Treatment Options for Stages I and II
Complete surgical resection of primary tumor followed by chemotherapy.In a randomized trial, seven of eight patients with stage I hepatocellular carcinoma survived disease free after adjuvant cisplatin-based chemotherapy. In a survey of childhood liver tumors treated prior to the consistent use of chemotherapy, only 12 of 33 patients with hepatocellular carcinoma who had complete excision of the tumor survived. This suggests that adjuvant chemotherapy...
Clinical trials should be strongly considered because of the rapid advances in the development of novel agents and combinations of agents designed to reverse or interrupt aberrant molecular pathways that support tumor growth.
Treatment option overview for patients with stage IV and recurrent melanoma
Although melanoma that has spread to distant sites is rarely curable, both ipilimumab and vemurafenib have demonstrated an improvement in progression-free survival (PFS) and overall survival (OS) in international, multicenter, randomized trials in patients with unresectable or advanced disease, resulting in U.S. Food and Drug Administration (FDA) approval in 2011. Ipilimumab is an antibody against the cytotoxic T-lymphocyte antigen (anti-CTLA-4). Vemurafenib is a selective BRAF V600E kinase inhibitor, and its indication is limited to patients with unresectable or metastatic melanoma with a demonstrated BRAF V600E mutation.
IL-2 was approved by the FDA in 1998 on the basis of durable complete response (CR) rates in a minority of patients (0%–8%) with previously treated metastatic melanoma in eight phase I and II studies. No improvement in OS has been demonstrated in randomized trials.
Dacarbazine (DTIC) was approved in 1970 based on overall response rates. Phase III trials indicate an overall response rate of 10% to 20% with rare CRs observed. An impact on OS has not been demonstrated in randomized trials.[2,3,4,5,6] Temozolomide, an oral alkylating agent, appeared to be similar to DTIC (intravenous administration) in a randomized phase with a primary endpoint of OS; however, the trial was designed for superiority, and the sample size was inadequate to prove equivalency.
Attempts over the past two decades to develop combination regimens, for example, multiagent chemotherapy;[7,8] combinations of chemotherapy and tamoxifen;[9,10,11] and combinations of chemotherapy and immunotherapy;[7,12,13,14,15,16,17] have not demonstrated an improvement of the combination on OS. However, advances in understanding of key molecular pathways are enabling rational development of combination therapy.
In smaller subsets of melanoma, activating mutations may occur in NRAS [neuroblastoma RAS viral (v-ras) oncogene homolog] (15%–20%), c-KIT (28%–39% of melanomas arising in chronically sun-damaged skin, or acral and mucosal melanomas), and CDK4 (cyclin-dependent kinase 4) (<5%), whereas GNAQ is frequently mutated in uveal melanomas. Drugs developed to target these mutations are currently in clinical trials.
Malignant melanoma has been reported to spontaneously regress; however, the incidence of spontaneous complete regressions is less than 1%.