Metastatic melanoma

Dacarbazine is the most active compound used for treating metastatic melanoma. It is also combined with anthracyclines and other cytostatics in the treatment of different sarcomas and Hodgkin s disease. Dacarbazine may cause severe nausea and vomiting. Myelosuppres-sion results in leukopenia and thrombocytopenia. Alopecia and transient abnormalities in renal and hepatic function also occur. 

Metastatic renal cell carcinoma has a poor prognosis and resists conventional chemotherapy. Immunotherapy with IL-2 and/or IFN-a is currently regarded as the most effective therapy with, however, modest response rates of 15-20%. Similar results are also observed in patients with metastatic melanoma and the response to IFN-a and IL-2 correlates with the occurrence of tumor-infiltrating CD4+ T-lymphocytes identified in aspirates from melanoma metastases. Determination of these cells therefore seems to be a method to predict responders prior to the initiation of cytokine therapy. 

Interleukin 2 therapy is approved by the Food and Drug Administration (FDA) for the treatment of metastatic melanoma, and it is a reasonable option for patients with this stage of the disease. 

Agarwala SS, Kirkwood JM. Temozolomide, a novel alkylating agent with activity in the central nervous system, may improve the treatment of advanced metastatic melanoma. Oncologist 2000 5 144-151. 

Atkins MB, Kunkel L, Sznol M, Rosenberg SA. High-dose recombinant interleukin 2 therapy in patients with metastatic melanoma Long-term survival update. Cancer J Sci Am. 2000 6(suppl 1) SI 1-14. 

Proleukin Aldesleukin (interleukin 2) Chiron Renal cell carcinoma, metastatic melanoma... 

In phase I clinical trials 47 patients, all of whom had previously failed standard treatments for solid tumors, received the drug in the UK, Italy, and Switzerland on three different schedules.123,124 Dose-limiting toxicities have been defined as bone marrow depression and diarrhea. The latter is treatable with loperamide. Signs of biological activity were seen. Notably one patient with metastatic pancreatic cancer showed a partial response (for 4 months) and two further patients, one with metastatic melanoma and one with bronchoalveolar carcinoma, also showed partial responses. In a phase I trial in combination with 5-FU, a partial response in breast cancer was observed.125 Furthermore, a reduction in tumor marker levels was observed in two patients, one with ovarian cancer, and one with colon cancer. Phase II studies have shown partial responses in cisplatin-resistant ovarian and nonsmall-cell lung cancer.126,127 The indications are that the profile of clinical activity is different and complementary to the mononuclear platinum agents. 

Bedikian AY, Richards J, Kharkevitch D, Atkins MB, Whitman E, Gonzalez R (2010) A phase 2 study of high-dose allovectin-7 in patients with advanced metastatic melanoma. Melanoma Res 20 218-226... 

Bergen M, Chen R, Gonzalez R (2003) Efficacy and safety of HLA-B7/beta-2 microglobulin plasmid DNA/lipid complex (Allovectin-7) in patients with metastatic melanoma. Expert Opin Biol Ther 3 377-384... 

Frytak, S., Creagan, E.T., Brown, M.L., Salk, D., and Nelp, W. (1993) A technetium labeled monoclonal antibody for imaging metastatic melanoma. Am. J. Clin. Oncol. 14,156-161. 

Noble, S. and Goa, K. 1997. Aldesleukin (recombinant interleukin-2) a review of its pharmacological properties, clinical efficacy and tolerability in patients with metastatic melanoma. Biodrugs 7(5), 394 4-22. 

Attia, P. et al., Autoimmunity correlates with tumor regression in patients with metastatic melanoma treated with anti-cytotoxic T-lymphocyte antigen-4, J. Clin. Oncol., 23 6043, 2005. 

H10. Hoyhtya, M., Hujanen, E., and T irpeenniemi-Hajanen, T., Modulation of type IV col-lagenase and invasive behaviour of metastatic melanoma (A2058) cells in vitro by monoclonal antibodies to type IV collagenase. Inti. J. Cancer 46, 282-286 (1990). 

Rasmussen M.A. Colding-Jorgensen, M. Hansen, L.T. Bro, R. Multivariate evaluation of pharmacological responses in early clinical trials - A study of rIL-21 in the treatment of patients with metastatic melanoma. British Journal of Clinical Pharmacology, 2010, 69 (4), 379-390. 

IL-2 promotes the growth of B cells for antibody production and induces the release of IFN-yand TNF (see below). It has been approved by the FDA for the treatment of different types of cancer, including metastatic melanoma and metastatic renal carcinoma. Examples of IL-2 for the treatment of malignant melanoma and a protein that targets IL-2 receptor in T-cell lymphoma are given in Exhibit 4.9. 

Rosenberg SA, Yang JC, Schwartzentruber DJ, et al. Immunologic and therapeutic evaluation of a synthetic peptide vaccine for the treatment of patients with metastatic melanoma. Nat Med 1998 4(3) 321-327. 

Hauschild, A. (2006) A phase II multicenter study on the HDACi MS-275, comparing two dosage schedules in metastatic melanoma. Abs. 8044, Annual Meeting of the American Society of Clinical Oncology, Atlanta, Ga. 

Wiemik PH, Schwartz EL, Einzig A, Strauman JJ, Lipton RB, Dutcher JP. Phase I trial of taxol given as a 24-hour infusion every 21 days responses observed in metastatic melanoma. J Clin Oncol 1987 5(8) 1232-1239. 

Guan, H., Nagarkatti, P.S. and Nagarkatti, M. (2007) Blockade of hyaluronan inhibits lL-2-induced vascular leak syndrome and maintains effectiveness of IL-2 treatment for metastatic melanoma. Journal of Immunolq (Baltimore, MD, 1950), 179, 3715-3723. 

Lymphoma, breast and ovarian cancer, oat cell lung cancer Acute myelogenous and acute lymphoblastic leukemia, lymphomas Metastatic melanoma, sarcomas, Hodgkin s disease... 

Thompson, J.A., PJ. Gold, D.R. Markowitz, D.R. Byrd, C.G. Lindgren, and A. Fefer, Updated analysis of an outpatient chemo-immunotherapy regimen for treating metastatic melanoma. Cancer J Sci Am, 1997. 3(Suppl 1) S29-34. 

Legha, S.S., S. Ring, O. Eton, A. Bedikian, A.C. Buzaid, C. Plager, and N. Papadopon-los. Development of a biochemotherapy regimen with concurrent administration of cisplatin, vinblastine, dacarbazine, interferon alfa, and interleukin-2 for patients with metastatic melanoma. J Chn Oncol, 1998.16(5) 1752-9. 

F. Role in therapy According to Micromedex, Roferon-A is recommended as the drug of choice in renal carcinoma and the chronic phase of chronic myelogenous leukemia. The role of Gleevec (Ima-tinib) in CML is yet to be determined, but it may replace the use of interferon alfa-2a. Roferon-A is an alternative (for unrespon-sive/intolerant patients) to current regimens of choice in hairy-cell leukemia, multiple myeloma, metastatic melanoma, and AIDS-related Kaposi s sarcoma. Other alpha interferons appear to have similar efficacy and can be used in lieu of Roferon-A in some instances. In particular, interferon alfa-2b (Intron) can be considered to have the same role as interferon alfa-2a in chronic hepatitis C, Kaposi s sarcoma, and hairy-cell leukemia. 

G. Other applications Roferon-A has also been used in renal cell carcinoma, multiple myeloma, metastatic melanoma, and primary resected cutaneous melanoma. 

Indications Treatment of adults with metastatic renal cell carcinoma and adults with metastatic melanoma... 

B. Indications and nse Proleukin is indicated for the treatment of adults with metastatic renal cell carcinoma. Proleukin is also indicated for the treatment of adults with metastatic melanoma. Careful patient selection is mandatory prior to the administration of the cytokine. 

E. Therapeutic response In renal cell carcinoma studies, an objective response was seen in 15% of patients, with 7% complete and 8% partial responders. In metastatic melanoma studies, an objective response was seen in 16% of patients, with 6% complete and 10% partial responders. In patients with HIV infection, Proleukin increases the CD4 count, with no effect on viral load. 

H. Other considerations Proleukin has been designated an orphan drug for use in the treatment of metastatic renal cell carcinoma, metastatic melanoma, non-Hodgkin s lymphoma, and primary immunodeficiency disease associated with T-cell defects. 

---