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Drug therapy for malignant melanoma

Malignant melanoma is relatively resistant to chemotherapy (20). Adjuvant treatment with chemotherapy has not improved survival and is not an established therapy for melanomas (21). Except for controlled clinical trials, it is only appropriate to offer chemotherapy to patients with metastases which cannot be removed surgically or should be treated with radiation. No studies have shown improved survival after chemotherapy. Most objective remissions last only for some months. However, some patients are good responders (3-5%) and may achieve long-lasting remissions.

Dacarbazine® (DTIC) is the most commonly used chemotherapy for disseminated disease and objective remissions are achieved in 10-20% of the patients (22). DTIC is administered intravenously once every third week. The treatment has relatively few side-effects. If there is no effect after 2-3 courses it should be discontinued. With simultaneous brain metastases, Temodal® is considered since it most likely penetrates the blood-brain barrier better (14). Termodal®  tablets are administered one daily for 5 days every 4th week. The effect is similar to DTIC (23).

For lack of effect of DTIC or Termodal®, other cytostatic drugs may be considered if BRAF inhibitor or immunotherapy is not relevant. Carboplatin® / Docetaxel® may be given intravenously every 3rd week, The regimen causes more side-effects and has no better effect than DTIC. Vinblastine is given intravenously once a week and 7-10% of the patients will benefit from the treatment. The same goes for Docetaxel® (intravenously once a week) and lomustin (CCNU) taken as tablets once every 6th week.

For inoperable local relapse and/or systemic illness in mucous membranes, it is appropriate to try chemotherapy. The regimens are the same as for malignant skin melanoma.

ILP – (Isolated limb perfusion) regional perfusion treatment

For multiple metastases located in the extremities where surgery is not appropriate, intensive regional perfusion treatment with melfalan, possibly in combination with tumor necrosis factor (TNF), under hyperthermia (heating of the extremity) should be considered. Studies have shown 90% total response after such treatment. Around 70% have complete remission with a combination of melfalan and TNF (33). Oslo University Hospital, The Radium Hospital is the national centre for such treatment.

Electrochemotherapy

For cutaneous metastases electrochemotherapy my be tried. The technique takes advantage of electrical impulses to enhance the permeability of cytostatic drugs, usually Bleomycin®; into the tumor cells. Good results are often achieved (34,35). Oslo University Hospital is the national centre for this treatment.

Immunotherapy

Melanoma is an immunogenic tumour well suited for immunotherapy (24). Tumour specific T-cells (CTL) have been identified in metastases from melanomas and immune response against melanoma associated antigens have been identified in serum.

Interferon alfa has been tried for metastatic melanomas but the response rate was low (25). Immunostimulation with interleukin2 in combination with chemotherapy has also been tried, but the effect is not better than with DTIC alone and there are considerable side-effects (26).

Adjuvant treatment after lymph node dissection or given to patients with thick melanomas show prolonged diease-free interval in some patients, but with no benefit in survival. The treatment is long lasting, give rise to considerable side-effects and is not standard treatment (25).

Yervoy® (ipilimumab) is a human monoclonal antibody towards CTLA4 (cytotoxic T-lymphocyteantigen4). Ipilimumab enhances T-cell activation and thereby the immune response against cancer cells. Ipilimumab  has shown an increased median survival of 2 months (15, 16). Some patients (15%) are long-term survivors. The treatment consists of 4 courses given with 3 weeks interval. The response often appears late, even after cessation of the treatment. A transient progression (pseudoprogression) is also commonly seen before the response. Ipilimumab should therefore not be applied in patients with rapidly progressing disease, debilitated general condition and/ or large tumour volume.

Yervoy® can cause serious side effects, the most common are autoimmune colitis, hepatitis, dermatitis and hypophysitis. It is very important that the patients report side-effects rapidly to departments experienced with such side-effects. The drug is accepted by FDA (US Food and Drug Administation) and EMA (European Medicine Agency) for treatment of melanomas with metastases. Ipilimumab is very expensive and Norwegian Hospitals are not approved to apply it without extra consession. In Norway (per September 2014) ipilimumab is given in a national phaseIV study (IPI-4 study).

Another naural inhibitor of T-cell activation is PD-1 (programmed death -1). Studies on antibodies against PD-1 are promising (26) and the antibody is expected to be accepted within a short time. A combination with ipilimumab and Nivolumab (PD-1 antistoff) is tested in a phse III study after promising results of a phase IV study (27).

Signal inhibitors

The discovery of a mutation on the gene coding for serine-threonine protein kinase, BRAF V600E mutation, in many melanomas represents a possibility for “targeted therapy”(36). BRAF inhibitors (Zelboraf® and Tafinlar®) interferes with melanoma cells in around 50% of the patients with this mutation (37). BRAF inhibitors also have effect on brain metastases.

BRAF mutation can be identified in 50% of the patients with skin melanomas and in around 10% of the patients with mucosla melanomas. Both Zelboraf® and Tafinlar® are given as tabets twice a day. The effect will usually appear rapidly with a considerable shrinkage of the tumour and improvement of symptoms. The respons is not seldom of relatively brief duration, 6-8 months (38). After an interval retreatment may cause new improvement in some patients, The most common side-effects are diarrhea, dry skin, itching, exanthema, baldness, photosensitivity (which may be severe), fatigue, considerable joint- and muscle pain and development of keratoacanthoma and spinocellular carcinoma. Tafinlar® causes less photosensitivity but often give rise to fever and hyperkeratosis. The therapy sometimes have to be discontinued due to the side-effects. This will be in cases when symptomatic treatment, dose reduction or a pause in the treatment does not help. Dose reduction of more than 50% is not recommended.

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