REVIEW

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A Systematic Review Assessing Clinical Utility of Curcumin

with a Focus on Cancer Prevention
Lynne Howells,* Rushad Malhotra Mukhtyar, Despoina Theofanous, Coral Pepper,
Anne Thomas, Karen Brown, and Sameena Khan

over the last 4 decades, exhibiting many

Scope: There is extensive pre-clinical evidence for utility of curcuminoids positive outcomes that have warranted
across many diseases with a particular focus on cancer prevention, yet there further investigation. More recently,
remains a paucity of clinical evidence for its approved use. To assess current there has been increasing interest in
knowledge on the broader potential for clinical efficacy of curcumin and in translation of preclinical findings into
the clinic, with numerous phase I and II
particular, in cancer prevention strategies, this study undertook a systematic clinical trials being undertaken or ongo-
review determining the number and quality of randomized controlled trials ing. The concept of curcumin as a lead
(RCTs) undertaken across any pathology. drug candidate with potential to deliver
Methods and Results: Search strategies for RCTs using a quantifiable amount clinical benefit has been under scrutiny
of curcuminoids, are applied across Medline (Medical Literature Analysis and however, due to its poor bioavailability
and rapid metabolism (reviewed in [1]).
Retrieval System Online), Embase (Excerpta Medica dataBASE), Cochrane and
Furthermore, curcumin is considered to
clinicaltrials.gov. There are 314 curcuminoid-based RCTs, with 100 of these have unfavorable chemical properties for
revealing significant within- and between-group changes relating to the reliable in-vitro investigation rendering
primary outcome. Twenty three studies are conducted in a setting where there it an “invalid metabolic panacea” (IMP)
is an increased risk of cancer. Fifteen of these meet all prescribed quality candidate and a “pan-assay interference”
criteria, and 10 reveal positive outcomes. (PAIN) compound.[2] Whether these
perceived drawbacks actually limit its
Conclusions: A substantial number of studies reveal positive outcomes potential for clinical efficacy remains a
following curcumin use. However, despite the vast array of preclinical data, subject of debate.[3,4]
there are relatively few RCTs conducted in the prevention setting. Future Randomized controlled trials
approaches to trials must deliver improved robustness and credibility of (RCTs) are a key tool to help us un-
curcumin-related research to facilitate approvals for use in clinical settings. derstand whether we can translate
mechanistically-driven pre-clinical data
into an outcome that has potential to
benefit patients. In turn, the output from RCTs can be used to bet-
1. Introduction ter guide our design of future pre-clinical strategies, teasing out
key mechanistic and pharmacokinetic inferences to pro-actively
Curcuminoids, derived from the spice turmeric, have undergone enhance targeting of future interventions. Within this context, a
extensive preclinical investigation for potential health benefits number of recent systematic reviews investigating curcuminoid
use in RCTs across varying pathologies have given an indication
Dr. L. Howells, Dr. R. Malhotra Mukhtyar, D. Theofanous, that pre-clinical evidence may indeed be successfully translated
Prof. A. Thomas, Prof. K. Brown, Dr. S. Khan in to clinical benefit, despite the relatively small numbers of par-
Leicester Cancer Research Centre
University of Leicester, Robert Kilpatrick Clinical Sciences Building
ticipants within these studies.[5–7]
Leicester Royal Infirmary Within this review, we sought to establish the characteristics
Leicester LE2 7LX, UK of all RCTs undertaken using any formulation containing quan-
E-mail: lh28@le.ac.uk tifiable amounts of curcuminoids, with the aim of establishing
C. Pepper the disease areas that have been most investigated, the number
Odames Library of studies that have reported positive outcomes, and the risk of
Victoria Building, Leicester Royal Infirmary
Leicester LE1 5WW, UK bias for data reported in these studies. We further focus on the
number and quality of RCTs specifically in the cancer prevention
The ORCID identification number(s) for the author(s) of this article setting, the mechanisms by which clinical benefit may have been
can be found under https://doi.org/10.1002/mnfr.202000977
elicited, and whether preparations exhibiting enhanced bioavail-
© 2021 The Authors. Molecular Nutrition & Food Research published by ability have been the formulation of choice within these trials.
Wiley-VCH GmbH. This is an open access article under the terms of the
Creative Commons Attribution License, which permits use, distribution This information is designed to help the curcumin research com-
and reproduction in any medium, provided the original work is properly munity to identify areas of good practice, realize areas in need of
cited. more clinical investigation, and determine where more robust
DOI: 10.1002/mnfr.202000977 data are required to improve the credibility of future research

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outputs that may influence clinical decision making, particularly
within the cancer prevention setting.
2. Experimental Section
Search strategies were applied across Medline (from 1946), Em-
base (from 1974), Cochrane (including the Cochane Database
of Systematic Reviews, CENTRAL (Cochrane Central Register
of Controlled Trials) and clinicaltrials.gov. Initial searches were
conducted on July 17, 2019, and the same searches re-run on
June 26, 2020 to ensure capture of the most recent data. The
broad search structure for Medline and Embase was as follows:
(1) curcumin*.mp; (2) curcuma.mp; (3) turmeric*.mp; (4) difer-
uloylmethane.mp; (5) Curcumin; (6) Curcuma; (7) zedoary ze-
doari*.mp; (8) nanocurc.mp; (9) 1 OR 2 OR 3 OR 4 OR 5
OR 6 OR 7 OR 8; AND [RCT filter] AND [human only filter].
The Medline filter strategy used the sensitivity- and precision-
maximizing filter described in the Cochrane handbook (techni-
cal supplement).[8] For the Embase filter strategy, the “best op-
timization of sensitivity and specificity” filter for RCTs[9] was
used in conjunction with the Cochrane sensitivity- and precision-
maximizing filter for human studies. When searching Cochrane
databases and clinicaltrials.gov, only the search terms (1-8) were
used as there was no need to include the RCT and human only
filters.
The inclusion criteria for clinical studies were: clinical stud-
ies published in the English language; drug or placebo-controlled
randomized trials including crossover trials; studies that used
curcuminoids or turmeric preparations with specified content
of curcumin or curcuminoids, regardless of the dosage and fre-
quency of administration.
The exclusion criteria were: review papers; population or ob-
servation studies; commentaries; correspondence; conference
abstracts; studies that lacked clinical outcome measure.
For data extractions where articles were not readily available
online or through library services, authors were emailed for the
missing texts, with follow-up reminders where necessary. Data
collection for extraction consisted of the following: intervention
description; sponsorship source; clinical setting; definition of
primary outcome; author’s name; author’s institution; country of
origin; year of publication; trial design; whether outcomes were
patient reported; whether study was prospective or retrospective;
inclusion/exclusion criteria; disease indication; whether given
with standard of care; numbers in each intervention group;
delivery system; dose; duration of intervention; primary clin-
ical outcome change from baseline; primary clinical outcome
change between groups. This review and protocol has not been
registered on PROSPERO.
All articles were imported into the web-based Covidence
systematic review software which allows independent dual-
screening of titles, abstracts, full text articles and data extractions.
Any conflicts in screening data were resolved at each stage by dis-
cussion between the lead authors until the final extracted data set
was established. Each study was assessed for quality risk of bias
by assessing reporting clarity of the following criteria: random se-
quence generation; allocation concealment; blinding; incomplete
outcome data (acknowledgement/description of dropouts); selec-
tive reporting (e.g., not reporting the stated primary outcomes for
the study). Each risk of bias was initially marked as low, high or
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unclear, with those reported as unclear by both reviewers subse-
quently deemed to be high risk.
This systematic review was conducted according to PRISMA
guidelines.
2.1. Dosage Information/Dosage Regimen
Numerous dosing strategies were highlighted within this review.
The number and type of differing formulations, dosages, and du-
ration of dose, are described in more detail in Section 3.3 and in
Tables 1 and 2. All interventions were specified as part of a clini-
cal trial protocol, and supplemental to any curcuminoid ingestion
via food intake.
3. Results
3.1. Included Studies
Out of 4440 studies initially imported for screening, 314 studies
underwent data extraction for outcome assessment (Figure 1).
3.2. Study Demographics
3.2.1. Study Numbers
The total number of curcuminoid-related RCTs has increased
over time, with 68 studies published in 2019 and 47 up to June
2020 (Figure 2). However, 13 of the 314 RCTs were reanalyses
of studies that had been previously published, and just described
differing outcomes from those reported in the original RCT. Over
22,000 participants were randomized across all studies (mean
per study 73; median 55), with approximately 91% of partici-
pants completing the studies. The majority of studies were par-
allel group designs, and 32 (10.2%) were crossover studies.
3.2.2. Funding
As outcome reporting has potential to be affected by the source
of study sponsorship, we analyzed where funding sources for
studies originated (Figure 3A). Most funding was from Higher
Education Institutes (25.8%) and Government bodies/Research
Councils (19.1%) or were studies sponsored by Industry (13.1%).
However, 31.2% of articles did not acknowledge any funding
source. Similarly, only 7/23 cancer prevention studies cited fund-
ing sources, all of which were from Higher Education Institutes
or Government bodies.
3.2.3. Geographical Origin
The majority of studies originated from Asia (34.7%) or the Mid-
dle East (35.0%) with Iran (106 studies) and India (55 studies)
contributing the highest number of RCTs (Figure 3B). This split
in geographic origin was even more pronounced within the pre-
vention setting, with 52% of studies originating from Asia, and
26.1% from the Middle East.
3.2.4. Clinical Setting
Out of 314 studies 85 (27.1%) had endpoints relating to
cardiovascular outcomes (including diabetes), 61 (19.4%) to
© 2021 The Authors. Molecular Nutrition & Food Research published by Wiley-VCH GmbH
 Table 1. Randomized control trials that have been undertaken in disease conditions associated with an increased cancer risk.

Quality
Participants Participants Curcuminoid Curcuminoid Treatment Criteria
Author Disease Primary outcomes Biomarker or PK outcomes randomized completed formulation Dose duration Findings and Significance met Ref

Amirchaghmaghi Oral lichen Response rate in None studied. Speculative 20 20 Curcumin tablets 2 g d−1 4 wk No significant differences in 5 [ 10 ]

2016 planus treatment of antioxidant effect response between groups

erosive-atrophic
oral lichen planus

Mol. Nutr. Food Res. 2021, 65, 2000977

Ara 2018 Oral sub- Oral submucous None studied. Speculative 100 100 Curcumin capsules 1 g d−1 6 mo Significant improvement in all 2 [ 11 ]
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mucous fibrosis antiinflammatory (via subjective signs and

fibrosis symptoms NFΚB) and antioxidant symptoms and
effect histopathological changes
with curcumin
Bakhshi 2020 Oral lichen Treatment efficacy None studied. Speculative 34 31 Nanomicelle 1% gel 3x daily 1 mo Efficacy index was significantly 5 [ 12 ]

planus modulation of immune curcumin gel higher in nanocurcumin group

response
[ 13 ]

2000977 (3 of 13)
Bommelaer 2020 Crohn’s Prevention of Serum curcumin evaluated. 62 53 Curcumin capsules 3 g d−1 6 mo Significantly more patients 5
disease endoscopic No relationship between receiving curcumin had severe
postoperative curcumin levels and rate disease recurrence than those
recurrence of endoscopic on placebo
postoperative recurrence
observed
Boube 2020 Crohn’s Endoscopic Investigated fecal Further Further Curcumin capsules 3 g d−1 6 mo Fecal calprotectin variation was a 1 [ 14 ]

disease postoperative calprotectin levels, but analysis of analysis of promising predictor of early
recurrence these were not Bommelaer Bommelaer endoscopic postoperative
subsequently related to 2020 2020 recurrence – no curcumin
curcumin intake related outcomes
Chainani-Wu 2007 Oral lichen Change in symptom None studied. Speculative 33 28 Sabinsa curcumin 2 g d−1 7 wk No change to symptom 5 [ 16 ]

planus scores at study immune modulatory and C3 complex reduction compared to

end antiinflammatory effect capsules placebo
Chainani-Wu 2012 Oral lichen Changes in signs No significant changes to 23 20 Sabinsa curcumin 6 g d−1 12 d A significantly greater reduction 5 [ 15 ]

planus and symptoms at CRP or IL-6 in response to C3 complex in clinical signs and
study end curcumin. capsules symptoms were observed in
the curcumin group
Cruz-Correa 2018 Familial Changes in polyp None studied. Speculative 44 34 Curcumin capsules 3 g d−1 12 mo No significant differences in 5 [ 17 ]

adeno- size and number alteration of microbiome mean polyp number or size
matous
polyposis
coli
Hazarey 2015 Oral sub- Compare efficacy of None studied. Speculative 30 30 Longvida curcumin 2 g d−1 3 mo Significant improvement in 0 [ 18 ]

mucous curcumin with fibrinolytic and lozenges symptoms compared with

fibrosis standard of care antiinflammatory action standard of care
(Continued)
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 Table 1. Continued.

Quality
Participants Participants Curcuminoid Curcuminoid Treatment Criteria
Author Disease Primary outcomes Biomarker or PK outcomes randomized completed formulation Dose duration Findings and Significance met Ref

Kedia 2017 Ulcerative Induction of No effect on hemoglobin or 62 41 Curcumin capsules 450 mg d−1 8 wk No significant difference in rates 5 [ 19 ]

Mol. Nutr. Food Res. 2021, 65, 2000977

colitis remission albumin in response to of clinical remission between
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curcumin groups
Kia 2015 Oral lichen Efficacy comparison None studied. Speculative 55 50 Curcuma longa root 5% paste 3x 4 wk Both treatments improved 5 [ 19 ]

planus of topical antioxidant and extract daily symptoms, but no significant

curcumin with antiinflammatory action difference between groups
triamcinolone
Koosirirat 2010 Chronic Inflammatory No changes to IL-8, IL-1𝛽, 36 36 Curcumin tablet 2.1 g d−1 4 wk Standard of care was significantly 2 [ 21 ]

H.pylori- cytokines TNF-𝛼 and COX-2 induced more effective at H. Pylori

infected by curcumin eradication than curcumin

2000977 (4 of 13)
gastritis
patients
Kuriakose 2016 Oral leuko- Clinical response No change to dysplastic 223 223 BCM95– 1.2 g d−1 6 mo Significant durable clinical 5 [ 22 ]

plakia histology observed in Biocurcumax response observed with

response to curcumin curcumin curcumin
capsules
Lang 2015 Ulcerative Efficacy in inducing None studied. Speculative 50 50 Curcumin capsule 3 g d−1 4 wk Curcumin induced significant 5 [ 23 ]

colitis remission immune modulatory and clinical remission and

antiinflammatory effect response
Lanjekar 2020 Oral sub- Efficacy in symptom None studied. Speculative 120 120 Curcumin 1% gel 3x daily 6 wk Curcumin induced significant 1 [ 24 ]

mucous improvement antioxidant, anticancer, mucoadhesive gel improvement in symptoms

fibrosis immunomodulatory,
antifibrotic and
antiinflammatory effect
Masoodi 2018 Ulcerative Treatment efficacy None studied – authors 58 56 Curcuminoid 2.4 g d−1 4 wk Curcuminoids resulted in 5 [ 25 ]

colitis recognized this as a nanomicelles significant symptom

limitation of the study improvement compared to
placebo
Pipalia 2016 Oral sub- Clinical efficacy SOD levels were significantly 46 40 Turmeric and black 2.4 g d−1 3 mo Turmeric with black pepper and 5 [ 26 ]

mucous improved in both pepper capsule nigella sativa was significantly

fibrosis treatment arms at study more efficacious than
end curcumin and black pepper
alone
(Continued)
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 Table 1. Continued.

Quality
Participants Participants Curcuminoid Curcuminoid Treatment Criteria

Mol. Nutr. Food Res. 2021, 65, 2000977

Author Disease Primary outcomes Biomarker or PK outcomes randomized completed formulation Dose duration Findings and Significance met Ref
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Piyush 2019 Oral sub- Clinical efficacy None studied. Speculative 60 60 Curcumin+ piperine 300 mg 2x daily 6 mo Curcumin significantly improved 4 [ 27 ]

mucous antioxidant and tablet clinical efficacy

fibrosis antiinflammatory action
Sadeghi 2020 Ulcerative Clinical outcomes Curcumin significantly 70 63 Curcumin capsules 1.5 g d−1 8 wk Changes in Simple Clinical 5 [ 28 ]

colitis and inflammatory reduced hs-CRP and ESR, Colitis Activity Index score
markers but did not affect TNF-𝛼 were significantly higher in the
curcumin group

2000977 (5 of 13)
Singla 2014 Ulcerative Change in ulcerative None studied. Speculative 45 30 Curcumin enema 140 mg d−1 8 wk Per protocol analysis showed 5 [ 29 ]

colitis colitis disease antioxidant and significantly better outcomes

activity index antiinflammatory action in curcumin group for clinical
response, clinical remission
and improvement on
endoscopy
Sugimoto 2020 Crohn’s Change in Crohn’s Curcumin did not 30 26 Theracurmin 360 mg d−1 12 wk Significant reduction in clinical 5 [ 30 ]

disease disease activity significantly change CRP bioavailable disease activity, including
score or hemoglobin levels curcumin increased clinical remission
capsules rates and reduction in
endoscopic Crohn’s disease
severity
Thomas 2017 Oral lichen Symptom reduction None studied. Speculative 50 44 Curenext oral 10 mg 3- or 6x 3 mo Statistically significant reduction 2 [ 31 ]

planus antioxidant and curcumin gel daily in burning sensation,

antiinflammatory action erythema and ulceration
Yadav 2014 Oral sub- Compare curcumin None studied. Speculative 40 40 Curcumin + 300 mg d−1 3 mo Curcumin significantly improved 3 [ 32 ]

mucous efficacy against antioxidant and piperine tablet burning sensation when
fibrosis intralesional antiinflammatory action compared to standard of care,
steroid injections but standard of care was more
effective

COX-2, Cyclo-oxygenase-2; CRP, C-Reactive Protein; ESR, Erythrocyte Sedimentation Rate; IL-6, Interleukin-6; NFkB, Nuclear Factor Kappa B; PK, Pharmacokinetic; SOD, Superoxide Dismutase; TNF𝛼, Tumor Necrosis Factor-𝛼.
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Table 2. Number and overall percentage of differing types of curcuminoid 3.2.6. Mechanisms of Action for Curcumin in Prevention Studies
delivery systems.
Despite all studies presenting a mechanism-driven rationale for
Delivery system Number Percent clinical use of curcumin, only 7/23 RCTs included biomarker as-
Enhanced bioavailability curcumin 111 35.4 sessment in their analyses that may bear relevance to curcumin’s
Curcumin capsule 94 29.9 putative mechanism of action. Inflammatory and antioxidant
Mixture capsule 32 10.2
biomarkers included C-reactive protein (CRP), interleukins (IL),
tumor necrosis factor-𝛼 (TNF-𝛼), cyclooxygenase-2 (COX-2) and
Turmeric capsule 24 7.6
superoxide dismutase (SOD). Only two of these studies reported
Curcumin gel 10 3.2
curcumin to have a beneficial effect on these biomarkers (namely
Curcumin mouthwash 10 3.2
SOD and CRP).
Turmeric powder 7 2.2
Curcumin powder 4 1.3
Curcumin cream 3 1.0 3.3. Dosing
Curcumin roll on 2 0.6
Curcumin suppository 2 0.6 3.3.1. Delivery Systems
Mixture cream 2 0.6
Mixture granules 2 0.6 Curcuminoid delivery systems were categorized into 23 dif-
Turmeric mouthwash 2 0.6
ferent types, with the majority of studies using enhanced
bioavailability formulations of curcumin (inclusive of studies
Curcumin enema 1 0.3
adding piperine to increase availability) (35.8%) or standard
Curcumin lozenges 1 0.3
curcumin capsules/tablets (29.7%) (Table 1). Curcuminoids
Curcumin mucoadhesive film 1 0.3
were administered with standard of care medication in 43%
Curcumin paste 1 0.3 of studies. In the studies conducted in patients at higher
Curcumin pastille 1 0.3 risk of cancer; however, 11/23 (47.8%) used curcumin cap-
IV curcumin 1 0.3 sules/tablets that were not formulated for enhanced bioavail-
Turmeric cream 1 0.3 ability, compared with 6 (26.1%) studies that used bioavailable
Turmeric mucosal film 1 0.3 formulations. Interestingly, all 6 of the studies that utilized
Turmeric gel 1 0.3 more bioavailable curcumin (in capsule format) showed a
positive outcome (1 oral leucoplakia, 3 oral submucous fibro-
“Enhanced bioavailability curcumin” includes formulations specifically designed to
sis, 1 Crohn’s disease, 1 ulcerative colitis), whereas only 4/11
enhance bioavailability such as nano- or phytosomal preparations, and studies where
curcuminoids were given with piperine; “Mixture” refers to formulations where the studies using non-enhanced bioavailability curcumin capsules
delivery system included a variety of other active ingredients such as polyphenolics. showed positive outcomes (2 oral lichen planus; 2 ulcerative
colitis).
inflammatory/rheumatoid outcomes, 21 (6.7%) to hepatobil-
iary outcomes, and 21 (6.7%) to periodontic/dental disease
3.3.2. Curcuminoid Dose
(Figure 3C).
Oral dosing regimens used a variety of doses, with standard cur-
3.2.5. Prevention Studies cumin doses ranging from 45 to 6000 mg d−1 , and enhanced
bioavailability curcumin similarly ranging from 50 to 6000 mg
Twenty three studies involving 1291 participants (representing (Table 2). The most common dose durations were 12 weeks
only 5.6% of the total number randomized across all studies) (21.7%), 8 weeks (16.8%), 4 weeks (12.0%) or a single dose (8.1%).
were undertaken in a setting where the disease under The maximum reported dose duration was 72 weeks.
investigation was associated with an increased cancer risk In the prevention setting, oral dosing with standard curcumin
(Table 3).[10–32] An increased cancer risk was defined by clini- ranged from 450 to 6000 mg d−1 , with enhanced bioavailability
cal evidence that the condition under investigation increased curcumin ranging from 300 to 2400 mg d−1 . Duration of dosing
relative risk for malignant transformation. Conducting studies ranged from 12 days to 24 weeks.
in populations at elevated risk for malignancy is crucial in
determining the potential for candidate preventive therapies
to inhibit the carcinogenic process. However, the primary 3.4. Quality Risk of Bias
endpoints for all of these studies were related to intervention
efficacy in terms of disease or symptom improvement, meaning Each study was associated with 5 reporting quality criteria (de-
that cancer prevention per se was not measured as a direct scribed in methods section), with 151/314 (48.1%) studies meet-
outcome. The settings, and numbers of studies within each ing all 5 quality criteria and 119/314 (37.9%) being reported in the
setting were: oral lichen planus (6), oral submucous fibrosis (6), last 5 years (Figure 4), suggesting that more recent studies have
ulcerative colitis (5), Crohn’s disease (3), familial adenomatous better reporting quality standards. For the prevention studies,
polyposis coli (1), gastritis with H. Pylori infection (1), and oral 15/23 (65%) studies met all 5 quality criteria, with 10/15 (67%)
leucoplakia (1). of these studies being reported in the last 5 years.

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Figure 1. PRISMA diagram showing study flow and reasons for exclusion.

3.5. Outcomes
Whilst the majority of studies reported their intended primary
outcomes and so fulfilled this quality criterion, 80 studies (25.5%)
did not present raw data in an evaluable format (e.g., charts only
without any numerical reference) and were therefore excluded
from further outcome assessments. Across all studies, 137/314
(43.6%) presented outcomes that showed significant (p ≤ 0.05)
within-group changes (i.e., changes from baseline to study end),
140/314 (44.6%) showed significant between-group changes at
the end of the study, and 100/314 (31.8%) showed both signifi-
cant within- and between-group changes relating to the intended
primary outcome.
In the prevention setting, from the 15 studies that met
all five quality criteria, 10 had positive clinical outcomes.
These outcomes related directly to efficacy[12] , symptom

Figure 2. Number of curcumin-related randomized control trials published over time. Grey bars represent number of non cancer prevention trials; black
bars represent number of cancer prevention-related trials.

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Figure 3. Basic information for included studies: Percent of studies in each type of funding stream (A), percent of studies originating from each geo-
graphic area (B), medical setting for the most common study outcomes (C).

improvement[15,20,25,28] , durability of clinical response[22] , clinical
remission[23,29,30] , and assessment by biomarker changes.[26]
This provides encouraging information to suggest potential for
positive patient benefit within the oral lichen planus, oral leu-
coplakia, ulcerative colitis, Crohn’s disease, and oral submucous
fibrosis settings.
3.6. Prevention of Cancer Therapy-Induced Toxicities
Cancer prevention studies typically focus on those patients at an
increased risk of cancer, but it is also important to note a number
of studies that have investigated prevention of therapy-induced
toxicities in cancer patients. Whilst this is not a traditional

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Figure 4. Percentage of total studies meeting differing numbers of quality criteria (A), and the percentage of studies meeting all five quality criteria over
time (shown as 5-year intervals) (B).

Table 3. Minimum, maximum, and median total daily dose of curcumi- meeting all five quality criteria and 4/5 (80%) suggesting that
noids taken in studies utilizing oral delivery systems. curcumin significantly reduced radiation-induced toxicities.
None of the studies undertook concurrent analyses of inflamma-
Delivery system Min [mg] Max [mg] Median [mg] tory or antioxidant biomarkers, although all suggested that this
Curcumin capsule 45 6000 1000 was likely the main mechanism for efficacy.
Enhanced bioavailability curcumin 50 6000 400
Mixture capsule 0.728 2790 250 4. Discussion
Mixture granules 30 100 65
There are increasing numbers of curcuminoid-based RCTs be-
Turmeric capsule 2.37 6000 1000
ing undertaken across a wide array of pathologies. Encouragingly,
Turmeric powder 200 23 750 4500
the quality of reporting for these studies has improved over the
last 5 years, lending credence to the outcome data. The necessary
reporting criteria for RCTs are well established,[41] with studies
cancer prevention setting, the anti-inflammatory properties, low not adhering to this reporting mechanism generally dismissed
toxicity and acceptability for long-term use of curcuminoids, from systematic reviews and meta-analyses. In these cases, even
offers similar rationale for use as for the cancer prevention where study outcomes are positive, they do not add to evidence
setting. There were eight such studies focusing on prevention supporting the wider clinical use of the agent under study, and
of radiation-induced side effects in head and neck, prostate in fact are detrimental to its credibility. In the past, the quality of
and breast cancer. Toxicity prevention studies randomized 1055 pre-clinical and clinical studies investigating curcuminoids has
participants (Table 4),[33–40] with five (62.5%) of these studies sometimes been questionable, which we believe has contributed

Mol. Nutr. Food Res. 2021, 65, 2000977 2000977 (9 of 13) © 2021 The Authors. Molecular Nutrition & Food Research published by Wiley-VCH GmbH
 Table 4. Table shows all RCTs investigating curcuminoid use for prevention of cancer therapy-induced toxicities.

Participants Participants Curcuminoid Curcuminoid Treatment Findings and Quality

Author Cancer type Primary outcomes randomized completed formulation Dose duration Significance Criteria met Ref

Arun 2020 Head and Changes to 64 61 BCM- 1.5 g d−1 Until Significant difference 5 [ 33 ]

Neck Objective WHO 95/curcugreen completion of between groups in

oral mucositis turmeric extract radiotherapy mucositis grade from

Mol. Nutr. Food Res. 2021, 65, 2000977

scale week 3
www.advancedsciencenews.com

Delavarian Head and Effect on oral 32 29 SinaCurcumin 80 mg d−1 6 wk Statistically significant 5 [ 34 ]

2019 Neck mucositis in nanocurcumin improvement in the

cancer patients receiving capsules severity of mucositis
radiotherapy following curcumin
treatment.
Hejazi 2013 Prostate Radio- protective 45 40 BCM-95 3 g d−1 1 week prior to Significant change in 5 [ 35 ]

cancer effects in patients (Biocurcumin) radiotherapy urinary symptoms,

undergoing curcumin until with patients taking

2000977 (10 of 13)

radiotherapy capsules completion. curcumin
experiencing milder
urinary symptoms
Rao 2014 Head and Severity of 80 80 Turmeric 400 mg turmeric 6 wk Turmeric significantly 5 [ 36 ]

neck cancer radiation-induced mouthwash capsule in delayed and reduced

mucositis 80 mL water levels of
(2.42% cur- radiation-induced oral
cuminoids) mucositis
Rao 2017 Breast cancer Appearance and 40 40 Vicco turmeric 16% w/w 5 wk Turmeric cream 4 [ 37 ]

severity of cream turmeric significantly reduces

radiation-induced extract—5 mL radiation dermatitis
dermatitis 5x daily
Ryan 2013 Breast cancer Severity of 35 30 Sabinsa Curcumin 6 g d−1 Throughout Significantly fewer 4 [ 38 ]

radiation-induced C3 complex course of curcumin-treated

dermatitis capsules radiotherapy patients had moist
desquamation
Ryan-Wolf Breast Cancer Severity of 695 578 Sabinsa Curcumin 6 g d−1 Throughout Curcumin did not 4 [ 39 ]

2018 radiation-induced C3 complex course of reduce radiation

dermatitis capsules radiotherapy dermatitis severity
+ 1 week post
radiotherapy
Saadipoor Prostate Radiation-induced 64 64 SinaCurcumin 120 mg d−1 Throughout Curcumin did not reduce 5 [ 40 ]

2019 cancer proctitis nanocurcumin course of radiation-induced

radiotherapy proctitis

WHO, World Health Organization.

www.mnf-journal.com

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to the wider skepticism of curcuminoids as potential therapeutic
candidates.
Almost one third of studies revealed significant (both from
baseline and between groups) positive effects of curcumin which
were directly related to the intended primary outcome. However,
most studies were phase II, meaning that only small numbers of
participants received the curcuminoid formulations (median of
55 participants in each study). A further confounding factor in
interpreting outcome data from trials with small numbers of par-
ticipants is the variability in dose, dosing schedule, duration of
dose, and proprietary formulations that have been incorporated
into the limited number of studies investigating each disease
state. Increasingly, new formulations containing curcuminoids
are being advanced from preclinical testing into clinical trials,
with regional areas often producing (or having access to) their
own specific formulations. Whilst this approach has the advan-
tage of advancing research into new formulations that may offer
greater bioavailability and/or efficacy, it does not contribute to
the assessment of the clinical utility of curcuminoids unless
such formulations are more widely adopted across the interna-
tional community. The huge variance between trial protocols in
terms of dose and duration of intervention observed during the
course of this review, may also limit the value of outcome data
even where potential for clinical benefit has been observed. In
order to add value to future trials, a useful scenario may be to
involve multiple collaborative sites as part of a “Curcumin Con-
sortium” assessing dosing strategies for different disease states.
A consensus opinion on the design of trials in terms of dosing
strategies may greatly advance the clinical utility of curcumin,
providing a robust evidence base that would be more readily
translatable across international approval and regulatory bodies.
A multi-national collaborative approach has proven successful in
the field of resveratrol research, with regular conferences specif-
ically bringing together the international resveratrol community
to assess and disseminate current levels of evidence.[42]
Additionally, initiation of multi-site trials would facilitate re-
cruitment of the large patient numbers necessary to ensure ro-
bustness of data. However, the challenges of sourcing funding
for such large studies within this field are well known.
An important part of this review was to better understand the
evidence for use of curcumin in cancer prevention strategies.
Chemoprevention (more recently termed “Therapeutic Cancer
Prevention” in an effort to avoid negative chemotherapy conno-
tations) trials are known to be exceedingly challenging (reviewed
in [43]). Whilst using agents of dietary origin may be seen as
advantageous within this setting due to their low toxicity and
wider acceptability, many of the challenges are further exacer-
bated by their pleiotropic nature and multiple mechanisms of
action. Within this review, the majority of these RCTs cited anti-
inflammatory or antioxidant effects of curcumin as the rationale
for the study conception. Disappointingly, only 30% of the studies
actually included putative biomarkers of efficacy as an endpoint,
meaning that it is hard to reverse translate results to further val-
idate the extensive preclinical data that gave rise to these trials
in the first place. It is therefore essential that secondary trial out-
comes include targeted biomarker analyses so that we can gain
a better understanding of how curcuminoid use in clinical trials
affects molecular targets to precipitate clinically meaningful out-
comes.
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This disconnect between clinical disease activity and reporting
of efficacy biomarkers is perhaps surprising, as there is much
compelling evidence for curcumin as an inflammatory mediator.
The studies in higher cancer risk groups that revealed efficacy
were all in disease states driven by inflammatory processes (oral
leucoplakia, oral submucous fibrosis, Crohn’s disease, ulcerative
colitis, oral lichen planus), which commonly involve NF-𝜅B, p38
MAPK and JNK signaling pathways and a milieu of inflammatory
cytokines including IL-1𝛽, IL-6, IL-8, IL-12, IL-23, IFN-𝛾, TNF𝛼,
PDGF𝛽 and bFGF.[44–46] Perturbation of inflammatory processes
and its link with cancer is well established,[47] although precise
mechanisms by which this occurs may vary between cancer types.
IL-6 in particular, has been shown to mediate pro-carcinogenic
inflammatory responses in progression of colorectal cancer[48] ,
with activation of NF𝜅B signaling via pro-inflammatory media-
tors established as one of the first linking factors between inflam-
mation and colorectal carcinogenesis.[49] NF𝜅B has since pro-
vided a key inhibitory target for curcumin chemoprevention in
an array of pre-clinical studies.[50–52] Inactivation of NF𝜅B leads
directly to downregulation of a number of pro-inflammatory in-
terleukins and cytokines including TNF𝛼, and decreases cyclo-
oxygeanse-2 expression and thus arachidonic acid-mediated
inflammation.[53] A recent meta-analysis of curcumin RCTs by
Tabrizi analyzed the effect of curcumin-containing supplements
on biomarkers of inflammation and oxidative stress, and revealed
curcumin to decrease TNFa, IL-6, hsCRP and malondialdehyde
in patients with obesity-related conditions such as metabolic syn-
drome or type 2 diabetes.[54] However, in Table 3 presented here,
only one trial revealed a significant decrease in hsCRP concur-
rent with a significant decrease in disease activity.[28]
The inflammasomes are potent inducers of IL-1𝛽 and IL-
18 and are responsible for the highly inflammatory form of
cell death, pyroptosis, so also play a significant role in tumor
progression.[48] Formation of the NLRP3 inflammasome com-
plex is disrupted by curcumin (reviewed in[55] ) with suppression
of NLRP3-dependant caspase-1 activation and IL-1𝛽 secretion
observed in mouse models of diet-induced inflammation[56]
and LPS-induced septic shock.[57] All of this evidence strongly
suggests that incorporation of inflammatory biomarker panels
into future curcumin trials will be key to determining whether
pre-clinical observations offer potential for clinical relevance
via disruption of the inflammation-mediated pro-carcinogenic
microenvironment.
Interestingly, the consensus varies on whether to use bioavail-
able formulations in prevention studies, with a greater number
choosing not to. If the studies didn’t show positive clinical out-
comes; however, then it was suggested that a more bioavailable
formulation could be advantageous—although this assumption
is largely made without the benefit of mechanistic or pharmacoki-
netic data being incorporated within the trial. Whilst curcumin
undergoes extensive first pass metabolism,[58] there is also evi-
dence to suggest that when standard curcumin is administered
orally, pharmacologically active levels of curcuminoids persist
and can still be recovered from the colonic mucosa even follow-
ing extensive bowel cleansing procedures.[53] As all of the studies
presented here related to gastrointestinal or oral epithelia, it may
be that curcuminoid formulations without enhanced bioavailabil-
ity could still be sufficient to provide clinical benefit via a topical
effect. Although bioavailable curcumin did appear anecdotally to

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offer a greater chance of positive clinical outcomes in the small
number of studies (6/6) where it was used in a prevention setting,
conclusions cannot be drawn without side by side comparisons
of the differing formulations.
A Google Scholar search of Curcumin AND Chemoprevention
from 2000 - 2020, produced 17700 hits, yet this has translated to
only 23 RCTs (7.3% of all RCTs in this review) recruiting less than
1300 participants across seven different types of conditions with
increased cancer risk. On the clinicaltrials.gov website, there are
currently (as of September 2020) no studies recruiting for any of
the conditions listed in Table 3 linked to increased cancer risk.
In light of the myriad of preclinical cancer prevention efficacy
data, that there are no studies in the pipeline pursuing meaning-
ful clinical cancer prevention endpoints via RCTs is somewhat
disappointing. Mansouri et al.[59] recently published a systematic
review investigating the effects of curcumin on cancer therapy,
collating evidence which suggests that curcuminoids are able to
alleviate side effects of chemo- or radio-therapy with concurrent
improvement of quality of life. This study, taken together with the
evidence presented here, gives some credence to potential benefi-
cial effects of curcumin use in pre-cancerous conditions, and for
radio-toxicity prevention in cancer patients. The main factors lim-
iting more firm conclusions—as previously described—are the
low total numbers of participants representing each disease state,
and the wide variation in dosing strategy.
Despite vast amounts of preclinical literature investigating
potential benefits of curcumin, relatively few randomized con-
trolled trials have been undertaken, particularly in the cancer
prevention setting. Encouragingly though, the quality of tri-
als has increased over recent years, and approximately one
third have reported positive clinical outcomes. In the cancer
prevention setting, there is evidence for positive clinical ben-
efit despite overall participant numbers being low. In order
to provide sufficient evidence for clinical adoption, curcumi-
noids must be shown to be beneficial in consistently designed,
mechanistically sound, appropriately powered and well-reported
studies, incorporating international multi-site studies where
possible.
Acknowledgements
Support was received from Cancer Research UK in conjunction with the UK
Department of Health on an Experimental Cancer Medicine Centre grant
[C10604/A25151]. The authors thank Prof A. Gescher for insightful com-
ments on the writing of this manuscript.
Conflict of Interest
The authors declare no conflict of interest.
Author Contributions
Conceptualization: L.H., K.B., A.T., S.K. Methodology: L.H., R.M., C.P.,
D.T., S.K. Formal analysis: L.H., R.M., D.T., S.K. Writing – original draft
preparation: L.H., K.B., S.K. Writing – review and editing: L.H., R.M., D.T.,
C.P., A.T., K.B., S.K.
Data Availability Statement
Data available on request from the authors—all articles from which data
are derived are freely available via PubMed or researchgate.
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www.mnf-journal.com
Keywords
cancer prevention, curcuminoids, quality risk of bias, randomized control
trials, systematic review
Received: October 30, 2020
Revised: April 29, 2021
Published online: June 3, 2021
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