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Efficacy and Safety of High-Dose Interleukin-2 Treatment in Melanoma Patients with a History of Brain Metastases

Ashwin Chandar, MD, Ann W. Silk, MD, Joseph I. Clark, MD, Gregory A. Daniels, MD, PhD, David F. McDermott, MD, Michael A. Morse, MD, Michael K. K. Wong, MD, PhD, Mark Stein, MD, Janice M. Mehnert, MD,
Published Online: Jul 11,2016

Abstract


Purpose: High dose interleukin-2 (IL-2) therapy results in infrequent but durable responses in metastatic melanoma (MM); however, its use in patients with brain metastases (BM) has been controversial due to safety concerns and limited data on efficacy in this population. The purpose of this retrospective study is to evaluate tumor response rates and toxicity profiles of IL-2 therapy in a more contemporary cohort of patients with MM and a history of BM.

Patients and Methods: A total of 320 patients who received IL-2 therapy with stage III or IV MM were included in a prospectively collected database. At the time of study entry, 38 patients had a history of BM, of whom 35 had received previous treatment for BM, which was mostly radiation therapy. A post-hoc analysis of overall survival using Kaplan-Meier (KM) curves, as well as tumor response rates, number of cycles of therapy completed, and toxicity profile by cycle and organ system was conducted. The 282 patients in the database without BM served as a control population.

Results: The average interval from diagnosis of BM to start of HD-IL2 therapy was 3.1 months (range: 0.39 to 13.5). Median follow up (mFU) was 22.0 months. The median overall survival (mOS) in MM patients with BM (n=38) was 12.2 months, versus 19.4 months in those patients without BM (n=282) (p = 0.23). Of the 38 patients with BM, 34 (89.5%) were evaluable for response to HD-IL2. The response rate was 11.8%, as compared to a response rate of 14.0% in subjects without BM. One patient (2.9%) achieved complete response (CR), 3 patients (8.8%) achieved partial response (PR), and 8 patients (23.5%) had stable disease (SD). IL-2 treatment cycle was concluded due to toxicity in the majority of patients in both cohorts and the most commonly affected systems were cardiac, renal, neurological, and gastrointestinal. Treatment-limiting neurologic toxicity was observed in 12.1% of patients with a history of BM and 13.2 % of patients without BM during Cycle 1.

Conclusion: This is the largest analysis reported to date of IL-2 treatment in patients with a history of BM. IL-2 was well tolerated in this cohort and the rate of neurologic complications was similar to the control group. The response rate and median survival are comparable to those observed for patients without a history of BM. IL-2 is safe and has therapeutic activity in melanoma patients with a history of treated BM.
 

Introduction


Melanoma is increasing in incidence with approximately 10,000 deaths annually in the United States. Considerable morbidity and mortality from melanoma is related to the potential for disease to metastasize to all locations in the body. Metastasis to the central nervous system (CNS) is especially problematic as it may be associated with significant clinical symptoms and early disease-related mortality. Nearly 40% of patients with stage IV melanoma develop brain metastases (BM), but this may underestimate the prevalence, as 55% to 75% of patients who died from melanoma were shown to have BM on autopsy.1-6 Despite modern treatments, such as stereotactic radiosurgery, median overall survival (OS) in MM patients with cerebral metastases is approximately 6 to 9 months.1,7 Karnofsky Performance Score as well as the number of BM are key prognostic factors in MM, and can be used to stratify patients into groups with a mOS range of 3.4 months to 13.2 months with the Graded Prognostic Assessment (GPA) scoring system.8 Abnormal LDH has also been shown to be a poor prognostic marker in MM patients with BM.9

The mainstay of therapy for melanoma BM has been a localized approach consisting largely of stereotactic radiation and craniotomy with tumor extirpation, when possible. Most systemic chemotherapy, such as dacarbazine, does not cross the blood-brain barrier. Some patients were treated with temozolomide, an alkylating agent that enters the CNS but was not associated with improved survival in patients with MM.10 Newer therapies, such as ipilimumab, have shown activity in MM patients with BM, and this is thought to be due to, at least in part, peripheral activation of T cells, which are able to enter and exert an anti-tumor effect in the CNS.11,12 Additionally, BRAF inhibitors such as vemurafenib and dabrafenib have shown activity against BM, with dabrafenib demonstrating an intracranial response rate of 39%.13 These new agents have brought forth a multi-disciplinary approach to the treatment of melanoma BM involving medical oncology, radiation oncology, and neurosurgery.

High dose interleukin-2 (IL-2) is consistently associated with a response rate of 17% to 20% and a median progression-free survival (PFS) of 13 months in those who responded to therapy.8,14-17 The use of IL-2 has often been restricted to patients without brain metastases due to concerns that it would lead to greater toxicity due to cerebral edema from capillary leak syndrome and reduced efficacy due to immunologic privilege of the CNS.18

In contrast to these concerns, several small studies have shown favorable outcomes with IL-2 treatment of patients with BM from metastatic melanoma.1,9,15,19 These studies suggested a similar toxicity profile in those with and without BM. In one study, 7 patients with stage IV disease were shown to have BM, and 1 showed a partial response after surgical resection of a solitary brain lesion. Out of a total of 8 patients, 1 was noted to have neurological toxicity, which was thought to be secondary to alcohol withdrawal rather than IL-2 treatment.15 Another study demonstrated that 2 patients with BM had some intracranial tumor response; 1 showed a mixed response and 1 showed a complete response; this patient had whole brain radiation and polyvalent vaccination prior to IL-2. There was 1 reported neurological adverse event out of 15 patients, which was characterized as confusion.19 A phase III trial of high-dose IL-2 treatment showed an increase in toxicity and response rate compared to low-dose IL-2 when patients were stratified for bone and liver metastases, but not BM.20


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Efficacy and Safety of High-Dose Interleukin-2 Treatment in Melanoma Patients with a History of Brain Metastases
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