Adjuvant Therapy for Cutaneous Melanoma

General

The incidence of cutaneous melanoma is increasing at a rate greater than that of any other malignancy. Although it represents the fifth and sixth most common cancer in American men and women, respectively, melanoma affects young members of society who are in their most productive years. For this reason, the cost to society is far greater than that of many other more prevalent solid tumors such as prostatic carcinoma. Treatment of localized, early-stage disease is associated with cure rates of 90% or better. Conversely, in its disseminated form, melanoma is a devastating illness refractory to a wide range of chemotherapy agents and combinations. Melanoma has shown significant benefit from immunotherapy with the prospect for cure in the adjuvant postoperative setting and long-lasting responses that provide a hope for patients with advanced disease.

Surgery remains the cornerstone of treatment for this tumor when it is discovered at local or local-regional stages. To this, systemic therapy has been added in the adjuvant setting, i.e. when all the detectable tumor has been resected. Although adjuvant treatment can theoretically be applied at any stage, it has traditionally been applied to treat patients with American Joint Committee on Cancer (AJCC) stages II and III.

What stages of disease are appropriately considered ‘high risk’ for adjuvant treatment?

Along with the search for effective treatments for melanoma over the past two decades, considerable research has been conducted to identify clinical and pathologic features that are prognostic for relapse, metastasis and overall survival (OS). These prognostic factors have been incorporated in the TNM staging system recently revised as the seventh edition of the AJCC staging system ( Tables 53.1 and 53.2 ).

Five independent prognostic factors are correlated with relapse and mortality. Breslow's tumor thickness is the single most important prognostic factor for localized melanoma and has eclipsed the importance of Clark's level of invasion for primary melanoma lesions that are ≤1.0 mm in thickness. Ulceration is the second most important prognostic factor for localized melanoma, defined as absence of intact epidermis overlying a significant portion of melanoma as evaluated in microscopic analysis. Its presence connotes a worse prognosis. In the 7th AJCC edition, the prognostic significance of the mitotic activity (histologically defined as mitoses/mm ² ) has been recognized as an important primary tumor prognostic factor. The mitotic rate (≥1/mm ² ) has now replaced the level of invasion as a primary criterion for defining the subcategory of T1b in addition to tumor ulceration. Regional metastases, either in the regional lymph nodes or intra-lymphatic (satellite or in-transit) metastasis, as well as the extent of lymph node tumor burden (i.e. micro- or macro-metastasis), are important predictors of outcome. The number of involved lymph nodes, defined by sentinel lymph node mapping or complete lymphadenectomy, best correlates with 10-year survival and has replaced the size of lymph nodes in the TNM staging system. In the 7th AJCC edition, there is no lower threshold of tumor burden defining the presence of regional nodal metastasis. Specifically, nodal tumor deposits less than 0.2 mm in diameter (previously used as the threshold for defining nodal metastasis) are not ignored in the staging of nodal disease, as a result of the consensus that smaller volumes of metastatic tumor are still clinically significant. Another important addition to the 7th AJCC edition is the criterion that the presence of nodal micrometastases is defined by the presence of any volume of tumor cells observed either by hematoxylin and eosin (H&E) or by immunohistochemical staining (in the 6th edition, only H&E could be used). Finally, the site of distant metastasis, the number of metastatic sites, and the serum lactate dehydrogenase (LDH) level are important prognostic factors for advanced-stage melanoma. These prognostic factors allow clinicians to identify patients at high risk for developing recurrence at local, regional and distant sites who would best benefit from adjuvant therapy.

The AJCC staging system divides patients into four stages depending on whether tumors are only localized to the skin (stage I and II), have regional metastases (to lymph nodes or satellite or in-transit intralymphatic sites, stage III), or have distant metastatic disease (stage IV). Subgroups are based on the interplay of the above-described prognostic factors and reflect the prognostic heterogeneity of patients with the same tumor. Traditionally, the high-risk group is described as subjects with primary deep melanomas (T4 N0 M0) or stage III disease, whereas the intermediate-risk group includes patients with melanoma thickness >1.0 mm.