The introduction of platinum-based combination chemotherapy has made an impressive change in the treatment of patients with advanced testicular cancer. Presently, chemotherapy is recommended for patients with stage IIC or stage III seminomas and nonseminomatous disease. Over 90% of patients respond to chemotherapy and, depending upon the extent and severity of disease, complete remissions are observed in 70–80% of patients. More than 50% of patients achieving complete remission are cured with chemotherapy. In patients with good risk features, three cycles of cisplatin, etoposide, and bleomycin (PEB protocol) or four cycles of cisplatin and etoposide yield virtually identical results. In patients with high-risk disease, the combination of cisplatin, etoposide, and ifosfamide can be used as well as etoposide and bleomycin with high-dose cisplatin.
Malignant melanoma is curable with surgical resection when it presents locally (see also Chapter 61). However, once metastasis has occurred, it is one of the most difficult cancers to treat because of drug resistance. While dacarbazine, temozolomide, and cisplatin are the most active cytotoxic agents for this disease, the overall response rates to these agents remain low. Biologic agents, including IFN-α and interleukin 2 (IL-2), have greater activity than traditional cytotoxic agents, and treatment with high-dose IL-2 has led to cures, albeit in a relatively small subset of patients. Ipilimumab binds to cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4), which is expressed on the surface of activated CD4 and CD8 T-cells. CTLA-4 normally acts as a brake on T-cell antitumor activity. Binding of ipilimumab results in inhibition of the interaction between CTLA-4 and its target ligands CD80/CD86 and thus enhances T-cell immune responses, which include T-cell activation and proliferation. This agent is approved for the treatment of metastatic melanoma. More recently, ipilimumab is recommended as adjuvant therapy for cutaneous melanoma following complete surgical resection, with treatment for up to 3 years.
Nivolumab and pembrolizumab are IgG4 antibodies that bind to the programmed death (PD)-1 receptor, which is expressed on T cells, and they inhibit the interaction between the programmed death ligand 1 (PD-L1) and ligand 2 (PD-L2) and the PD-1 receptor. The PD-1 signaling pathway mediates an immune escape mechanism, and inhibition of this pathway enhances T-cell immune response, leading to T cell activation and proliferation. Each of these agents is approved for unresectable or metastatic melanoma as monotherapy. In addition, nivolumab is also approved in combination with ipilimumab for BRAF V600 mutation–positive unresectable or metastatic melanoma.
The BRAF V600E mutation has been identified in the large majority of melanomas. This mutation results in constitutive activation of BRAF kinase, which then leads to activation of downstream signaling pathways involved in cell growth and proliferation. Two oral and highly selective small molecule inhibitors of BRAF V600E are approved for metastatic melanoma: vemurafenib and dabrafenib. Studies are ongoing to determine their activity in combination with other cytotoxic and biologic agents for metastatic melanoma as well as their potential role in the adjuvant and neoadjuvant therapy of early stage melanoma.