**4. Melanoma classification and staging**

The classification schemes **Breslow's thickness (depth)** and **Clark's level** have been developed based on either the vertical thickness of the lesion in millimeters or the anatomic level of invasion of the layers of skin. Breslow's depth is considered significant factor in predicting the progression of the melanoma. Increased tumor thickness is correlated with metastasis and poorer prognosis. Tumors are classified into four categories based on the depth: thickness of 0.75 mm or less, thickness of 0.76–1.5 mm, thickness of 1.51–4 mm and thickness greater than 4 mm.

Clark's level of invasion has far less importance and is used only in the staging of thin melanomas (<1 mm). Tumors are classified into five levels:

Level I – melanoma involves only epidermis (melanoma *in situ*);

Level II – melanoma invades papillary dermis but not papillary-reticular dermal interface;

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

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

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

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*Imiquimod* cream may be used to stimulate the local immune response in early stage mela-

The decision to treat melanoma by adjuvant therapy has the opposing arguments: the risk of

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

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 metas-

*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.

sible 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

*-*guanine,

*-*methylguanine is respon-

Mechanism of action of both compounds is mainly related to the methylation of *O*<sup>6</sup>

mediated by methyldiazonium ion, a highly reactive derivative. *O*<sup>6</sup>

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

recurrence, progression and high toxicity, and price of treatment.

patients.

noma patients (**Figure 1**) [19, 20].

advanced inoperable stages [21].

tasis, with disappointing results.

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

Level V – penetration of melanoma into the subcutaneous tissue.

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 0 and stages I–IV.

**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 dehydrogenase [17].

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

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, after surgical removal [18].
