A phase I/II study of gemcitabine-based chemotherapy plus curcumin for patients with gemcitabine-resistant pancreatic cancer
- 1.6k Downloads
Curcumin, a plant-derived natural polyphenol, could be a promising anti-cancer drug and shows synergic effects with cytotoxic agents. We evaluated the safety and feasibility of combination therapy using curcumin with gemcitabine-based chemotherapy.
Gemcitabine-resistant patients with pancreatic cancer received 8 g oral curcumin daily in combination with gemcitabine-based chemotherapy. The primary endpoint was safety for phase I and feasibility of oral curcumin for phase II study.
Twenty-one patients were enrolled. No dose-limiting toxicities were observed in the phase I study and oral curcumin 8 g/day was selected as the recommended dose for the phase II study. No patients were withdrawn from this study because of the intolerability of curcumin, which met the primary endpoint of the phase II study, and the median compliance rate of oral curcumin was 100% (Range 79–100%). Median survival time after initiation of curcumin was 161 days (95% confidence interval 109–223 days) and 1-year survival rate was 19% (4.4–41.4%). Plasma curcumin levels ranged from 29 to 412 ng/ml in five patients tested.
Combination therapy using 8 g oral curcumin daily with gemcitabine-based chemotherapy was safe and feasible in patients with pancreatic cancer and warrants further investigation into its efficacy.
KeywordsCurcumin Gemcitabine Pancreatic cancer
We thank Hiroe Tada and Miyuki Niimi for their contributions to data management, Emi Shimada, and Dr Vladimir Badmaev for their contributions to curcumin shipment. This work was supported by the Grant-in-Aid for Young Scientists (21790661) from the Japan Society for the Promotion of Science, Japanese Research Foundation for Clinical Pharmacology and Smoking Research Foundation.
- 1.Aggarwal S, Ichikawa H, Takada Y, Sandur SK, Shishodia S, Aggarwal BB (2006) Curcumin (diferuloylmethane) down-regulates expression of cell proliferation and antiapoptotic and metastatic gene products through suppression of IkappaBalpha kinase and Akt activation. Mol Pharmacol 69:195–206PubMedGoogle Scholar
- 2.Ali S, Ahmad A, Banerjee S, Padhye S, Dominiak K, Schaffert JM, Wang Z, Philip PA, Sarkar FH (2010) Gemcitabine sensitivity can be induced in pancreatic cancer cells through modulation of miR-200 and miR-21 expression by curcumin or its analogue CDF. Cancer Res 70:3606–3617PubMedCrossRefGoogle Scholar
- 3.Bayet-Robert M, Kwiatkowski F, Leheurteur M, Gachon F, Planchat E, Abrial C, Mouret-Reynier MA, Durando X, Barthomeuf C, Chollet P (2010) Phase I dose escalation trial of docetaxel plus curcumin in patients with advanced and metastatic breast cancer. Cancer Biol Ther 9:8–14PubMedCrossRefGoogle Scholar
- 4.Burris HA 3rd, Moore MJ, Andersen J, Green MR, Rothenberg ML, Modiano MR, Cripps MC, Portenoy RK, Storniolo AM, Tarassoff P, Nelson R, Dorr FA, Stephens CD, Von Hoff DD (1997) Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol 15:2403–2413PubMedGoogle Scholar
- 5.Cheng AL, Hsu CH, Lin JK, Hsu MM, Ho YF, Shen TS, Ko JY, Lin JT, Lin BR, Ming-Shiang W, Yu HS, Jee SH, Chen GS, Chen TM, Chen CA, Lai MK, Pu YS, Pan MH, Wang YJ, Tsai CC, Hsieh CY (2001) Phase I clinical trial of curcumin, a chemopreventive agent, in patients with high-risk or pre-malignant lesions. Anticancer Res 21:2895–2900PubMedGoogle Scholar
- 10.Golombick T, Diamond TH, Badmaev V, Manoharan A, Ramakrishna R (2009) The potential role of curcumin in patients with monoclonal gammopathy of undefined significance–its effect on paraproteinemia and the urinary N-telopeptide of type I collagen bone turnover marker. Clin Cancer Res 15:5917–5922PubMedCrossRefGoogle Scholar
- 13.Kumar A, Dhawan S, Hardegen NJ, Aggarwal BB (1998) Curcumin (Diferuloylmethane) inhibition of tumor necrosis factor (TNF)-mediated adhesion of monocytes to endothelial cells by suppression of cell surface expression of adhesion molecules and of nuclear factor-kappaB activation. Biochem Pharmacol 55:775–783PubMedCrossRefGoogle Scholar
- 14.Kunnumakkara AB, Guha S, Krishnan S, Diagaradjane P, Gelovani J, Aggarwal BB (2007) 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 67:3853–3861PubMedCrossRefGoogle Scholar
- 17.Oettle HPU, Stieler J et al (2005) Oxaliplatin/follnic acid/5-fluorouracil [24 h] (OFF) plus best supportive care versus best supportive care alone (BSC) in secondary-line therapy of gemcitabine-refractory advanced pancreatic cancer (CONKO 003). J Clin Oncol 23:315sGoogle Scholar
- 21.Sharma RA, Euden SA, Platton SL, Cooke DN, Shafayat A, Hewitt HR, Marczylo TH, Morgan B, Hemingway D, Plummer SM, Pirmohamed M, Gescher AJ, Steward WP (2004) Phase I clinical trial of oral curcumin: biomarkers of systemic activity and compliance. Clin Cancer Res 10:6847–6854PubMedCrossRefGoogle Scholar
- 24.Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, Verweij J, Van Glabbeke M, van Oosterom AT, Christian MC, Gwyther SG (2000) New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 92:205–216PubMedCrossRefGoogle Scholar
- 29.Yamauchi J, Kanai M, Matsumoto S, Nishimura T, Yazumi S, Kami K, Kawaguchi Y, Yasuda H, Kitano T, Misawa A, Ishiguro H, Yoshikawa K, Yanagihara K, Fukushima M, Doi R, Chiba T (2008) Clinical outcome of gemcitabine/S-1 combination therapy for advanced pancreatic cancer. Pancreas 36:327–328PubMedCrossRefGoogle Scholar