Melanoma, malignant cancer of the pigmented cells (melanocytes), has increased in incidence. This cancer is the most serious form of skin cancer, with a higher likelihood of recurrence or metastatic spread than other forms of skin cancer. Other less common sites for origination of melanoma include the pigmented layer of the retina, or mucosal areas such as the rectum. Principle treatment is surgical, with wide excision. The extent of local disease is defined by the T stage (tumor depth of invasion), and the N stage (presence of nodal involvement). TNM staging for melanoma may be found at http://en.wikipedia.org/wiki/Melanoma. Nodal staging is important in defining overall stage, so resection of lymph nodes to determine involvement has become a standard practice, in patients other than the shallowest depths of invasion (with more significant chances of nodal involvement). The risk of lymph node sampling may include lymphedema, so sampling of nodes by selective means (sentinel lymph node dissection) is often employed first, with full regional lymphadenectomy reserved for cases with initially positive sentinel lymph nodes. Patients with positive lymph nodes and no other evidence of metastatic disease spread are Stage III in overall stage. The 5-year survival for Stage III disease ranges from 25-60%, depending on the extent of involvement.
Efforts to improve the outcome of Stage III melanoma patients have focused on immunotherapy, because adjuvant radiation or chemotherapy have not improved outcome. High dose Interferon-alpha-2b (Intron-A) has been studied in large, randomized placebo-controlled adjuvant Phase III studies (ECOG 1684, ECOG 1690). Lower doses have also been studied in other randomized clinical trials. An overview of the results of those randomized studies has been published (http://jco.ascopubs.org/cgi/content/full/20/7/1818). The ECOG studies reported improvement in disease free survival (DFS), and the ECOG 1684 study reported an overall survival (OS) improvement that was not confirmed in other studies. Interferon therapy has potentially serious toxicities, including abnormal liver functions, rash, fatigue, anemia, thrombocytopenia, leukopenia, abnormal thyroid function, and exacerbation of autoimmune phenomena. Many patients are unable to complete interferon therapy at high dose, and the value of low dose therapy is not as certain. In the ECOG interferon protocol, continuation of lower dose interferon continues for up to one year, and many patients are unable to complete the duration of therapy. Studies utlizing a newer form of interferon (pegylated interferon alpha, the EORTC Trial 18991) have been reported more recently (ASCO 2007 Annual Meeting, Abstract 8504). That study demonstrated reduced relapse, but again, survival was not improved. Overall, the conclusion can be reached that Stage III melanoma patients should be offered interferon therapy, or a clinical trial of new treatment.
Ipilimumab (MDX-010, Anti-CTLA4) is an antibody therapy that activate the immune response against melanoma. Ipilimumab has been studied in patients with metastatic melanoma, and responses have been seen in 13% of patients treated, some of which were fairly durable. The response rate appears to be somewhat higher than that of interferon in metastatic patients.
Therefore, ipilimumab has entered testing for adjuvant therapy of Stage III melanoma. This study is the BMS CA184-029/EORTC 18071 study http://clinicaltrials.gov/ct2/show/NCT00636168. Patients with completely resected melanoma, with adequate lymph node dissection staging, good performance status, and absence of autoimmune disease are potential candidates. Patients may not have received other adjuvant therapy for disease, and they must enter the study and be randomized within 12 weeks of surgery. Other inclusion and exclusion criteria do apply. The study is placebo controlled. CORT has been selected as a participating site in this trial. For more information on the study, visit the CORT website (www.CORTPA.com), or contact a Research Coordinator at 972-566-5588.
Tags: adjuvant therapy, anti-CTLA4, BMS CA184-029, EORTC, EORTC 18071, immunotherapy, interferon, Intron, Intron-A, Ipilimumab, MDX-010, Melanoma, Stage III
