Abstract and Introduction
Abstract
Patients with advanced melanoma have few treatment options, and survival is poor. However, improved understanding of how the immune system interacts with cancer has led to the development of novel therapies. Ipilimumab is a monoclonal antibody that inhibits cytotoxic T-lymphocyte antigen–4 (CTLA-4), a key negative regulator of host T-cell responses. This article presents cases of patients receiving ipilimumab in clinical trials along with a discussion of their significance and relevance to nursing practice. The patients showed different response patterns to ipilimumab and also had various typical immune-related adverse events (irAEs), which were managed successfully. The atypical response patterns produced by ipilimumab likely reflect its mechanism of action, which requires time for the immune system to mount an effective antitumor response. Meanwhile, lesions may appear to enlarge as a consequence of enhanced T-cell infiltration, although this may not necessarily be true disease progression. Patients receiving ipilimumab may respond very differently compared to how they might react to chemotherapy. Responses can take weeks or months to develop; therefore, clinicians should not terminate treatment prematurely, providing the patient's condition allows for continuation. Early recognition of irAEs combined with prompt management will ensure that events are more likely to resolve without serious consequences.
Introduction
Prompt diagnosis and surgery are effective for early-stage melanoma, with almost 100% of patients with resected localized stage I or II tumors surviving to five years after diagnosis (Horner et al., 2009); however, melanoma continues to be an ongoing challenge in its advanced stages. Only 15% of patients with metastases will still be alive five years after diagnosis (Horner et al., 2009), and survival rarely exceeds 12 months (Eggermont, 2006). Since dacarbazine (also known as DTIC) was first introduced in the 1970s, survival has remained fundamentally unchanged in patients with advanced melanoma (Serrone, Zeuli, Sega, & Cognetti, 2000), underscoring an urgent need for new treatment strategies.
The arrival of cytokine- and vaccine-based immunotherapies in the early 1990s was promising, but those therapies have delivered little to date. Interferon-a (approved as adjuvant monotherapy or in various combination regimens) and interleukin-2 (IL-2) (approved as monotherapy) have produced only modest survival benefits offset by limited utility because of toxicity, and vaccines have been largely ineffective (Hauschild, 2009; Hauschild et al., 2008; Riley & Agarwala, 2008; Schadendorf et al., 2009). DTIC and IL-2 remain the reference therapies, and innovation has stayed within the confines of clinical trials (National Comprehensive Cancer Network, 2010).
High doses of IL-2 produce durable responses in about 5%–15% of patients with melanoma; therefore, targeting the patients' immune systems instead of their cancer has remained at the forefront of new developments (Atkins et al., 1999). Tumors often are highly antigenic and, therefore, can be recognized as foreign by the immune system. However, IL-2's ability to elicit an immune response declines over time as the cancer progresses (Swann & Smyth, 2007). Essentially, tumors learn how to escape from immune control (Drake, Jaffee, & Pardoll, 2006). This happens through a series of tumor-driven effects that begin at the tumor site but extend regionally in time, resulting in a complex and as yet incompletely understood interplay between the tumor itself and the host immune system, collectively called immunoediting (Dougan & Dranoff, 2009; Dunn, Old, & Schreiber, 2004; Kim, Emi, Tanabe, & Arihirok, 2006). The patient's immune system eventually can no longer mount an effective response against the tumor, and the cancer progresses. Treatment strategies that help the patient's immune system to mount a more effective antitumor response are being pursued, with much work involving patients with advanced melanoma.