EDITORIALS
Coffee and Colorectal Cancer: Grounds for Prevention?
See “Association between coffee intake after
diagnosis of colorectal cancer and reduced
mortality,” by Hu Y, Ding M, Yuan C, et al, on
page 916.
C offee is one of the most widely and frequently
consumed beverages worldwide. Although it is often
linked with caffeine, coffee is a complex mixture of >1000
bioactive compounds, many of which have antioxidant
capacity including polyphenols, diterpenes, melanoidins, and
various minerals.1,2 Coffee has been shown to have
anti-inflammatory and insulin-sensitizing properties and is
associated with lower levels of inflammatory cytokines3–5 and
C-peptide (Figure 1A).1,6 Owing to these broad potential
mechanisms and wide-ranging bioactive compounds, coffee
drinking has been investigated in relation to a variety of health
disorders, with beneficial effects consistently reported for the
metabolic syndrome and diabetes, liver and digestive disor-
ders, cardiovascular disease, and overall mortality.7 In 2017, 3
large-scale cohort studies from the United States and Europe
reported that coffee drinkers had significantly lower risk of
premature death from a variety of causes.8–10 Owing to its
effects on gut motility and the gut microbiome (Figure 1A),
there has been particular emphasis on the relationship
between coffee and digestive tract disorders, and there is
accumulating evidence to support a specific link between
coffee and colorectal cancer. Indeed, a 2011 meta-analysis of
15 prospective studies revealed that coffee consumption
was inversely associated with risk of developing colorectal
cancer.11
In this issue of Gastroenterology, researchers from Harvard
University report findings on both prediagnostic and post-
diagnostic coffee intake in relation to colorectal cancer mor-
tality among those diagnosed with stages I through III
colorectal cancer (Figure 1B).12 They pooled data from the
Nurses’ Health Study (n ¼ 121,700) and the Health Pro-
fessionals Follow-up Study (n ¼ 51,529) and obtained 1599
patients diagnosed with stage I, II, or III colorectal cancer,
among whom 803 died during 7.8 years of follow-up, of which
188 were deaths owing to colorectal cancer. In this study, the
authors reported a lower risk of colorectal cancer mortality for
those with stage III colorectal cancer consuming 4 cups of
coffee per day after diagnosis, compared with those who did
not drink coffee (hazard ratio, 0.33; 95% confidence interval,
0.13-0.82). These findings confirm those of the only other
comparable study by Guercio et al13 in 2015 of patients with
stage III colon cancer. Unlike the previous investigation in
2015, this new study also included those with stages I and II
disease and, although the interaction by stage was not statis-
tically significant, there was no association for coffee intake
and mortality for the earlier stage cancers.
This new analysis has several strengths, including the
long follow-up period, the relatively large sample size and
790
well-characterized cohorts, and, most uniquely, the repeated
administration of dietary questionnaires to enable the
assessment of coffee intake both before and after diagnosis.
However, there are some important limitations of the study
to consider. Both cohorts contributing data to this analysis
are formed of health professionals; although this means that
they may be more likely to understand the importance of
providing accurate data, they may also be different from the
general population in other ways; for example, they could be
more health conscious and also more likely to work night
shifts and long hours, which may affect their tendency to
consume coffee. It is also important to note that these re-
sults are derived from observational data based on esti-
mated coffee drinking habits during the previous year. It is
well-known that coffee consumption is linked to other
health-related behaviors; therefore, residual confounding
may persist despite multivariable adjustment of the
regression models. In addition, although the study observed
an overall inverse association between postdiagnostic coffee
intake and colorectal cancer mortality (Figure 1B), stratified
analyses revealed that the effect was restricted to those with
stage III disease; this observation is notable and should be
investigated further to determine whether coffee and other
lifestyle factors have a greater impact on patients with
higher stage tumors.
This study is important because there are an estimated
3.5 million individuals living with colorectal cancer world-
wide,14 and currently there are no specific dietary or lifestyle
recommendations for patients with cancer owing to a lack of
convincing evidence to support them. The best advice we can
provide to these patients is that they follow the guidelines for
cancer prevention, which are based on studies of the diets of
healthy individuals and examining cancer incidence, and not
on patients with cancer and the effects on survival. Research
that identifies dietary or lifestyle factors that improve sur-
vival among patients with cancer, such as in the current
study, are of tremendous value.
Although this research is provocative, it is important to
verify the effects of coffee on cancer outcomes in random-
ized controlled trials. Given that coffee does not seem to
have harmful effects,7 it is an ideal candidate to examine
within the context of a trial. Further, if the observed asso-
ciation between coffee drinking and survival among patients
with colorectal cancer is causal, it raises the prospect that
coffee, or components of coffee, could be used as an adjunct
to treatment to improve survival.
Understanding the biological basis for the relationship
between coffee and the natural history of colorectal cancer is
also crucial, because it could tell us more about the biological
processes that lead to the development and progression of
colorectal cancer and provide clues on potential preventive
pathways. Endogenous factors such as metabolic variability
and the gut microbiome will affect how coffee is metabolized
and, potentially, the bioactivity of its constituent compounds.

Figure 1. (A) Potential
mechanisms linking coffee
consumption to a lower
risk of colorectal cancer
(CRC) mortality. (B) The
association between post-
diagnostic coffee con-
sumption and colorectal
cancer (CRC) mortality and
all-cause mortality.
Future studies that can identify the components of coffee
that are related to colorectal cancer and that evaluate the
metabolic impact of coffee drinking will likely help to eluci-
date potential underlying mechanisms. For this purpose,
metabolomics has been utilized to identify biomarkers
associated with coffee intake,15 but further work is required
to determine the association between these biomarkers and
colorectal cancer incidence and mortality.
As the third most common incident cancer in the world
and the fourth leading cause of cancer-related death, colo-
rectal cancer is a major public health challenge.14 Given that
coffee is one of the most commonly consumed beverages
worldwide, incorporating coffee drinking into prevention
and clinical management strategies for patients with colo-
rectal cancer is an appealing prospect that could have
tangible public health benefits.
AMANDA J. CROSS
Imperial College London
London, UK
MARC J. GUNTER
International Agency for Research on Cancer
Lyon, France
References
1. Alicandro G, Tavani A, La Vecchia C. Coffee and cancer
risk: a summary overview. Eur J Cancer Prev 2017;
26:424–432.
EDITORIALS
2. Jeszka-Skowron M, Zgoła-Grzes kowiak A,
Grzeskowiak T. Analytical methods applied for the
characterization and the determination of bioactive
compounds in coffee. European Food Research and
Technology 2015;240:19–31.
3. Lopez-Garcia E, van Dam RM, Qi L, et al. Coffee con-
sumption and markers of inflammation and endothelial
dysfunction in healthy and diabetic women. Am J Clin
Nutr 2006;84:888–893.
4. Wu T, Willett WC, Hankinson SE, et al. Caffeinated coffee,
decaffeinated coffee, and caffeine in relation to plasma
C-peptide levels, a marker of insulin secretion, in U.S.
women. Diabetes Care 2005;28:1390–1396.
5. Kempf K, Herder C, Erlund I, et al. Effects of coffee
consumption on subclinical inflammation and other risk
factors for type 2 diabetes: a clinical trial. Am J Clin Nutr
2010;91:950–957.
6. Higdon JV, Frei B. Coffee and health: a review of recent
human research. Crit Rev Food Sci Nutr 2006;
46:101–123.
7. Poole R, Kennedy OJ, Roderick P, et al. Coffee con-
sumption and health: umbrella review of meta-analyses
of multiple health outcomes. BMJ 2017;359:j5024.
8. Gapstur SM, Anderson RL, Campbell PT, et al. Associa-
tions of Coffee Drinking and Cancer Mortality in the Cancer
Prevention Study-II. Cancer Epidemiol Biomarkers Prev
2017;26:1477–1486.
9. Gunter MJ, Murphy N, Cross AJ, et al. Coffee drinking
and mortality in 10 European countries: a multinational
cohort study. Ann Intern Med 2017;167:236–247.
791
EDITORIALS
10. Park SY, Freedman ND, Haiman CA, et al. Association of
coffee consumption with total and cause-specific mor-
tality among nonwhite populations. Ann Intern Med 2017;
167:228–235.
11. Yu X, Bao Z, Zou J, et al. Coffee consumption and risk of
cancers: a meta-analysis of cohort studies. BMC Cancer
2011;11:96.
12. Hu Y, Ding M, Yuan C, et al. Association between coffee
intake after diagnosis of colorectal cancer and reduced
mortality. Gastroenterology 2018;154:916–926.
13. Guercio BJ, Sato K, Niedzwiecki D, et al. Coffee intake,
recurrence, and mortality in stage iii colon cancer: results
from CALGB 89803 (Alliance). J Clin Oncol 2015;
33:3598–3607.
14. Ferlay J, Soerjomataram I, Dikshit R, et al. Cancer inci-
dence and mortality worldwide: sources, methods and
major patterns in GLOBOCAN 2012. Int J Cancer 2015;
136:E359–E386.
Introducing Traditional Herbal Medicine into Conventional Health
Care in Treating Ulcerative Colitis: Primum Non Nocere
See “Efficacy of indigo naturalis in a multicenter
randomized controlled trial of patients with
ulcerative colitis,” by Naganuma M, Sugimoto S,
Mitsuyama K, et al, on page 935.
B ecause inflammatory bowel disease (IBD) usually
shows a chronic relapsing and remitting course
with medical intractability in a substantial proportion of
patients, various types of alternative medicines have been
tried for treating IBD. Herbal medicine or phytotherapy is
one form of alternative medicine that has been practiced
for centuries, particularly in traditional Chinese medicine.
Complementary and alternative medicine have been re-
ported to be used by 30% to 50% of patients with IBD.1,2
To date, there have been several placebo-controlled trials
that have evaluated the efficacy of alternative medicinal
agents such as marijuana, curcumin, aloe vera, extracts of
Andrographis paniculata, and wheat grass juice (Triticum
aestivum) for patients with IBD.2 Positive results have been
observed in oral curcumin,3 paniculata extracts,4 and
wheat grass juice5 treatments for patients with active ul-
cerative colitis (UC; Table 1). However, most studies have
small to modest sample sizes and the use of alternative
strategies are still limited owing to uncertain dosing and
safety issues.
Indigo naturalis (also referred to as Qing-Dai) is an herbal
preparation extracted from leaves and stems of Baphicacan-
thus cusia (Nees) Bremek that has been used as a blue dye
since ancient times.6,7 Indigo naturalis has also been used as
an antipyretic, an antiphlogistic, and as a hemostatic remedy
for centuries in traditional Chinese medicine.8,9 For specific
diseases, it was reported to be efficacious for psoriasis7,10–12
and chronic hemorrhagic radiation proctitis13 in studies from
China and Taiwan.
792
15. Guertin KA, Loftfield E, Boca SM, et al. Serum
biomarkers of habitual coffee consumption may
provide insight into the mechanism underlying the
association between coffee consumption and
colorectal cancer. Am J Clin Nutr 2015;101:
1000–1011.
Reprint requests
Address requests for reprints to: Amanda J. Cross, Imperial College London,
Norfolk Place, London, W2 1PG, UK. e-mail: amanda.cross@imperial.ac.uk.
Conflicts of interest
The authors disclose no conflicts.
Most current article
© 2018 by the AGA Institute
0016-5085/$36.00
https://doi.org/10.1053/j.gastro.2018.02.006
For the treatment of IBD, a previous retrospective case
series of 9 patients9 and an open-label, prospective pilot
study of 20 patients14 suggested the efficacy of oral indigo
naturalis for inducing remission in active UC. Based on
those encouraging results, in this issue of Gastroenter-
ology, Naganuma et al6 reported results from the first
randomized, controlled trial to investigate the safety and
efficacy of indigo naturalis in patients with moderate to
severe UC. In this study, a total of 86 subjects were
randomly assigned to groups given a daily dose of 0.5, 1.0,
or 2.0 g indigo naturalis or placebo (1:1:1:1 ratio) for 8
weeks. The primary endpoint was clinical response at
week 8 and secondary endpoints included clinical remis-
sion, endoscopic remission, and levels of quantitative fecal
blood test and fecal calprotectin at week 8. However, the
trial was early terminated owing to an external reason:
the report of a possible adverse event of pulmonary
arterial hypertension (PAH) in a patient with UC who used
self-purchased indigo naturalis 2 g/d for 6 months.15 In
the intention-to-treat analysis, a significant, dose-
dependent linear trend was observed in proportions of
patients with clinical responses (13.6% to placebo [3 of
22]; 69.6% to 0.5 g indigo naturalis [16 of 23]; 75.0% to
1.0 g indigo naturalis [15 of 20]; and 81.0% to 2.0 g indigo
naturalis [17 of 21]) (Cochran-Armitage trend test P <
.0001 compared with placebo). Clinical remission rates at
week 8 were also significantly higher in the 1.0 g indigo
naturalis group (55.0%; P ¼ .0004) and the 2.0 g indigo
naturalis group (38.1%; P ¼ .0093) than in the placebo
group (4.5%). Mucosal healing rates were 13.6% (3 of 22)
in the placebo group, 56.5% (13 of 23) in the 0.5 g indigo
naturalis group, 60.0% (12 of 20) in the 1.0 g indigo
naturalis group, and 47.6% (10 of 21) in the 2.0 g indigo
naturalis group (Cochran-Armitage trend test P ¼ .0278
compared with placebo). Moreover, a quantitative fecal