Kanai M, Yoshimura K, Asada M, et al. A phase I/II study of gemcitabine-based chemotherapy plus curcumin for patients with gemcitabine-resistant pancreatic cancer. Cancer Chemother Pharmacol. 2010 Sep 22. [Epub ahead of print]
phase I/II safety and feasibility study of oral curcumin
The primary endpoint for the phase I study was safety of 8 grams of oral curcumin. The primary endpoint for the phase II study was treatment completion rate of oral curcumin. Secondary endpoints for phase II were response rate, overall survival (OS), and compliance.
21 patients with advanced pancreatic cancer who had progression of disease on single agent gemcitabine chemotherapy.
No dose-limiting toxicities were observed in the phase I study of 8.0 grams of curcumin daily in 3 patients. None of the 21 participants in the study discontinued the trial due to intolerability of curcumin. Plasma curcumin was tested in 5 patients and ranged from 29–91 ng/ml, except for one patient with a level of 412 ng/ml. Compliance was very good, with 19 (90%) participants able to consume more than 90% of the prescribed daily dose. Seventeen (81%) participants died during the study period and 3 were alive at the time of publication. Median overall survival (OS) was 161 days (95% CI, 109–223 days). One-year survival rate was 19%.
Curcumin’s anticancer effects at high doses are well established. Its anticancer effects are largely due to its ability to lower the activation of NF-kB, which results in its antiproliferative, anti-angiogenic, anti-invasive, and pro-apoptotic effects on cancerous cells. In addition, there is in vitro demonstration of its effects as a synergistic agent with several chemotherapies, including 5-fluorouracil, vinorelbine, and gemcitabine.1,2 Given curcumin’s potential as both an anticancer agent and a chemotherapy sensitizing agent, there is keen interest in finding the appropriate applications and doses for its use in integrative oncology.
This small trial demonstrated that high doses of curcumin are well tolerated by advanced pancreatic cancer patients, despite possible compromised digestion.
This small trial demonstrated that high doses of curcumin are well tolerated by advanced pancreatic cancer patients, despite possible compromised digestion. While it is presumed that consuming the curcumin with fat would optimize absorption, this is not disclosed anywhere in the paper. Patients were given the option of dividing the dose throughout the day to increase tolerability, which the authors speculate may have accounted for better tolerance than previous trials.
While safety and tolerability was established with this trial, what about patient outcomes? There is good reason to speculate that the combination of curcumin and gemcitabine has had a synergistic cytotoxic effect. Kunnamakkara et al demonstrated in vitro and in a mouse model of pancreatic cancer that the combination of curcumin with gemcitabine led to less tumor volume post treatment than gemcitabine alone.3 A more recent study corroborated this, showing curcumin with gemcitabine acted synergistically in tumor reduction of bladder cancer.4
Median survival time for patients that have progressed on gemcitabine and receive supportive care only is approximately 10 weeks.5 In this trial, median survival was 23 weeks. However, it should be noted the secondary endpoints of response rate and overall survival may have been affected by the comedication S-1. Of the 21 participants enrolled in the study, 19 received S-1, an oral fluoropyrimidine that has shown possible benefit in patients with advanced pancreatic cancer.6,7 This certainly confounds what we can conclude from the application of curcumin and gemcitabine.
The use of curcumin with gemcitabine in patients with advanced pancreatic cancer deserves more research as both in vitro and in vivo data suggests synergistic cytotoxic effects. Until more definitive research is published, we should certainly consider curcumin’s use in patients taking gemcitabine, as there is no indication that this will interfere with treatment. Keep in mind, though, that the dose should be high to replicate the research.
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1. Du B, Jiang L, Xia Q, Zhong L. Synergistic inhibitory effects of curcumin and 5-fluorouracil on the growth of the human colon cancer cell line HT-29. Chemotherapy 2006;52:23-28.
2. Sen S, Sharma H, Singh N. Curcumin enhances Vinorelbine mediated apoptosis in NSCLC cells by the mitochondrial pathway. Biochem Biophys Res Commun. 2005;331:1245-1252.
3. Kunnumakkara AB, Guha S, Krishnan S, Diagaradjane P, Gelovani J, Aggarwal BB. Curcumin potentiates antitumor activity of gemcitabine in an orthotopic model of pancreatic cancer through suppression of proliferation, angiogenesis, and inhibition of nuclear factor-kappaB-regulated gene products. Cancer Res. 2007;67(8):3853-3861.
4. Tharakan ST, Inamoto T, Sung B, Aggarwal BB, Kamat AM. Curcumin potentiates the antitumor effects of gemcitabine in an orthotopic model of human bladder cancer through suppression of proliferative and angiogenic biomarkers. Biochem Pharmacol. 2010;79(2):218-228.
5. Boeck S, Heinemann V. Second-line therapy in gemcitabine-pretreated patients with advanced pancreatic cancer. J Clin Oncol. 2008;26(7):1178-1179.
6. Okusaka T, Funakoshi A, Furuse J, et al. A late phase II study of S-1 for metastatic pancreatic cancer. Cancer Chemother Pharmacol. 2008;61(4):615-621.
7. Nakai Y, Isayama H, Sasaki T, et al. A pilot study for combination chemotherapy using gemcitabine and S-1 for advanced pancreatic cancer. Oncology. 2009;77(5):300-303.