**6. Surgery and chemotherapy**

The treatment of cutaneous melanoma has historically been essentially surgical. Much progress has been made in this area, and the resection margins have been established based on tumor depth. Candidates are also identified for lymphadenectomy, avoiding the morbidity of the procedure in patients who do not require it.

Topical formulations are examined and, where available, skin penetration properties of the various drugs are detailed. New strategies for targeted drug delivery to skin cancers are considered with an emphasis on studies conducted *in vitro* with porcine or human tissue, or in patients.

Level III – melanoma invades and expands papillary dermis up to the interface with, but not

Cancer staging system, called the TNM (Tumor, Node, Metastasis) system by the American Joint Committee on Cancer (AJCC) is used for clinical staging [16]. The stage of melanoma refers to the thickness, depth of penetration, and the degree to which the melanoma has spread. The staging is used to determine treatment. There are five stages of melanoma: stage

**Stage 0** refers to melanoma *in situ*, which means melanoma cells are found only in the outer layer of skin or epidermis. This stage of melanoma is very unlikely to spread to other sites of the body. **Stage I** the primary melanoma is still only in the skin and is very thin. Stage I is divided into stages IA and IB, depending on the thickness of the melanoma and the mitotic rate. **Stage II** melanoma is thicker than stage I melanoma, extending through the epidermis and further into the dermis, the dense inner layer of the skin. It has a higher chance of spreading. Stage II is divided into IIA, IIB and IIC depending on thickness the melanoma and ulceration. **Stage III** melanoma has spread through the lymphatic system, either to a regional lymph node located near where the cancer started or to a skin site on the way to a lymph node. Stage III is also divided into IIIA, IIIB and IIIC depending on the size and number of lymph nodes involved with melanoma and whether the primary tumor appears ulcerated under a microscope. In **stage IV**, melanoma has spread through the bloodstream to other places of the body, such as lung, liver, brain, bone, soft tissue, or gastrointestinal tract. Stage IV is further divided into M1a, it means the cancer has only spread to distant skin and/or soft tissue sites; M1b involves metastasis to the lung; and M1c describes distant metastasis at any other location or an elevated serum lactate dehy-

Similar to other tumors the progressive stage of melanoma is predictive for therapeutic success. Early stage melanomas (thin tumors) result in a 97% 5-year survival rate of the patients,

The treatment of cutaneous melanoma has historically been essentially surgical. Much progress has been made in this area, and the resection margins have been established based on tumor depth. Candidates are also identified for lymphadenectomy, avoiding the morbidity of

Level IV – melanoma invades reticular dermis but not into subcutaneous tissue;

Level V – penetration of melanoma into the subcutaneous tissue.

112 Human Skin Cancers - Pathways, Mechanisms, Targets and Treatments

**5. Current possibilities for the therapy of melanoma**

into, reticular dermis;

0 and stages I–IV.

drogenase [17].

after surgical removal [18].

**6. Surgery and chemotherapy**

the procedure in patients who do not require it.

*Imiquimod* cream may be used to stimulate the local immune response in early stage melanoma patients (**Figure 1**) [19, 20].

The decision to treat melanoma by adjuvant therapy has the opposing arguments: the risk of recurrence, progression and high toxicity, and price of treatment.

The risk of recurrence and death after complete surgical resection of clinically detectable primary cutaneous melanoma ranges from low, intermediate to high risk depending on the stage of disease at diagnosis. This is determined by the depth, ulceration status and mitotic rate of the primary tumor, the presence of regional nodal disease or distant metastasis. For highrisk melanoma, adjuvant therapy is aimed at eradicating melanoma micrometastases in the patients that carry an unacceptable risk of mortality from melanoma recurrence. The ultimate goal of adjuvant therapy is to provide a potential cure before progression of melanoma into advanced inoperable stages [21].

A little progress has been made in systemic treatment since the 1970s when the use of dacarbazine was introduced for the treatment of patients with tumor progression or distant metastasis, with disappointing results.

*Dacarbazine* and *temozolomide* (**Figure 1**) belong to the group of alkylating agents. These triazene compounds have excellent pharmacokinetic properties and limited toxicity. The active moiety of these drugs is represented by the triazenyl group of three adjacent nitrogen atoms, which are responsible for the physico-chemical and antitumor properties of the molecule. Mechanism of action of both compounds is mainly related to the methylation of *O*<sup>6</sup> *-*guanine, mediated by methyldiazonium ion, a highly reactive derivative. *O*<sup>6</sup> *-*methylguanine is responsible for incorrect base pairing and damaging of DNA [22]. Dacarbazine is a prodrug structurally related to purines activated by liver microsomes. This chemotherapeutic agent was approved by the Food and Drug Administration (FDA) for the treatment of melanoma, and often regarded as the standard treatment for advanced melanoma. However, therapy with

**Figure 1.** Chemical structures of imiquimod, dacarbazine, and temozolomide.

dacarbazine is characterized with low overall response rates (approximately 10–15%) and there is no valid evidence of survival benefit [23]. Temozolomide is a monofunctional alkylating agent of the imidotetrazine class. It is stable at the acid pH of the stomach and administered orally with 100% bioavailability [22].

with ipilimumab leads to a significant extension of the survival of patients with metastatic melanoma. Side effects of ipilimumab are related to the mechanism of its action. Typical side effects are accompanied by diarrhea, skin rash, pruritus, enteritis, vitiligo, endocrinopathies and hepatotoxicity. Ipilimumab is approved in the USA for the treatment of patients with advanced melanoma and in Europe for patients with previously treated advanced melanoma. *Tremelimumab*, another drug of this group, is human therapeutic monoclonal antibody IgG2, with the same mechanism of action as ipilimumab. This antibody is currently in progress in

Possibilities for the Therapy of Melanoma: Current Knowledge and Future Directions

http://dx.doi.org/10.5772/intechopen.70368

115

Ipilimumab, in combination with high dose IL-2, and tremelimumab, in combination with interferon alfa provide increased overall response rate, progression-free survival, or higher percentage of complete responses. *Interferon alfa* is FDA approved in adjuvant treatment for patients with high-risk melanoma and it has significant immunomodulatory effects [31–33]. Interferon alfa monotherapy has limited utility in the treatment of stage IV melanoma; therefore, its antitumor activity has led to profound investigation of its use in combination with

Cancer immunotherapy can be achieved by inhibition of the PD-1/PD-Ll axes, which affect the overall survival in an important fraction of patients. PD-1 is an inhibitory receptor that is upregulated on activated lymphocytes. PD-1 has two known ligands, PD-L1 and PD-L2, which can be expressed on tumor and stromal cells; PD-L1 expression can be induced by

*Pembrolizumab* (Keytruda®, Merck & Co) is the first anti-PD-1 immunotherapeutic agent approved by FDA. Keytruda® was granted FDA approval on September 4, 2014 for the treatment of patients with unresectable or metastatic melanoma. This molecule is a potent and highly selective humanized monoclonal antibody of IgG4-kappa isotype, designed to directly block the interaction between PD-1 receptor, expressed on T-cells, and its ligands, PD-L1 and PD-L2, without antibody-dependent cell-mediated or complement-dependent cytotoxicity. In practice, blocking PD-1 activity is believed to prevent inhibition of T-cell immune surveillance of tumors and, in some models, has resulted in decreased tumor growth [26]. The recommended dose of pembrolizumab is 2 mg/kg administered as an intravenous infusion over 30 min every 3 weeks until disease progression or unacceptable toxicity. Most common adverse reactions (reported in ≥20% of patients) included fatigue, cough, nausea, pruritus,

Another approach, which has already been tested, is to combine anti-PD-1 and anti-CTLA-4 treatment and is represented by *nivolumab* (Opdivo®, Bristol-Meyers Squibb). Nivolumab is used alone or in combination with ipilimumab [37, 38]. Combination therapy with anti-CTLA-4 and anti-PD-1 monoclonal antibodies has recently led to remarkable antitumor

BRAF-mutant and BRAF-wild type patients, who progressed after ipilimumab therapy, were included into the Phase III study. One group of patients received nivolumab (3 mg/kg every 2 weeks), and in comparator group patients were treated with chemotherapy. Patients treated with nivolumab demonstrated higher response rate compared to the chemotherapy group—32%

cytokines produced by tumor-infiltrating lymphocytes [35].

rash, decreased appetite, constipation, arthralgia, and diarrhea [36].

effects, long-term survival and potential cures [39].

phase II/III clinical study [30].

other therapies [34].
