Panahi Y, Saadat A, Beiraghdar F, Sahebkar A. Adjuvant therapy with bioavailability-boosted curcuminoids suppresses systemic inflammation and improves quality of life in patients with solid tumors: a randomized double-blind placebo-controlled trial. Phytother Res. 2014 Mar 19. Epub ahead of print.
A randomized, double-blind, placebo-controlled clinical trial: Biweekly assessments were conducted to determine compliance and regularity of consuming medication as well as any adverse effect(s). Biomarkers of inflammation and quality of life (QoL) scores were measured at baseline and at the end of the trial.
Subjects were 80 men and women, 40 assigned to each group, aged 25 to 65 years with histologically documented solid tumors currently under treatment with standard chemotherapy regimens. Chemotherapy was maintained throughout the trial. Groups were matched according to baseline characteristics including age, weight, gender, smoking habit, and history of radiotherapy. The predominant types of cancer were colorectal, gastric, and breast cancer. Chemotherapy regimens commonly used were docetaxel–cisplatin–5-fluorouracil (5-FU, to treat gastric and breast cancer); topotecan-cyclophosphamide-etoposide (breast cancer); cyclophosphamide–methotrexate–5-FU (breast cancer); and 5 FU–based regimens (colon cancer).
Study Medication and Dosage
Patients were randomized to receive either curcuminoids (curcumin) or matched placebo for 8 weeks. Curcuminoids were dosed via a phytosomal preparation (Meriva,™ Indena SpA, Milan, Italy). Each patient was asked to take three 300-mg Meriva capsules. This product preparation is approximately 20% curcumin per capsule, so subjects received approximately180 mg of curcuminoids per day.
Measure of efficacy was assessed using the health-related University of Washington QoL (UW-QoL) index and serum levels of mediators implicated in systemic inflammation. The UW-QoL is a validated scale that consists of 12 domain items. Responses to each of the 12 domains are given a score between 0 (worst) and 100 (best). Biochemical analysis included the serum measurement of these indices: interleukin (IL)-6, IL-8, tumor necrosis factor alpha (TNFα), transforming growth factor-beta (TGF-β), high-sensitivity C-reactive protein, calcitonin gene-related peptide, substance P, and monocyte chemotactic protein-1. All measures were collected at baseline and at end of trial.
Findings revealed significant clinical benefit, as represented by study measures, for those subjects in the curcumin group. Significant reductions of serum markers were noted in both groups with the exception of substance P, which was reduced only in the curcumin group (P<0.001) and remained statistically unchanged in the placebo group (P>0.05). However, the degree of change in the curcumin group was statistically significantly higher as compared to the placebo group for all parameters with the exception of IL-6 and IL-8. Notably, reductions in IL-8 were seen in both groups; however, the placebo group experienced a greater reduction in this marker. QoL scores did not significantly differ in each group after stratification for the type of cancer (reflecting benefit irrespective of type of cancer) or between subgroups receiving or not receiving radiotherapy—ie, radiotherapy did not make a difference in QoL improvement. Furthermore, researchers were able to make correlations between QoL score and individual moderators. Changes in TGF-β and IL-8 were found as significant predictors of QoL changes in the curcuminoids and placebo groups, respectively. Overall, QoL improved to a much greater extent in the curcumin group vs the placebo group.
Curcumin is the familiar name given the 3 curcuminoids that make up 4% to 5% of Curcuma longa (turmeric). Curcumin’s multiple immune-regulating benefits and antiinflammatory characteristics are well proven. This constituent of the pungent, yellow spice offers preventive properties and has been studied in the management of numerous cancers.1-5 Some of its actions include (but are not limited to)
- the inhibition of certain genes that trigger cancer,
- the prevention of metastases and angiogenesis,
- the stimulation of apoptosis in malignant cells,
- the enhancement of chemotherapy and radiation without potentiating toxic side effects, and
- the potential management of skin damage caused by radiation.1,3-5
While all of this may be true, there have been concerns about using curcumin with chemotherapy.
Multiple complex drug interactions may create undue risk for the patient seeking to combine natural medicines with chemotherapeutic therapies. Each individual chemotherapeutic agent may act via multiple cytotoxic pathways, and likewise, each agent is metabolized in a unique way, usually through the liver (via many unique cytochrome isoenzymes) but also through the kidney, intestinal cells, lungs, central nervous system, gastric mucosa, prostate, and in some cases even the skin. In addition, it is common practice that each chemotherapeutic regimen is preceded by premedications (which typically consist of dexamethasone, diphenhydramine, and/or omeprazole) and postmedications if needed. Each medication is metabolized in its own particular way. This creates a slippery slope for the physician looking to combine natural therapies with conventional chemotherapy treatments without risk of adverse interactions.
Although we may understand the pharmacology and pharmokinetics of many cytotoxic medications, our understanding of curcumin pharmokinetics remains less clear.
It remains important for all practitioners integrating natural agents in oncology to not only follow the “Do no harm” rule but also to acknowledge “the healing power of nature” and remember the goal of prevention. All 3 notions are relevant in the realm of cancer care. The practice of integrative oncology—and in particular naturopathic oncology—often lacks the necessary research studies and data to guide us through some of these gray areas. Use of curcumin during chemotherapy is an area where the data do not yet provide clarity.
The primary concern about using supplements in conjunction with chemotherapy is the effect they may have on long-term outcomes. The current study does little to address this concern. While curcumin significantly alters inflammatory processes and decreases indices associated with poorer well-being, chemotherapy works to generate reactive oxygen species and activate apoptosis. If curcumin inhibits these pathways, it could be hypothesized that its conjunctive use with chemotherapy may result in poorer long-term outcomes—ie, shorter-term survival and an increased risk of recurrence.
Several studies have evaluated the use of curcumin with common chemotherapeutics. However, a majority of these studies are in vitro—with very few in vivo—making any extrapolation for use in human beings of questionable accuracy.
Bharat Aggarwal, MD, a well-known and highly respected advocate for the use and benefits of curcumin, has spent decades studying its use in cancer care. He and Ajay Goel, PhD, recently summarized studies on the use of curcumin alongside some traditional chemotherapeutic agents. While these publications are void of any placebo-controlled clinical trials, they do provide some insight into future and potential use of curcumin adjunctively. Their findings can be summarized as the following points:
- Curcumin treatment reverted all cisplatin-induced alterations, including significantly lowering serum TNFα levels, restoring renal function, reducing lipid peroxidiation, and enhancing the levels of glutathione and activities of superoxide dismutase and catalase in a rat model.6
- In an animal model of methotrexate-induced mucosal barrier injury, treatment with curcumin resulted in NF-κB inhibition and partial amelioration of villous atrophy.7
- Oral treatment with curcumin 10 days before or daily after a single intratracheal installation of bleomycin protected against bleomycin-induced pulmonary fibrosis, as evidenced by protection against changes in total lung hydroxyproline, alveolar macrophage production of TNFa superoxide, and nitric oxide.8
Aggarwal goes on to state,
Given the shortcoming of current chemotherapy and radiation treatments for cancer management, it is obvious that such treatments in the future must be combined with more effective and safer drug compounds. In this regard, given all the encouraging evidence. . . curcumin seems to be an ideal safe and highly effective compound that can be used in adjunct in such therapeutic strategies.9
In my opinion, given the limited clinical data, Aggarwal’s statement may be premature. However, it could foreshadow the utility of curcumin in the future. Furthermore, Aggarwal’s work may speak to the potential benefits of curcumin use before or after chemotherapy to negate unwanted side effects and promote cytotoxic benefit. Use away from chemotherapy treatment would remove completely the risk of interference with efficacy.
While I do espouse caution regarding the long-term effects of concommittant use of curcumin with chemotherapies, there are some recent rodent studies highlighting the use of curcumin adjunctively with doxorubicin (DOX), capecitabine, and cisplatin. While by no means should these results be extrapolated to humans, it is interesting to see the data to date.
A 2011 study evaluated the use of curcumin in mice receiving DOX chemotherapy, an agent known to induce cardiotoxicity. Mice treated with both curcumin and DOX showed significant improvement in cardiac functional parameters when compared to mice treated with DOX alone. In addition, reduced expression of Bcl-2 and pAkt was observed in mice treated with DOX alone, while mice given combination treatment showed levels similar to control.10 Researchers concluded that a combination treatment of curcumin and DOX is a viable option for treatment of cancer with reduced cardiotoxic side effects.
In another study, capecetibine was combined with curcumin in mice with colorectal cancer. Results indicated the combination of curcumin and capecitabine performed better than either agent alone in reducing tumor volume, Ki-67 proliferation index, and microvessel density marker CD31. In addition, the combination treatment was highly effective in suppressing ascites and distant metastasis to the liver, intestines, lungs, rectum, and spleen.11 As in the current study under review, the effect was accompanied by suppressed activated NF-κB and NF κB–regulated gene products. Concluding remarks suggest that curcumin sensitizes colorectal cancer to the antitumor and antimetastatic effects of capecitabine by suppressing NF-κB cell signaling pathway.
A 2014 study of mice evaluated the use of curcumin (with α-tocopherol) and its hepatoprotective effect against cisplatin’s inherent oxidative stress. The study employed curcumin (200 mg/kg body weight) and α-tocopherol 24 hours before cisplatin infusion. Results found that pretreatment with combined curcumin and α-tocopherol improved the liver enzymes, lipid peroxidation biomarkers, liver histopathology, and gene expression of liver nicotinamide adenine dinucleotide phosphate-oxidase in cisplatin-treated mice.12 In addition, cisplatin has no known cytochrome p450 (CYP) reaction, and the renal clearance of free (ultrafilterable) platinum also exceeds the glomerular filtration rate, indicating that cisplatin or other platinum-containing molecules are actively secreted by the kidneys.
As is evident from the following reviews, curcumin may play a beneficial role in some cytotoxic regimens. Granted, clinical trials are lacking. Although we may understand the pharmacology and pharmokinetics of many cytotoxic medications, our understanding of curcumin pharmokinetics remains less clear. Despite the promise of these preliminary studies, this detail cannot be overlooked.
We do know that curcumin, through cell and animal studies, interacts with some liver isoenzymes and has been indicated as a potent inhibitor of CYP 1A1/1A2, a less potent inhibitor of CYP 2B1/2B2, and a weak inhibitor of CYP 2E1.13 Inhibition of CYP has also been demonstrated in vitro and in other animal research.14-23 In addition, curcumin has been shown to act as an inhibitor of permeability glycoprotein. A study from 2013 cites this mechanism as the reason the chemotherapy drug irinotecan was increased in the colonic lining of rats pretreated with curcumin,24 a result that points to possibly enhanced therapeutic benefit in the treatment of colon cancer, although the potential of increasing cytotoxic side effects was not studied. In general, the clinical effects of curcumin metabolism remain unclear.
So what does any of this mean when reviewing the study at hand? Bottom line: The data are promising. However, it may not yet be possible to extrapolate to current clinical practice. The breadth of chemotherapeutic agents used in this study makes it impossible to decipher how any one chemotherapeutic agent interacts with curcumin. Furthermore, QoL is a very broad and encompassing term. As defined by the US Centers for Disease Control and Prevention, QoL is an individual’s perceived quality of daily life—that is, an assessment of well-being or lack thereof.25 This includes all emotional, social, and physical aspects of the individual’s life. In healthcare, health-related QoL (HRQoL) is an assessment of how the individual’s well-being may be affected over time by a disease, disability, or disorder. Yes, it is evident that biochemical markers (several known for their role in tumor progression and development) decreased in beneficial ways in the curcumin studies. However, their value cannot clearly be associated with HRQoL. The UW-QoL scores do provide a clearer measurement of HRQoL. These data show promise in the promotion of patient well-being. Finally, the number of tumors studied makes it impossible to ascertain tumor response and clinical outcome, the ultimate endpoint in almost all promising oncological clinical trials.
What we can say is that curcumin may offer benefits for advancement both in the study of clinical oncology and in patient well-being. When so many patients succumb to the toxic side effects of chemotherapy and radiation, it makes sense to offer steps to reduce these effects and increase the potential for patients to live long and healthy lives. As integrative practitioners, it behooves us to offer therapies to our patients that improve both longevity and QoL. Curcumin may be best used before or after chemotherapy with much more caution given to its use during chemotherapy, despite the improvement in QoL shown in the current study reviewed. We just do not know if—or how—the efficacy of chemotherapy treatments is affected by curcumin. We must first do no harm, prevent “dis-ease,” and rely on the healing power of nature. Regarding curcumin, let further research be our guide.
- Aggarwal BB, Yost D. Healing Spices. New York, NY: Sterling Publishing; 2011.
- Gupta SC, Kim JH, Kannappan R, Reuter S, Dougherty PM, Aggarwal BB. Role of nuclear factor- (kappa)B- mediated inflammatory pathways in cancer-related symptoms and their regulation by nutritional agents. Exp Biol Med (Maywood). 2011;236(6):658-671.
- Karin M, Greten FR. NF-kappaB: linking inflammation and immunity to cancer development and progression. Nat Rev Immunol. 2005;5(10):749-759.
- Shishodia S, Chaturvedi MM, Aggarwal BB. Role of curcumin in cancer therapy. Curr Probl Cancer. 2007;31(4):243-305.
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- Kuhad A, Pilkhwal S, Sharma S, Tirkey N, Chopra K. Effect of curcumin on inflammation and oxidative stress in cisplatin-induced experimental nephrotoxicity. J Agric Food Chem. 2007;55(25):10150-10155.
- van’t Land B, Blijlevens NM, Marteijn J, et al. Role of curcumin and the inhibition of NF-kappaB in the onset of chemotherapy-induced mucosal barrier injury. Leukemia. 2004;18(2):276-284.
- Punithavathi D, Venkatesan N, Babu M. Curcumin inhibition of bleomycin-induced pulmonary fibrosis in rats. Br J Pharmacol. 2000;131(2):169-172.
- Goel A, Aggarwal BB. Curcumin, the golden spice from Indian saffron, is a chemosensitizer and radiosensitizer for tumors and chemoprotector and radioprotector for normal organs. Nutr Cancer. 2010;62(7):919-930.
- 10. Dayton A, Selvendiran K, Meduru S, et al. Amelioration of doxorubicin-induced cardiotoxicity by an anticancer-antioxidant dual-function compound, HO-3867. J Pharmacol Exp Ther. 2011 Nov;339(2):350-357. Epub 2011 Jul 28.
- Kunnumakkara AB, Diagaradjane P, Anand P, et al. Curcumin sensitizes human colorectal cancer to capecitabine by modulation of cyclin D1, COX-2, MMP-9, VEGF and CXCR4 expression in an orthotopic mouse model. Int J Cancer. 2009;125(9):2187-2197.
- Palipoch S, Punsawad C, Koomhin P, Suwannalert P. Hepatoprotective effect of curcumin and alpha-tocopherol against cisplatin-induced oxidative stress. BMC Complement Altern Med. 2014 Mar 28;14:111.
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- US Centers for Disease Control and Prevention. Health-related quality of life (HRQOL). Available at: http://www.cdc.gov/hrqol/. Accessed July 29, 2014.