotherapy in malignant melanoma.     

Treatment of High Risk Resected Melanoma in Australia: Current Landscape and Practises

Stage III melanoma involves regional lymph nodes and/or in-transit or satellite disease, without spread to distant metastatic sites. Stage IIIA melanoma includes a T1a-T2a primary lesion with N1a or N2a nodal involvement, whilst stage IIID melanoma includes a T4b primary lesion with N3a-N3c nodal involvement. With surgery alone, patients with stage IIIA melanoma have 10-year survival rates of ~88%; however, patients with stage IIID melanoma have 10-year survival rates of only ~24%. Targeted therapy and immunotherapy are being explored in stage III disease as adjuvant therapy after surgical resection, to eliminate micro-metastatic disease and thereby prevent relapse of melanoma and increase patient survival. A number of pivotal trials published in the last two years have shown improved relapse-free survival (RFS) and overall survival in patients with stage III melanoma treated with adjuvant therapy. COMBI-AD showed adjuvant dabrafenib and trametinib improving RFS compared with placebo (HR 0.49; 95% CI 0.40–0.59). Checkmate-238 demonstrated an improvement in RFS of adjuvant nivolumab over ipilimumab (HR 0.68, P < 0.001) whilst Keynote-054 demonstrated an improvement in RFS with adjuvant pembrolizumab over placebo (HR 0.57, P < 0.001). Many nuances need to be considered when interpreting this data, including implications of an updated staging system, which patients are suitable for adjuvant therapy and the choice between adjuvant targeted therapy and immunotherapy in BRAF mutant patients. This review article summaries the currently available literature on adjuvant targeted therapy and provides a guide on applying this data in everyday practise.     

Lichen planus and leukocytoclastic vasculitis induced by interferon alpha-2b in a subject with HCV-related chronic active hepatitis

Lichen planus (LP) has been reported in association with chronic active hepatitis, primary biliary cirrhosis and other chronic liver diseases. The occurrence of LP in persons with hepatitis C virus (HCV) was reported by Robert et al., and the possible relationship between LP and hepatitis virus has also been supported by cases of LP following hepatitis B vaccination. Exacerbation or appearance of LP during the treatment of chronic hepatitis C, lymphoproliferative diseases and melanoma with alpha-interferon (IFN-alpha) and improvement of these diseases after discontinuation of this drug indicate that IFN-alpha may possibly induce LP. We present a case of cutaneo-mucous LP in a woman with chronic active hepatitis treated with IFN-alpha and in whom local leukocytoclastic vasculitis was induced by the intradermal injection of a very low dose of IFN-alpha.     

Treatment of Chlamydia trachomatis infections: comparison of 1- and 2-g doses of erythromycin daily for seven days

Erythromycin is recommended as the alternative to tetracyclines for the treatment of Chlamydia trachomatis infections. However, the usual dose of erythromycin (2 g daily for a week) is frequently associated with gastrointestinal side effects. The goal of this study was to determine whether 1 g of erythromycin daily for a week would be as effective as the 2-g daily dose but without the adverse gastrointestinal effects associated with the larger dose. A total of 114 patients were entered into a randomized double-blind study; 76 patients completed treatment, 13 patients discontinued treatment because of adverse effects, and 25 failed to complete therapy or to return after treatment was initiated. Twelve (27%) of the 45 patients treated with 1 g of erythromycin had cultures positive for C. trachomatis after therapy, as compared with three (10%) of 31 patients treated with a 2-g dose. Only 34% of those treated with 1 g of erythromycin developed adverse gastrointestinal effects, as compared with 71% of those who received 2 g of the drug. Of the 13 patients who discontinued treatment because of side effects, 11 were receiving the 2-g dose. This study indicates that the smaller 1-g dose of erythromycin is inadequate therapy for C. trachomatis infections and that the standard 2-g dose is frequently associated with adverse effects that require discontinuation of therapy.     

Type 1 cytokine response and treatment outcome of genital HPV lesions.

OBJECTIVES: To determine the role of type 1 cytokines as predictors of response to treatment of genital HPV lesions with laser ablation with or without adjuvant systemic interferon alpha 2b (IFN-alpha). METHODS: Measurement of serum interleukin 2 (IL-2), IL-2 soluble receptor alpha (sIL-2 alpha), interferon gamma, and human papilloma virus (HPV) DNA in patients undergoing treatment of genital HPV lesions with carbon dioxide laser and systemic IFN-alpha. A randomised, placebo controlled study of 92 cases with 6 months of follow up. RESULTS: High IL-2/sIL-2 alpha was associated with 60% to 70% protection against recurrences both in the IFN-alpha and placebo groups (OR = 0.4, 90%, CI 0.1-2.5; OR = 0.3, 90% CI 0.0-1.8, respectively). Diagnostic phase serum IL-2 predicted favourable outcome (OR = 0.2, 90% CI 0.0-1.0) in women with high load of HPV DNA or HPV 16/18 DNA regardless of the adjuvant therapy. CONCLUSIONS: Serum IL-2 determinations may identify women with good prognosis following laser ablation of genital HPV lesions.     

Predictive value of serum S100B for monitoring patients with metastatic melanoma during chemotherapy and/or immunotherapy

In the immunohistology of malignant melanoma the use of polyclonal antibodies against protein S100 is well established. Recently, it was shown that S100B, a subunit of the S100 protein family, is detectable in the serum of melanoma patients and correlates with the stage of the disease in patients with metastatic melanoma. In the present study, the first evaluation of a large number of treatment observations (n = 77) in 64 different patients during chemotherapy and/or immunotherapy for advanced metastatic melanoma (stage IV) is presented. All patients received treatment according to standardized protocols comprising 8 weeks of treatment followed by routine staging procedures to evaluate therapeutic outcome. In 13 patients with tumour enlargement after first-line therapy, a second-line treatment was subsequently given. S100B immunoradiometric assay (IRMA) tests were performed before, during and after treatment at scheduled time points. In the interim analysis at 4 weeks 29 of 37 (78%) patients with tumour progression during treatment showed a raised S100B level. In the final analysis at 8 weeks, 31 of these 37 patients (84%) demonstrated rising S100B values (P < 0.001). Patients who responded to treatment (stable or regressing metastatic disease) showed constant or declining S100B levels in 38 of 40 patients (95%) at the interim analysis, at 8 weeks this was further increased to 39 of 40 patients (98%; P < 0.001). Thus, the use of S100B for monitoring treatment is adequate in the majority of cases. Our observations are of great interest for therapeutic trials of adjuvant and palliative therapies as the rise of S100B levels might indicate that re-staging and/or changes in therapy strategies should be chosen.     

Sentinel lymph node micrometastasis and other histologic factors that predict outcome in patients with thicker melanomas

BACKGROUND: In patients with melanoma, lymph node staging information is obtainable by the surgical techniques of lymphatic mapping and sentinel lymph node (SLN) biopsy. Although no survival benefit has been proven for the procedure, the staging information is useful in identifying patients who may benefit from further surgery or adjuvant therapy. Currently, however, it is not being recommended for patients with thick melanomas (> 3-4 mm). The risk of hematogenous dissemination is considered too great in these patients. Recent studies indicate, however, that a surprising number of patients with thick melanomas become long-term survivors, and the lymph node status may be predictive. None of the conventional microscopic features used to gauge prognosis in patients with melanoma have proven helpful in distinguishing the survivors with thick melanoma from those who will die of their disease. OBJECTIVE: Our purpose was to evaluate the influence of SLN histology and other microscopic parameters on survival of patients with thick melanomas. METHODS: A computerized patient database at the Cutaneous Oncology Clinic at H. Lee Moffitt Cancer Center was accessed to obtain records on patients with melanomas thicker than 3.0 mm (AJCC T3b). A retrospective analysis was conducted with attention paid to histologic variables, sentinel node status, and survival. Survival curves were constructed with the Kaplan-Meier method, and a Cox-Mantel rank testing was used to establish statistical significance. RESULTS: Between 1991 and 1999, 201 patients were diagnosed with melanoma thicker than 3.0 mm, and 180 were alive at an average follow-up of 51 months. Of these, 166 were alive without disease. The mean overall and disease-free survival rates were 78% and 66%, respectively. There was a statistically significant difference in disease-free survival (3-year) between SLN-positive and SLN-negative patients (37% vs 73%, respectively; P =.02). The overall survival (3-year) for the SLN-positive patients was less than the node-negative patients (70% vs 82%), but it was not statistically significant (P =.08). The disease-free survival for patients with ulcerated lesions was less than for nonulcerated lesions (77% vs 93%, P =.05). None of the other histologic parameters studied, including Breslow thickness, Clark level, mitotic rate, or regression, had an influence on the overall or disease-free survival in this group of patients with thick tumors. CONCLUSIONS: The results indicate that the SLN node status is predictive of disease-free survival for patients with thick melanomas. A surprising number of patients in the study were free of disease after prolonged follow-up. None of the histologic features of the primary tumor were helpful in predicting outcome, except for ulceration. SLN biopsy appears to be justified for prognostic purposes in patients with thick melanomas.     

Tolerance and feasibility of adjuvant treatment of stage II malignant melanoma with high-dose interferon-alpha]

BACKGROUND: The use of high-dose interferon alpha as adjuvant therapy has been shown for the first time to improve recurrence-free and overall survival in stage II malignant melanoma. The aim of our work was to evaluate the toxicity of this therapeutic scheme during a 1-year period in 13 patients with malignant melanoma. PATIENTS AND METHODS: Thirteen patients, mean age 56 years, with stage II melanoma were included. Interferon alpha was administered at the dose of 20 MU per m2 body surface area five days per week for four weeks during the induction phase and at the dose of 10 MU subcutaneously three times a week for 48 weeks in the maintenance phase. Patients underwent clinical assessment daily and had blood tests twice a week during the induction phase. Weekly blood tests and monthly examinations were then performed during the maintenance phase. Clinical and biological toxicity was evaluated in accordance with the WHO scores. Grade 3 toxicity led to a 30 p. 100 dose reduction and treatment was interrupted in case of grade 4 toxicity. RESULTS: A flu-like syndrome (grade 1-2) and digestive disorders, nausea, anorexia related to dysgeusia or dry mouth were observed in most of the patients during the induction phase and persisted in 30% of the patients during the maintenance phase. Six patients developed a state of depression (grade 2-3) which persisted during the maintenance phase, inciting us to prescribe an antidepressor regimen for all our patients. One patient developed major reversible alopecia at dose reduction. Nine patients had grade 1 or grade 2 neutropenia and four had grade 3 neutropenia. Seven patients developed grade 1-2 thrombocytopenia, six had elevated transaminase levels (grade 1-2) and two moderately elevated CPK. CONCLUSION: At the end of the induction phase of interferon alpha therapy in 13 patients with malignant melanoma, 8/13 had received 100 p. 100 of the theoretical dose and 11/13 had received 80 p. 100. At the end of the treatment protocol, 5/10 patients had received 100 p. 100 of the theoretical dose and 8/10 more than 80 p. 100. The proposed protocol appears to be feasible without major risk. Rigorous clinical and biological surveillance is mandatory.