B. Culliney

l-Carnitine Supplementation for the Treatment of Fatigue and Depressed Mood in Cancer Patients with Carnitine Deficiency: A Preliminary Analysis

Abstract: Nutritional factors are among the postulated causes of fatigue, a highly prevalent symptom in the cancer population, with serious impact on patients’ quality of life. Deficiency of the micronutrient carnitine may play a role by reducing energy production through fatty acid oxidation. We present preliminary data of an open‐label, dose‐finding study to determine safety and maximally tolerated dose (MTD) of 1 week of l‐carnitine supplementation in cancer patients with fatigue and carnitine deficiency. Patients who met inclusion/exclusion criteria underwent carnitine level determination. Eighty‐three percent of these patients (15/18) had carnitine deficiency. Preliminary data analysis of 13 patients showed that total carnitine increased from 30.0 ± 6.9 to 41.0 ± 12.1 (mean ± SD) after 1 week of supplementation (P= 0.01), and free carnitine increased from 24.3 ± 6.1 to 33.8 ± 9.8 (P= 0.004). Outcome measures were fatigue (BFI score), depression (CES‐D), sleep disruption (ESS), and performance status (Karnofsky). Median (min, max) BFI score at baseline was 73 (46, 82) versus 50 (3, 82) after 1‐week supplementation (P= 0.009). CES‐D score at baseline was 29 (16, 42) and 22 (8, 32) after 1 week (P= 0.028). ESS at baseline was 46.5 (0, 69) and 30.4 (0, 72) after 1 week (P= 0.015). Karnofsky score did not change significantly (P= 0.38). We are currently conducting a randomized, double‐blind, placebo‐controlled study to rigorously assess the role of l‐carnitine for the treatment of fatigue and depression in cancer patients.

L-carnitine supplementation in patients with advanced cancer and carnitine deficiency: a double-blind, placebo-controlled study.

Carnitine deficiency is prevalent in populations with chronic illness, including cancer. In a recent open-label study, L-carnitine supplementation was well tolerated and appeared to improve fatigue and other outcomes in cancer patients. To further evaluate this finding, adult patients with advanced cancer, carnitine deficiency (free carnitine more than 35 micromol/L for males or less than 25 micromol/L for females, or acyl/free carnitine ratio of more than 0.4), moderate to severe fatigue, and a Karnofsky Performance Status (KPS) score of 50 or more, were randomly assigned to receive either L-carnitine (0.5 g/day for two days, followed by 1g/day for two days, and then 2g/day for 10 days) or placebo. This double-blind phase was followed by an open-label phase, during which all patients received L-carnitine supplementation for two weeks. Outcomes included the fatigue subscale of the Functional Assessment of Cancer Therapy-Anemia (FACT-An), the Linear Analog Scale Assessments (LASA), the Mini-Mental State Exam (MMSE), and the KPS. Twenty-nine patients (12 placebo, 17 L-carnitine) were included in the intent-to-treat (ITT) analysis. From baseline to the end of the double-blind phase, serum total and free L-carnitine increased from 32.9+/-3.8 to 56.6+/-20.5 (P=0.004), and from 22.9+/-19.4 to 45.3+/-17.2 (P=0.004), respectively, in the L-carnitine-treated group, and from 28.2+/-10.2 to 36.2+/-8.7 (P=ns), and from 22.6+/-7.9 to 28.7+/-8.6 (P=ns) in the placebo group, respectively. The planned ITT analysis revealed no significant improvement in any of the studys endpoints, and these negative findings were not different when data from two patients who did not adhere to the protocol were eliminated. However, an exploratory covariate analysis that excluded these two protocol violators and included outcome data from both the double-blind and open-label phases demonstrated significantly improved fatigue on the FACT-An fatigue subscale (P<0.03), and significantly improved FACT-An functional well-being subscale (P<0.03), and KPS (P<0.003), in the group that started with L-carnitine during the double-blind phase. These data do not support the conclusion that L-carnitine in the doses tested reverses cancer-related fatigue in carnitine-deficient patients. However, L-carnitine supplementation does increase L-carnitine serum levels, and the positive findings in an exploratory analysis justify a larger study to determine if this strategy could be of benefit for a subpopulation of cancer patients.

Phase II trial of the histone deacetylase inhibitor romidepsin in patients with recurrent/metastatic head and neck cancer.

OBJECTIVES Patients with advanced squamous cell carcinoma of the head and neck (SCCHN) have limited treatment options. Inhibition of histone deacetylases (HDACs) represents a novel therapeutic approach warranting additional investigation in solid tumors. METHODS A phase II trial of single agent romidepsin, an HDAC inhibitor, was performed in 14 patients with SCCHN who provided consent for pre- and post-therapy samples of accessible tumor, blood and uninvolved oral mucosa. Romidepsin was administered at 13 mg/m(2) as a 4-h intravenous infusion on days 1, 8 and 15 of 28 day cycles, with response assessment by RECIST every 8 weeks. RESULTS Objective responses were not observed, although 2 heavily pretreated patients had brief clinical disease stabilization. Observed toxicities were expected, including frequent severe fatigue. Immunohistochemical analysis of 7 pre- and post-treatment tumor pairs demonstrated induction of p21(Waf1/Cip1) characteristic of HDAC inhibition, as well as decreased Ki67 staining. Exploratory microarray analyses of mucosal and tumor samples detected changes in gene expression following romidepsin treatment that were most commonly associated with regulation of transcription, cell cycle control, signal transduction, and electron transport. Treatment with romidepsin did not alter the extent of DNA methylation of candidate gene loci (including CDH1 and hMLH1) in SCCHN tumors. CONCLUSIONS Single agent romidepsin has limited activity for the treatment of SCCHN but can effectively achieve tumor-associated HDAC inhibition. Although tolerability of romidepsin in this setting may be limiting, further evaluation of other HDAC inhibitors in combination with active therapies may be justified.