Management of toxicities associated with high-dose interleukin-2 and biochemotherapy.

High-dose interleukin-2, administered as a single agent or in combination with antineoplastic agents, known as biochemotherapy, holds the promise of durable remissions for patients with metastatic renal cell carcinoma and metastatic melanoma. The toxicities arising from high-dose interleukin-2-based therapies affect every organ system, causing significant acute morbidity. Administration of high-dose interleukin-2-based therapies requires specialized care and knowledge because of the severity and uniqueness of toxicities compared with the toxicities encountered with other forms of anticancer therapy. However, the toxicities of high-dose interleukin-2-based therapies are predictable and manageable by vigilant monitoring and appropriate supportive care protocols. To maximize outcomes, both acute and delayed toxicities require vigilant monitoring and adroit symptom management. This review details the pathophysiology, monitoring parameters, and management strategies for patients receiving high-dose interleukin-2-based therapy, with a focus on new and important management principles.

Retrospective analysis of the safety and efficacy of high-dose interleukin-2 after prior tyrosine kinase inhibitor therapy in patients with advanced renal cell carcinoma.

Although tyrosine kinase inhibitors (TKI) are the most common first-line therapy for metastatic renal cell carcinoma, high-dose interleukin-2 (HD-IL2) remains the only agent that provides durable complete responses. The optimal sequence of these agents remains uncertain. This retrospective multi-institutional study examined the safety and efficacy of HD-IL2 following TKI therapy. After IRB approval at 7 HD-IL2 centers, data relating to patient, disease, and treatment characteristics among 40 consecutive patients with metastatic renal cell carcinoma who were treated with HD-IL2 after at least 1 prior TKI therapy were retrospectively collected. The most common cardiac adverse events were grade 3 hypotension and vascular leak syndrome. Six patients (15%) experienced other grade ≥3 cardiac adverse events. There were 2 treatment-related deaths due to congestive heart failure, occurring in 1 patient with short TKI to HD-IL2 interval and another patient with an abnormal baseline cardiac stress test. Best responses included 2 CRs (5%, duration 40+ and 62+ mo), 3 PRs (8%, duration 6, 11, and 24 mo), 13 SD (32%, median duration 12 mo), 20 PD (50%), and 2 not evaluable patients. Median overall survival was 22 months. Administration of HD-IL2 could be safe and effective after TKI therapy; however, careful selection of patients is critical. We recommend baseline cardiac risk factor assessment, screening with both cardiac stress test and echocardiogram, and allowing a TKI to HD-IL2 interval of at least 2 months.

A neoadjuvant biochemotherapy approach to stage III melanoma: analysis of surgical outcomes.

AIMS: Completion lymph node dissection (CLND) and adjuvant therapy are recommended for node-positive melanoma patients. We sought to analyze our institution's experience with neoadjuvant biochemotherapy in stage III patients. METHODS: Clinical information was extracted from a retrospective database on stage III melanoma patients. Eligible patients received two cycles of biochemotherapy prior to their CLND. RESULTS: There were 153 patients available for analysis. The average tumor depth was 2.5 mm. More than half of all patients presented with sentinel lymph node-positive disease. Surgical complications occurred in 23% of patients. Patients who experienced an adverse event during their neoadjuvant therapy had a worse overall survival when compared with those who did not (p = 0.005). CONCLUSION: Our data suggest that aggressive neoadjuvant treatment prior to CLND does not impact surgical complications. Our surgical outcomes are similar to the current literature when adjuvant therapy is used in stage III melanoma. The inability to tolerate neoadjuvant therapy in stage III melanoma is a negative prognostic indicator.

Targeting metastatic melanoma.

PURPOSE: New medications and combination treatment strategies for patients with metastatic melanoma are discussed. SUMMARY: Bcl-2 is an inhibitor of apoptosis that is overexpressed in approximately 80% of melanoma cell lines and is believed to contribute to the development of resistance to cytotoxic chemotherapy in patients with melanoma. Oblimersen, an antisense oligonucleotide that stops the translation of Bcl-2 mRNA to protein, significantly improved progression-free survival when administered in combination with dacarbazine. Overall survival was significantly improved in patients with low levels of serum lactate dehydrogenase (LDH), but not in patients with elevated LDH. RAF proteins are a family of serine/threonine kinases that regulate many aspects of cellular function. RAF mutations occur in 70% of melanoma cell lines. Although RAF kinases are thought to be important in the pathogenesis of melanoma, RAF inhibition with sorafenib has not significantly improved survival in patients with advanced disease. Cytotoxic T-lymphocyte antigen 4 (CTLA-4) is a naturally occurring inhibitor of T-cell function that prevents the complete activation of T cells upon exposure to antigens by antigen-presenting cells. Two monoclonal antibodies to CTLA-4 (tremelimumab and ipilimumab) have been developed to promote T-cell activation in melanoma and other types of cancer. Phase I and phase II clinical trials of these agents in patients with metastatic melanoma have demonstrated promising effects on tumor progression, with objective response rates of approximately 20% and sustained responses in some patients. Several vaccines have been developed to stimulate immune system responses against melanoma. Despite promising early findings with polyvalent melanoma vaccine and with vaccine containing heat shock proteins, results with these agents in larger clinical trials have been disappointing. CONCLUSION: Ongoing clinical trials continue to evaluate these and other novel approaches to the treatment of metastatic melanoma.