Reviewed: Dhillon N, Aggarwal BB, Newman RA, et al. Phase II trial of curcumin in patients with advanced pancreatic cancer. Clin Cancer Res. 2008;14(14):4491–4499.
Pancreatic cancer is almost always lethal, and most patients die within 1 year of diagnosis. The only drugs approved by the Food and Drug Administration that are currently available for treatment are gemcitabine and erlotinib. Both of these drugs elicit responses in only a small percentage of patients (less than 10%), and their effect on survival is measured in weeks. Thus, effective treatments are urgently needed. Many studies have shown that nuclear transcription factor-κB (NF-κB) is activated in patients with pancreatic cancer; therefore, an agent that targets NF-κB may prove effective in the treatment of this disease.
Previous laboratory research has shown that curcuminoids, a group of compounds derived from the traditional herb and spice turmeric (Curcuma longa, Zingiberaceae), suppress NF-κB activation, cell growth associated with apoptosis (programmed cell death), and the growth of human pancreatic cancer xenografts in mice. These curcumoinds are curcumin, desmethoxycurcumin, and bisdesmethoxycurcumin. Phase I human clinical trials of curcuminoids have shown that they are safe at doses up to 8 g/day but that their oral bioavailability may be poor. Thus, this phase II clinical trial was undertaken to determine whether orally administered curcuminoids have biological activity in patients with advanced pancreatic cancer.
Twenty-five patients (13 men, 12 women; aged 43-77) with histologically confirmed pancreatic cancer and a Karnofsky performance score greater than 60 were enrolled in this nonrandomized, open-label, phase II trial, which was conducted at the University of Texas
M.D. Anderson Cancer Center in Houston, Texas. As controls, cytokine levels were measured in 48–62 healthy volunteers depending on the cytokine assessed. The patients ingested a daily dose of 8 g of curcuminoids in capsule form (1 capsule = 1 g curcuminoids [900 mg curcumin, 80 mg desmethoxycurcumin, and 20 mg bisdesmethoxycurcumin]; Sabinsa Corp., Piscataway, NJ). Concomitant chemotherapy or radiotherapy was prohibited, but supportive care was allowed. Disease staging, a physical examination, and blood sampling were performed at baseline and at 4 and 8 weeks. Blood samples were used to measure the following values: cytokine concentrations (interleukin-6, -8, -10, and interleukin-1 receptor antagonist), carcinoembryonic antigen concentrations, and peripheral blood mononuclear cell expression of NF-κB and cyclooxygenase-2 (COX-2). The adverse events were assessed on the basis of the National Cancer Institute Expanded Common Toxicity Criteria (http://ctep.cancer.gov/forms/CTCAEv3.pdf), and tumor response was evaluated on the basis of the Response Evaluation Criteria in Solid Tumors.
Twenty-four patients were available for the toxicity evaluation, and 21 patients were available for evaluation of the response to treatment with curcuminoids. Circulating concentrations of curcumin in blood serum were low, which indicated poor oral bioavailability. However, 2 patients exhibited a favorable response to curcuminoids. Pancreatic cancer remained stable in 1 of these patients for greater than 18 months. "Marked" tumor regression (73%) and significant (P < 0.05) increases in serum interleukin-6, -8, and -10 and in interleukin-1 receptor agonist were observed in the other patient.
NF-κB activation decreased with curcuminoids treatment, but not significantly compared with the healthy controls. COX-2 expression decreased significantly (P < 0.03) with curcumin treatment. Blood concentrations of curcumin peaked at 22–41 ng/mL and remained relatively constant over the first 4 weeks of the study. Carcinoembryonic antigen concentrations decreased gradually over 1 year in 1 patient, which indicated an improvement in cancer status. No treatment-related toxicity was observed.
The results of this study indicate that orally administered curcuminoids are tolerated well at doses of 8 g/day for up to 18 months and have “biological activity in some patients with pancreatic cancer.” Although curcumin was poorly absorbed, biological activity (i.e., tumor regression and increase in cytokine concentrations) was evident at steady-state. Because curcumin is hydrophobic (i.e., not water soluble), it cannot be administered intravenously unless encapsulated in a liposome, which would presumably result in higher circulating concentrations of curcumin in the blood. The authors intend to conduct clinical trials in pancreatic cancer patients with the use of liposomal curcuminoids, which they hope will result in more consistent blood concentrations of curcumin and a better pharmacologic effect.
—Brenda Milot, ELS