Special ReviewImmune-mediated Disease in Ipilimumab Immunotherapy of Melanoma with FDG PET-CT
Introduction
It is estimated by the American Cancer Society that melanoma of the skin will affect 76,100 patients in the United States in 2014 and will cause approximately 9710 deaths. In the male population of the United States, melanoma will be the fifth leading newly diagnosed type of cancer after prostate, lung and bronchus, colon and rectum, and urinary bladder. The lifetime risk of developing melanoma of the skin for men is estimated to be 1 in 34 (American Cancer Society).
Metastatic melanoma is commonly treated with systemic chemotherapeutic agents including, but not limited to, interferon alpha (IFNα), pegylated IFN, vemurafenib, High dose interleukin-2 (HD-IL2), dacarbazine, temozolomide, platinum compounds, and taxanes. A meta-analysis conducted in 2010 by Tarhini and Thalanayar on IFNα treatment showed 18% and 11% risk reduction for recurrence and death, respectively (1). However, there are many side effects of IFNα, including fatigue, fever, weight loss, thyroid dysfunction, reversible hepatic dysfunction, myelosuppression, and depression (2). High-dose IL-2 has been used in a subset of patients with Eastern Cooperative Oncology Group (ECOG) of 0 and excellent organ function, with progression-free survival of 8.9 months and median survival of 12 months for responders. However, the side effects can be severe and can include hypotension, arrhythmia, fever, chills, metabolic acidosis, neurotoxicity, nausea, dyspnea, oliguria, and rash (2). As a result, overall survival in patients receiving IL-2 has not been evaluated in randomized phase III trials (3).
Recently approved immunomodulating agents by the Food and Drug Administration for the treatment of metastatic melanoma, such as ipilimumab, are promising as monotherapy or in combination with other agents, for a subgroup of patients with advanced melanoma with 3-year overall survival rates in the range of 20%–26% (4), with some patients surviving up to 10 years. This is especially important in light of the fact that the 5-year survival of advanced melanoma is 5%–10% (5). It has also been shown that ipilimumab is effective in patients who progressed on HD-IL2 (6). Ipilimumab is usually dosed at 3 mg/kg intravenous (IV) more than 90 minutes on day 1 followed by three more doses of 3 mg/kg IV every 3 weeks (3 mg/kg IV every 3 weeks for a total of four doses) (7).
The mechanism of action of ipilimumab is binding to the CTLA-4 receptor on T cells, which causes the regulation of the host's natural T cell-mediated response (8). Immune-mediated effects include hepatitis, dermatitis, neuropathies, endocrinopathies, and other manifestations (9). The most common, low-grade, but potentially life-threatening immune-related adverse events (irAEs) following ipilimumab therapy are dermatologic, gastrointestinal, ocular, neurologic, hepatic, autoimmune, and hematologic in nature (10). A recent publication that reviewed the use of ipilimumab in 110 patients found that colitis was the most common treatment-related toxicity (11). Endocrinopathies (12), colon perforation (13), and colitis (14) have also been reported by other authors.
The time to onset of these irAEs varies. Some occurred during induction therapy (dermatologic, gastrointestinal, hepatic, endocrine), whereas others manifested weeks to months after completion of therapy, depending on the affected organ (10). Guidelines have been established to manage the irAEs (10). The most common treatments are hormone replacement for endocrine irAEs, and corticosteroids for most other irAEs. Early identification and prompt treatment of these mostly manageable and reversible side effects help with resolution of symptoms in a timely fashion.
The aim of this retrospective study is to review findings of immune-mediated side effects in the patients who underwent ipilimumab therapy and had an F-18 FDG positron emission tomography-computed tomography (PET-CT), to facilitate use of F-18 FDG PET-CT for monitoring immunotherapy of malignant melanoma by improving recognition and differential diagnosis of immune-mediated side effects for accurate interpretation of the results of F-18 FDG PET-CT.
Section snippets
Materials and Methods
18F FDG PET-CT whole-body scan was performed in a method as described previously 15, 16. Briefly, the patients fasted for at least 4 hours and were subjected to F-18 FDG PET-CT at approximately 60–90 minutes after intravenous injection of F-18 FDG (370–740 MBq), using a Siemens Biograph PET-CT scanner (Knoxville, TN). During the PET and CT image acquisitions, patients were instructed to breathe at a shallow inspiration. PET data are acquired in three-dimensional mode using 3-minute bed
Results
Four patients with variable findings of immune-mediated side effects on F-18 FDG PET-CT, following treatment of malignant melanoma with ipilimumab, were identified in this retrospective study (Table 1).
Discussion
The restaging and management of patients with metastatic melanoma can be well done with FDG PET-CT (19). FDG18 PET-CT has recently been adopted to evaluate response to treatment and for restaging following therapy, and it shows promise 20, 21. Sachpekidis et al. recently reported that following two cycles of ipilimumab treatment, FDG PET-CT was highly predictive of treatment outcome in a retrospective evaluation of 22 patients who had unresectable metastatic melanoma (20).
Various
Acknowledgment
This study was supported by the University of Texas Southwestern Medical Center at Dallas, Texas, USA.
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This study is not being simultaneously submitted to any other medical journal.
This study is original and does not duplicate similar studies published or being considered for publication by other scientific journals.
All of the authors played a role in the conception, development, planning, execution, analysis or interpretation of the research, and writing of the study. We collectively agree and accept responsibility for the contents of the study submitted.