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.     

Malignant melanoma--future prospects

As the incidence and already high mortality rates of malignant melanoma have been steadily increasing in recent decades, the early detection and excision of malignant melanoma have imposed as the most important task. Staging of malignant melanoma is determined according to the level of invasion (Clark level) and vertical thickness (Breslow scale). Besides operative therapy, which is the only effective treatment for malignant melanoma, postoperative adjuvant chemotherapy, immunotherapy, radiotherapy, and biologic therapy also are of great importance. In recent years, immunologic strategies including tumor vaccine and adjuvant therapy with interferon-alfa have been attempted to improve survival of patients with more advanced malignant melanoma. A recent melanoma research has focused on target therapy such as immunotherapy (vaccines, monoclonal antibodies, dendritic cells) and gene therapy. Genetic immunization has become an attractive strategy for the development of melanoma vaccines, because a number of antigens recognized by cellular components of the immune system have been identified at the molecular level. Numerous chemotherapeutic agents have shown activity in the treatment of metastatic malignant melanoma, such as dacarbazine (dimethyl triazene imidazole carboxamide); other agents have been used, however, with less success. However, a very modest effect was recorded in advanced malignant melanoma. There are many experimental trials using combined therapy for malignant melanoma, including chemotherapy (dimethyl triazene imidazole carboxamide) and biologic therapy (interleukin (IL)-2, interferon (IFN)-gamma, IFN-alfa). The results obtained open particularly interesting prospects in the field of malignant melanoma with high relevance for its development and progression. Molecular therapeutics and vaccine development will probably be an important focus for the future melanoma treatment.     

Safety of pegylated interferon-alpha-2a in adjuvant therapy of intermediate and high-risk melanomas

Pegylated (PEG)-IFN-alpha-2a is a modified form of recombinant human IFN-alpha-2a with sustained absorption and prolonged half-life. Our aim was to evaluate its safety profile in adjuvant treatment of high-risk melanoma patients in a single centre setting and to compare this safety profile with data obtained from the literature for a) low dose IFN-alpha and b) high dose IFN. Eighteen consecutive melanoma patients (AJCC 2002 stages IIa-IIIc) were retrospectively analyzed for toxicities associated with adjuvant PEG-IFN-alpha-2a (180 microg/week s.c.). The most frequently reported adverse events were constitutional side effects (78%), myelosuppression (83%) and hepatotoxicity (78%). The proportion of patients receiving PEG-IFN-alpha-2a and suffering from myelosuppression and liver toxicity was significantly higher than for patients reported in the literature undergoing low-dose IFN-alpha treatment (P = 0.008, P = 0.001 respectively), while fatigue and depression were seen less frequently with PEG-IFN-alpha-2a. By contrast, compared to patients treated with high-dose IFN-alpha, PEG-IFN-alpha-2a treated patients less frequently experienced fatigue (P < 0.001), neutropenia (P < 0.068) and neuropsychiatric (statistically not significant) adverse events. In conclusion, subcutaneously delivered PEG-IFN-alpha-2a is well tolerated in a once-weekly dose of 180 mug by most patients with high risk malignant melanoma. The frequency of side effects is increased compared to low dose, but reduced compared to high dose standard IFN-alpha. Due to its pharmacokinetic properties, pegylated IFN-alpha has, as in the treatment of hepatitis C, potential for increased efficacy in adjuvant therapy of melanoma.     

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.     

Immuntherapie des Melanoms

Even early clinical studies showed that adjuvant chemotherapy achieved no therapeutic benefit for melanomas so that in the current guidelines its use is only recommended within the framework of clinical studies. For over 30 years interferons have been used in the adjuvant treatment of primary high risk melanomas as well as in the treatment of metastasized melanomas. They function in an antiviral, immune modulating and antitumor fashion. Direct and indirect effects on tumor cells could be demonstrated for interferons. In Europe low dosage interferon therapy is approved and has become widely established for stage II melanomas, whereas in the USA high dosage therapy for stage III and since March 2011 therapy with pegylated interferon in stage III are also approved. In this article the most important study results will be dealt with in detail. In summary, according to the current study situation therapy with interferon should be offered especially to patients with ulcerated primary melanoma and microscopic lymph node infiltration. Many attempts have been made in the last decades to positively influence the survival time of distant metastasized melanoma by systemic therapy. The recent development of the antibody ipilimumab against cytotoxic T-lymphocyte protein 4 (CTLA-4) could show for the first time a survival advantage in the therapy of melanoma patients in advance stage disease. The licensing of ipilimumab has meant that there is now a new standard available for the second line therapy of malignant melanoma which will be included in the guidelines on therapy of malignant melanoma. A further interesting option for adjuvant therapy is currently vaccination with the recombinant melanoma-associated protein 3 (MAGE-A3) protein in combination with the adjuvant AS015.     

Cutaneous Malignant Melanoma Associated with Papillary Thyroid Cancer

As the survival from cutaneous malignant melanoma and its clinical concerns have been steadily increasing, the possibility has been raised of an increased risk of second primary cancers in the patients with malignant melanoma. Especially, recent studies have identified an association between cutaneous malignant melanoma and thyroid carcinoma. We here report on a case of cutaneous malignant melanoma that developed in a 61-year-old female patient who had hypothyroidism caused by papillary thyroid carcinoma. We suggest that the individuals who have cutaneous malignant melanoma may be predisposed to other primary cancers and especially thyroid carcinoma. Continuous monitoring of the thyroid function in melanoma patients is required because hypothyroidism can worsen due to malignant melanoma and this is probably associated with thyroid carcinoma.     

How does a diagnosis of thin cutaneous malignant melanoma affect survival rates?

Cutaneous malignant melanoma is a type of skin cancer that you can die from. The number of patients being diagnosed with malignant melanoma of the skin is rising in most countries. About 4000 patients were diagnosed in Sweden in 2018. The risk of dying from cutaneous melanoma is very much dependent on the thickness of melanoma, a measure given by the pathologist after removing the melanoma. The risk of dying increases with increasing thickness. Most patients who are diagnosed with cutaneous melanoma will have thin melanomas, i.e. 1 mm or thinner. In our study, we wanted to define the survival rate for 31 670 patients diagnosed with thin cutaneous melanomas between 1990 and 2017 in Sweden. We collected data about the patients from the Swedish Melanoma Registry where Swedish malignant melanomas are registered. Moreover, we had information from the Swedish Cause of Death Registry to identify which of the patients had died from melanoma. We found that the risk of dying from a thin melanoma in Sweden was generally very low. Ten‐year survival rate was 97% and 20‐year survival was 95%. In addition, we were also able to confirm an increasing survival with time, i.e. for every year after the diagnosis of a thin melanoma, survival chance became even better. Women had a somewhat better survival chance than men. In conclusion we found that patients with thin cutaneous malignant melanoma in Sweden generally have a good disease outcome with only a minority dying from thin melanomas. Linked Article:   Isakasson et al. Br J Dermatol 2021; 184 :60–67 .     

Anorectal melanoma--3 case reports and a review of the literature

Anorectal melanoma is an uncommon disease. Histologically, the tumor may mimic adenocarcinomas, small cell carcinomas, and sarcomas; grossly, the lesion often mimics hemorrhoids. We report 3 cases of anorectal melanoma: a 40-year-old woman with anorectal melanoma with local recurrence after an abdominoperineal resection (APR); a 30-year-old woman with anorectal melanoma and multiple liver metastases returning with multiple masses in the rectum and 2 nodules above and below the left clavicle after receiving chemotherapy; and a 62-year-old woman with inguinal node metastases. The histologic findings in all 3 cases revealed malignant tumor composed of atypical melanocytes diagnosed as malignant melanoma of the rectum. In the first case, APR with pararectal lymphadenectomy was performed. Histopathology revealed nodal metastasis. The patient was noncompliant with chemotherapy and died after several months. In the second case, chemotherapeutic treatment was begun. Seven months after receiving chemotherapy, the patient returned with multiple metastases. The final case was lost to follow-up after referral to an oncologist. Anorectal melanoma is highly aggressive and unresponsive to both radical surgery and local control. Although supplemental therapy may improve quality of life and prolong survival, the 5-year survival rate is 10% with a mean survival time of 15 to 25 months. In the 3 cases presented, metastatic disease was present at the time of diagnosis. At this stage, APR with lymphadenectomy followed by some form of adjuvant therapy is our recommended treatment.     

Psychoonkologische Aspekte des malignen Melanoms

Background and Methods

Despite the increasing prevalence of malignant melanoma, psychosocial aspects have found little attention. A systematic review was conducted in order to identify psycho-oncological articles on patients with malignant melanoma.

Results

Out of a total of 31 studies, 12 examine quality of life in malignant melanoma patients and 6 studies monitor quality of life in the course of therapy. Most studies originate from English-speaking countries (USA, UK, AU); few German studies have been published. Methodological limitations of the studies include cross-sectional assessment, unreported return rate, small sample sizes and comparability (heterogeneous or non-standardized psychosocial measures).

Conclusions

In addition to the tumor stage, psychosocial characteristics (coping with disease, social support) have a substantial effect on quality of life. Results from psychotherapy trials with malignant melanoma patients are encouraging. Given the overall high survival rates of malignant melanoma, quality of life and needs for care of long-term survivors need to be assessed.     

Systemic therapy of advanced metastatic malignant melanoma with a combination of fibroblast interferon-beta and recombinant interferon-gamma

Eighteen patients with advanced metastatic malignant melanoma (stage IVUICC 1987) were entered into a prospective trial with a combination of systemic fibroblast interferon-beta and recombinant interferon-gamma. Treatment was performed over a 6-week period with 3 x 5 x 10(6) U i.v. interferon-beta and 5 X 100 micrograms s.c. interferon-gamma every week. Under this therapy 16 patients showed a progressive disease, and 2 patients had a stable disease. The median time of survival was 7.5 months. Successive immunological examinations showed no significant immunomodulating effect after the 6 weeks of interferon treatment. We conclude that the combination of interferon-beta and -gamma is insufficient in the treatment of advanced metastatic malignant melanoma when administered by this dose, route and schedule.     

S-100β-Protein im Serum als Tumormarker beim malignen Melanom Aktueller Kenntnisstand und klinische Erfahrungen

S100 is an acidic-calcium-binding protein, composed as a heterodimer of two isomeric subunits alpha and beta and was first described in cells of neuroendocrine origin. It plays an important role in various cellular processes such as cell differentiation and proliferation and interacts with the tumour suppressor gene p53.S100 is also present in melanoma cells and its immunhistochemical detection is widely used in the histopathological diagnosis of malignant melanoma. S100 has been detected in the serum of patients with malignant melanoma and many clinical studies have been performed to establish this protein as a tumor marker in different stages of the disease. The data suggest that S-100 beta-protein in serum of patients with malignant melanoma could be an independent prognostic marker and an additional clinical parameter for progression of metastatic disease and serological monitoring during systemic therapy. However there are patients in stage of lymph node- or systemic metastasis with negative S-100 beta-serum levels and no correlation to the course of disease. Our results confirm the findings for patients in stage III/IV. However, the percentage of S-100 beta-positive patients in stage III/IV is lower than reported in the literature, if repeatedly positive samples are excluded from statistical analysis. For monitoring in stage I and II it seems to be not helpful.     

Surgical outcomes in patients with cutaneous malignant melanoma in Europe – a systematic literature review

There is limited comparative evidence of the outcomes of different types of surgical management in patients with malignant melanoma in Europe. To address that gap we conducted a systematic literature review to summarize studies reporting outcomes of surgical procedures in patients with malignant melanoma in Europe. Medline was searched for European studies published in English, between 2004 and 2014 reporting surgical outcomes in adults with cutaneous malignant melanoma. We identified 23 studies that evaluated 18 332 patients treated surgically between 1979 and 2009 from 11 European countries. Most of the studies (21/23) were observational; the two remaining studies were randomized controlled trials (RCTs). Studies compared the effect of a range of surgical interventions on a range of clinical outcomes, more commonly overall survival (OS) and disease‐free survival (DFS)/recurrence‐free survival (RFS). Wider excisions were not associated with improved survival in patients with melanoma thickness ≥2 mm in both studies (RCTs), however, recent results based on long‐term follow‐up data associate 3 cm excision margins (vs. 1 cm) with favourable survival outcomes. There was some evidence that complete lymph node dissection after positive sentinel lymph node offers survival benefits over therapeutic lymph node dissection. Sentinel lymph node biopsy was not shown to be associated with significant OS benefits, however, it was overly related with higher rates of DFS/RFS. This review highlights the difficulties of making comparisons between different types of surgical procedures for malignant melanoma. As surgery remains the main treatment, this is an important field, and further evidence, particularly from RCTs, is needed.     

Rechallenge of targeted therapy in metastatic melanoma

Rechallenge of targeted therapy in patients with BRAFV⁶⁰⁰‐mutated melanoma plays an important role, because of the prolonged overall survival of melanoma patients. Patients may be rechallenged after a drug‐free interval following adverse drug reactions, after radiation therapy or surgery, following disease progression on subsequent immunotherapy or chemotherapy, or after disease progression without interim therapeutic intervention. To date, only few data has been published on treatment outcomes associated with rechallenge. The articles published on this topic included a total of 238 patients. In general, it was shown that patients did respond to rechallenge, even if they had previously experienced disease progression on targeted therapy. Patient response varied from stable disease to partial response and even complete remission in some cases. Our analysis showed overall response rates to rechallenge of 47 %, with disease control rates of 67 %. While mean progression‐free survival was 6.4 months, this was shorter than after the first round of targeted therapy (mean progression‐free survival of 9.2 months). Rechallenge of targeted therapy offers another option in the management of melanoma patients who have received extensive prior treatment. In particular, it will be important to clarify whether the type of interim treatment has an impact on the response to rechallenge.     

Altered clinical course of malignant melanoma in HIV-positive patients

OBJECTIVE: To determine whether the natural history of melanoma is different in patients who test positive for human immunodeficiency virus (HIV) compared with matched control subjects. DESIGN: Retrospective cohort analysis. SETTING: Ambulatory care at 2 university-affiliated medical centers. PATIENTS: Each HIV-positive melanoma patient (n = 17) was randomly matched with 2 HIV-negative patients (HIV status unknown, but without risk factors for HIV) based on the melanoma subtype, tumor thickness, Clark level, tumor location, and sex and age of the patient. MAIN OUTCOME MEASURES: Disease-free survival and overall survival of HIV-positive and HIV-negative melanoma patients were compared using a matched-pairs analysis. CD4 cell counts were recorded at the time of melanoma diagnosis and disease recurrence. RESULTS: Melanoma patients who were HIV positive had a significantly shorter disease-free survival (P =.03) and overall survival (P =.045) compared with HIV-negative melanoma patients by matched-pairs analysis. There was an inverse relationship between CD4 cell counts and time to first melanoma recurrence. CONCLUSIONS: The natural history of malignant melanoma in HIV-positive patients is more aggressive compared with matched HIV-negative melanoma patients. Altered immune response and comorbid disease may play a role in the poor clinical outcome of HIV-positive patients. These findings have important implications in the management of melanoma in the setting of HIV disease.     

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.     

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.     

The management of high-risk melanoma: staging,treatment, and nursing issues

The incidence of malignant melanoma continues to increase. Treatment of high-risk disease requires a rigorous course of therapy. Nurses who care for these patients must understand the disease and its therapy to adequately prepare patients for treatment. The diagnosis, staging, treatment, and symptom management for high-risk melanoma are reviewed.     

Molecular diagnostics in melanoma

Molecular pathology is rapidly evolving, featuring continuous technologic improvements that offer novel clinical opportunities for the recognition of disease predisposition, for identifying sub-clinical disease, for more accurate diagnosis, for selecting efficacious and non-toxic therapy, and for monitoring of disease outcome. Currently, the identification and prognosis of primary cutaneous melanoma is based on histologic factors (tumor depth and ulceration) and clinical factors (number of lymph node and/or distant metastases). However, metastasis can occur in patients with thin melanomas, and sentinel lymph node biopsy does not identify all patients at risk for distant metastasis. New markers exist that correlate with melanoma progression, which may aid in melanoma identification, prognostication, and detection of minimal residual disease/early recurrence. Moreover, not many therapeutic options exist for melanoma as no regimen prolongs survival. Emerging data with investigational therapies suggest that certain markers might play a crucial role in identifying patients who will respond to therapy or show utility in the monitoring the response to therapy. Herein, molecular diagnostics that can potentially benefit the individual melanoma patient will be discussed.     

Malignant melanoma and levodopa

A patient with Parkinson's disease developed a malignant melanoma within a congenital nevus after starting levodopa therapy. Levodopa has a central role in the metabolism of the melanocyte but data do not permit the conclusion that it promotes the development of malignant melanoma. However, patients receiving levodopa should be monitored for skin changes suggestive of melanoma.     

Can melatonin and its metabolites boost the efficacy of targeted therapy in patients with advanced melanoma?

Despite groundbreaking new treatments such as checkpoint inhibition and targeted therapy, the overall response and survival rates are limited in patients with metastatic melanoma. Here, we hypothesize that melatonin and its metabolites could be promising boosters of the efficacy of BRAF/MEK inhibitors in patients with advanced melanoma. Melatonin, a well-known endogenous synchronizer of the circadian biorhythm has a variety of promising effects for melanoma biology. It regulates proliferation, apoptosis and oxidative phosphorylation via melatonin receptors, and receptor-independent pathways due to its lipophilicity. By means of interfering with the above cellular pathways, melatonin and related compounds may alter the cAMP-PKA-MITF axis, modulate tumor cell metabolism, affect MAPK signalling pathway thereby enhancing the suppressive effect of BRAF/MEK inhibitors on melanoma cell growth, and survival. Such findings could fuel preclinical studies and clinical studies where melatonin or its metabolites are combined with targeted therapy to better treat patients with metastatic melanoma.