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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
This review was undertaken to better evaluate the potential efficacy and toxicity associated with high-dose IL-2 therapy in the contemporary era. A retrospectively and prospectively collected database, Proleukin® Observational Registry to Evaluate the Treatment Patterns and Clinical Response in Malignancy (PROCLAIMSM), was established in 2011.21 This is the largest IL-2 database and contains demographic, clinical and outcome data on patients with MM receiving IL-2 at 35 different academic and community medical centers. The database was accessed to determine treatment outcomes and adverse event profiles in MM patients with BM treated with high-dose IL-2.
 

Methods


Patient Population

Data were collected from the observational database PROCLAIM. To be included in the prospective cohort of the registry, patients must sign informed consent forms, have been at least 18 years of age, and have received an initial course (2 cycles) of IL-2. Patients who received more than 1 course of IL-2 and/or already undergone a post-treatment scan were not eligible for enrollment, in order to control for bias arising from results of the scan. For patients reporting BM, the sites were queried for the date of BM diagnosis and all treatments for BM. Baseline characteristics on gender, age, tumor staging, ECOG performance status, melanoma subtype, mutation testing, as well as pre-treatment LDH were gathered. The number of BM per patient and the use of steroids were not captured in the database. All sites were required to have approval by their respective institutional review boards (IRBs) prior to subject enrollment.

Treatment and Assessments

All patients were treated with IL-2 as clinically indicated; patients were administered a dose of 600,000 to 720,000 IU/kg IV bolus every 8 hours on days 1 to 5 (Cycle 1) and days 15 to 19 (Cycle 2) with a maximum of 28 doses per two-cycle course.22 The total number of cycles and IL-2 doses received by each patient was recorded. Tumor response to IL-2 was captured by imaging of the extracranial and intracranial compartments 4 to 6 weeks after completing 1 course of IL-2. Assessment of tumor response was determined by the treating investigator using either RECIST or WHO criteria per the site’s standard procedure.

The reason for cycle conclusion was recorded; potential reasons included completion of planned doses, toxicity, patient preference, death, etc. If toxicity was given as the reason for cycle conclusion, the site could list up to 3 different systems (ie, cardiac, neurologic, renal, etc.) and the specific toxicity within each system was noted. For example, a neurologic toxicity could be further categorized as agitation, confusion, psychosis, and not otherwise specified. Overall survival data were measured from the start of IL-2 treatment to either the patient’s date of death or date of follow up. Cause of death was recorded.

Statistical Analysis

Analysis was performed from data that were locked on September 24, 2015. Descriptive statistics were provided for baseline characteristics. Follow up time was measured from the IL-2 start date to either the date of death or date of last follow-up. The method of Kaplan and Meier was used to obtain survival curves, mOS, and survival rates with corresponding 95% confidence intervals and was compared using the log-rank test. Tests for association for categorical variables used the Chi square test and given the small sample size the Fisher exact test was utilized when necessary. The two-sample t-test was utilized when testing for an association between the group’s means for continuous variables. Throughout the analysis p-values of <0.05 were considered statistically significant. All statistical computations were performed using SAS 9.4.
 

Results


Patient Population

Of the patients from the prospective cohort diagnosed with metastatic melanoma (N=320), the patients with BM at baseline (n=38) were identified versus patients without BM at baseline (n=282). TABLE 1 provides descriptive statistics for patient demographics. Of the 320 patients identified, 123 (38.4%) were female and the rest were male. The median age was 53 (range, 21-84) and 271 (84.7%) were less than 65 years of age with 49 (15.3%) being over the age of 65 years. The ECOG performance status was 0 in 221 (69.1%), 1 in 90 (28.1%), and 2 in 3 (1%) of the patients. There were no differences in the age, sex or ECOG performance status of patients in the BM cohort compared to the non-BM cohort. While definition of BM places all patients as Stage IV M1c, the non-BM group also had a large number of stage IV M1c patients (120; 37.5%). The majority of patients in both cohorts were reported to have elevated LDH levels prior to starting IL-2 (82.8% for BM group and 67.8% for non-BM group; P = .39).

The average interval from initial diagnosis to diagnosis of BM was 34.9 months (min: 0.03, max: 176). Of the 37 patients with complete data available, there were 7 (18.9%) that were diagnosed with BM during the first year of initial cancer diagnosis. Two of those 7 patients were diagnosed with metastatic disease at the time of their initial presentation. The average interval from diagnosis of BM to start of HD-IL2 therapy was 3.1 months (min: 0.39, max: 13.5). Nine (24.3%) of these patients started HD-IL2 within a month or less from being diagnosed with BM.

Of the 38 BM patients all but 3 patients (7.89%) received local treatment for BM prior to starting HD-IL2. There was 1 patient who had not received any prior oncological treatments prior to starting HD-IL2. Of the 35 BM patients who had received prior treatment for brain metastases, 32 received some form of radiation therapy—27 had stereotactic radiosurgery and 6 patients received whole brain radiotherapy (WBRT). Five patients had undergone surgical resection for BM.




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