web viewthe effects of nutritional interventions on recurrence in survivors of colorectal adenomas...
TRANSCRIPT
The effects of nutritional interventions on recurrence in survivors of colorectal adenomas
and cancer: a systematic review of randomized controlled trials
Running title: systematic review diet and CRC survivors
Margie van Dijk1, Gerda K Pot1*
1King’s College London, Diabetes and Nutritional Sciences Division, School of Medicine, Franklin-Wilkins
Building, London, UK
* Corresponding author
[email protected], King’s College London, Diabetes and Nutritional Sciences Division, Franklin-Wilkins Building, 150 Stamford Street, SE1 9NH, London; tel +44 20 78484437
Journal: European Journal of Clinical NutritionWord count: 3200Number of tables/figures: 2 (including 1 in online supplementary information/3 including one in online supplementary information) Conflict of interest: none
Key words: colorectal cancer, colorectal adenoma, recurrence, dietary factors, randomized
controlled trial
1
1
2
3
4
5
6
7
8
910
1112
1314
1516
17
18
19
ABSTRACT
Word count: 237
Background/Objectives: Nutrition and dietary supplementation may modulate outcomes in
colorectal cancer (CRC) survivors. However no recent systematic review has focused on
randomized controlled trials (RCTs). The aim of this systematic review was to examine the
effects of nutritional RCTs in survivors of colorectal adenomas and cancer.
Methods: Medline, Embase, Scopus, Web of Science and the Cochrane Library were
searched to identify research between April 2006 and January 2014. The primary outcomes
were colorectal adenoma and cancer recurrence. Each included study was assessed for risk
of bias. Meta-analyses using random effects models were performed where two or more
RCTs investigated the same dietary intervention.
Results: Eight completed RCTs, all in colorectal adenoma survivors, were identified with four
investigating the effect of folic acid. A meta-analysis of the four folic acid RCTs showed no
statistically significant effect of folic acid on colorectal adenoma recurrence (RR=0.93; 95%
CI: 0.69, 1.25). The impact of the remaining completed RCTs, investigating anti-oxidant
supplementation, green tea extract, prebiotic fibre and phytoestrogens/insoluble fibre,
could not be reliably estimated due to the limited number and heterogeneity of the
interventions. In addition, three heterogeneous ongoing RCTs were identified, investigating
green tea (n=1) and eicosapentaenoic acid (n=1) in colorectal adenoma survivors and dietary
modifications (n=1) in CRC survivors in remission.
Conclusions: Overall, this systematic review highlights the need for further research,
especially in CRC survivors, as we identified no completed and only one ongoing RCT in this
population.
2
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
INTRODUCTION
Globally, colorectal cancer (CRC) is the third most common cancer and ranks fourth in terms
of mortality.1 Due to earlier diagnosis, improved treatment and increased general life
expectancy the number of CRC survivors is rising. For both colon and rectal cancer, a 5-year
survival of 60% has been observed in patients diagnosed between 2005-9 in 22 countries. 2
Despite improvements in survival, it has been estimated that up to 50% of CRC survivors will
develop cancer recurrence at some point in their lives.3
Research on cancer survivorship and nutrition and dietary supplementation is still
inconclusive.4,5 In 2007, the World Cancer Research Fund (WCRF) and the American Institute
of Cancer Research (AICR) found insufficient evidence to support an association between
nutrition and dietary supplementation and modified outcomes in cancer survivors,4 based
on results from a systematic review of randomized controlled trials (RCTs) undertaken in
2006.6 The key reasons for this finding were variable study quality and research
heterogeneity in terms of cancer site and exposure that consequently made it difficult to
draw conclusions from the results.4 Conversely, for primary prevention of CRC, the
WCRF/AIRC judged there to be convincing evidence from numerous high quality studies that
red and processed meat, alcoholic drinks in men, overall and abdominal fatness and adult
attained height increased risk while physical activity and dietary fibre were protective
against CRC.7 Evidence from dietary supplementation studies was too limited to draw
conclusions from the results.7 Therefore, there is a need to establish whether similar or
other nutrition and dietary supplements play a role in the recurrence of CRC.
We identified two recent reviews in 20108 and 20139 that evaluated the effects of diet on
recurrence and survival in CRC survivors. Both reported insufficient evidence to support an
3
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
61
62
63
64
65
association between specific foods, nutrients or dietary patterns and CRC recurrence and
only identified observational studies. Three further reviews, two published in 201110,12 and
one prepared for Macmillan Cancer Support in 2010,11 that included CRC with other cancer
sites in their analysis, were also unable to report any site-specific associations for CRC
survival due to limited evidence. None of the aforementioned reviews, including the
systematic review9 were able to identify sufficient studies to undertake any quantitative
analyses. We judged it plausible that recent dietary RCTs in CRC survivors had not been
identified since only one of the aforementioned reviews was systematic9, not all included
RCTs in their search criteria and all highlighted a need for further cancer survivor research.
Our interest also included patients with a history of pre-malignant colorectal adenomas
(“colorectal adenoma survivors”) as a larger body of research has been conducted in this
population who are considered to be at increased risk of developing CRC.13 Additionally,
evidence suggests that there is a very high intake of dietary supplements in cancer survivors
with a recent systematic review indicating that 64 – 81% use vitamin and mineral
supplements14 despite a lack of evidence for them having a beneficial effect on recurrence
or even possible detrimental effects.4 Therefore, we aimed to systematically review the
literature on RCTs investigating nutritional interventions in CRC survivors in remission and
CRC adenoma survivors.
4
66
67
68
69
70
71
72
73
74
75
76
77
78
79
80
81
82
83
METHODS
Design
We undertook a systematic review in accordance with the Preferred Reporting Items for
Systematic Review and Meta-analysis (PRISMA) statement15 and Cochrane handbook for
Systematic Reviews of Interventions.16
Search Strategy
A structured search of Medline, Embase, Scopus, Web of Science and the Cochrane Library
was conducted in January 2014. We used Medical Subject Headings (MeSH terms) and title
and/or abstract words for CRC OR colorectal adenomatous polyp AND survivor AND
nutrition and related terms to identify relevant studies. The full Medline search strategy is
shown in Figure S1, available online as supplementary information. The bibliographies of
selected studies, recent reviews and other relevant papers were hand-searched to identify
additional eligible RCTs. A search of grey literature was also undertaken to detect the
presence of publication bias and research registers were searched for ongoing trials. The
search was restricted to studies since April 2006 to identify those published after the WCRF
cancer survivor systematic review search.6
Inclusion criteria
The following studies were eligible for inclusion: RCTs, RCT protocols and summaries of
ongoing RCTs involving CRC survivors in remission and patients with a history of colorectal
adenomas. Nutritional interventions involving dietary changes of macro or micronutrients
or a particular food type or any vitamin, mineral or other dietary supplement were included.
Eligible outcomes were CRC recurrence and mortality, all-cause mortality, colorectal
5
84
85
86
87
88
89
90
91
92
93
94
95
96
97
98
99
100
101
102
103
104
105
adenoma recurrence, biomarkers of pre-cancerous cell or tumour progression, disease-free
survival and health-related quality of life (QoL). There was no language restriction to the
search.
Exclusion criteria
RCTs that were conducted before or during cancer treatment were excluded due to the
confounding effect on outcome of treatment and disease pathology. RCTs involving
polymorphisms or other genetic factors that influenced CRC risk were excluded. We also
excluded RCTs that investigated the combined effect of diet and physical activity to enable
us to assess the specific effect of diet.
Data extraction and risk of bias
Publications were initially screened electronically based on title and abstract (MvD). Full
texts were retrieved and examined to decide on their eligibility. One reviewer (MvD)
extracted the data from eligible studies including author, year of publication, dietary
factor(s) investigated, setting (population, number of centres, country, age), outcome
investigated, sample size, treatment, follow up period and main findings (for completed
trials only) . Data was also extracted for each completed study to assess the risk of bias,
using the recommendations from the Cochrane Handbook.16
Data synthesis and analysis
We undertook a meta-analysis using REVMAN 5.217 where two or more RCTs investigated
the same dietary intervention and when the extracted data provided sufficient information
to obtain the mean and standard deviation of the sought, continuous outcomes necessary
for data pooling. Unpublished data required for the meta-analysis was requested directly
6
106
107
108
109
110
111
112
113
114
115
116
117
118
119
120
121
122
123
124
125
126
127
from the authors. We employed a random effects model to estimate relative risks (RR) with
95% confidence intervals and the Chi2 test was used to assess the presence of heterogeneity
with p<0.10 indicating statistical heterogeneity.16 To assess the level of heterogeneity, the I2
test was used with 50-90% considered to be suggestive of substantial heterogeneity.16 RCTs
with heterogeneous interventions were reviewed narratively. A sensitivity analysis was also
performed to exclude data from studies that were assessed as having a high risk of bias.
7
128
129
130
131
132
133
RESULTS
Search results
The initial search identified 609 unique citations, which were screened electronically by title
and abstract (Figure 1). Full-text screening was performed on 19 papers, with 8 papers
meeting the inclusion criteria. Three further studies were identified from review paper
bibliographies (n=2) and research registers (n=1). No foreign language or unpublished
completed RCTs were identified. The search identified a total of 11 studies for inclusion in
the review: 8 completed RCTs published between 2007 and 2013 and 3 on-going RCTs.
Characteristics of included studies
An overview of the characteristics of the included studies is shown in Table 1. The eight
completed RCTs investigated folic acid (n=4),18-21 multivitamins (n=1),22 green tea extract
(n=1),23 pre-biotic dietary fibre (n=1)24 and phytoestrogens and insoluble fibre (n=1).25 All
involved colorectal adenomas survivors. We identified no completed RCT in CRC survivors in
remission that met our inclusion criteria. The on-going interventions investigated green tea
(n=1)26 and eicosapentaenoic acid (n=1)27 in colorectal adenoma survivors and dietary
changes (n=1) in CRC survivors in remission with the effect of physical activity assessed in a
separate group .28
Characteristics of Completed Studies
The selected studies were undertaken in North America (n=4),18,20-21,24 Europe (n=3)19,22,25 and
Asia (n=1).23 Five studies were multi-centred,18-19,22-24 two were single-centred20,25 and one
was conducted by mail.21 More men than women were included in the studies (with the
exception of one)21 reflecting the higher incidence of CRC in men. Mean age was between
8
134
135
136
137
138
139
140
141
142
143
144
145
146
147
148
149
150
151
152
153
154
155
57 and 65 years. Six studies had colorectal adenoma recurrence as their main outcome.18-23
Two studies investigated biomarkers of abnormal cell progression.24-25
Qualitative analysis
Folic acid supplementation
There was heterogeneity in the dosage of folic acid supplementation between studies with
0.5 mg/day,19 1 mg/day18,21 and 5 mg/day.19 The duration of treatment was three years,19-20
5-6.5 years 21 and 6-8 years (split into two phases of 3 years and 3-5 years).18 Our analysis of
the Cole et al.study18 only related to the first 3 years phase as the results for the folic acid
only and placebo only groups were not reported for the second phase.
Antioxidant supplementation
One study by Bonelli et al. investigated the effect of multivitamin supplementation on
colorectal adenoma recurrence.21 The study reported a statistically significant reduction in
colorectal adenoma recurrence with antioxidant supplementation (selenium, zinc, vitamin
A, C and E) versus a placebo (adjusted HR=0.61; 95% CI: 0.41, 0.92). `
Green tea extract (GTE) supplementation
One study investigated the effect of GTE on colorectal adenoma recurrence, reporting a
statistically significant reduction in the intervention group (RR= 0.49; 95% CI: 0.24, 0.99) in
subjects who completed the RCT.23 However, an intention-to-treat analysis found no
significant difference between the two groups.
Prebiotic dietary fibre supplementation
9
156
157
158
159
160
161
162
163
164
165
166
167
168
169
170
171
172
173
174
175
A 6-month trial compared the effects of prebiotic dietary fibre with two other interventions
(a statin and a nonsteroidal anti-inflammatory drug) and a placebo.24 No significant
difference was observed in the percentage change in the number of rectal aberrant crypt
foci (ACF) between the dietary fibre and control group (-3.6% (95% CI -88% to 83%) versus -
10% (-100% to 117%), p=0.92, median value (range) of %∆ACF). There was also no
significant difference in biomarkers of proliferation (Ki67) or apoptosis (caspase-3) between
groups (p>0.05).
Phytoestogens and insoluble dietary fibre supplementation
A 60-day trial with 60 participants investigated the effects of a dietary intervention of
phytoestrogens and insoluble fibre.25 The authors reported a statistically significant increase
in ER-β protein in the intervention group versus the control (0.82 ± 0.08 v 0.77 ± 0.10;
p=0.04), a potential biomarker of CRC that decreases during disease progression, suggestive
of a protective effect. No statistically significant differences were observed in the
expression of any other estrogen receptor proteins or mRNA.
Quantitative analysis
A meta-analysis was performed on four folic acid studies.18-21 One study did not publish
sufficient data necessary for meta-analysis.20 However, the necessary data was acquired
indirectly from another published systematic review29 as it was not provided by the author.
The four studies included a total of 1,615 subjects and 444 cases of colorectal adenoma
recurrence. Three studies were large scale trials,18-19,21 which individually randomized 339
(folic acid only and placebo only sub-groups combined),18 467 (folic acid only and placebo
10
176
177
178
179
180
181
182
183
184
185
186
187
188
189
190
191
192
193
194
195
196
only subgroups combined)19 and 672 subjects.21 The fourth study was smaller with a total of
137 randomized subjects.20
The meta-analysis showed no significant association between folic acid and colorectal
adenoma recurrence (RR=0.93; 95% CI: 0.69, 1.25; Figure 2). As substantial heterogeneity
was observed between the four studies (I2=71%), a sensitivity analysis was performed to
exclude the Jaszewski et al trial.20 Justification for this exclusion included the small number
of study participants, the high dosage of folic acid compared to other studies (5 mg/day v
0.5-1 mg/day), and the higher risk of bias (see below). The sensitivity analysis also found a
non-significant association between folic acid and colorectal adenoma recurrence but the
direction of the association was reversed (RR=1.06; 95% CI: 0.87, 1.29).
Risk of Bias
The risk of bias of included studies in relation to specific criteria is summarized in in Table
S1, which is available online as supplementary information. No study was assessed as risk
free, generally due to a lack of included information rather than specific evidence suggestive
of a trial being high risk. Most studies indicated how the participants had been randomized
with the exception of one.25 Only one study failed to provide data for an intention-to-treat
analysis22 However, power calculations were omitted from three studies,20-21,23 with only one
study adequately powered.18
Of the folic acid RCTs, the Jaszewski study20 was considered the lowest quality trial, with a
drop-out rate of 31%, discrepancies in the published data and no information provided on
power calculations.
11
197
198
199
200
201
202
203
204
205
206
207
208
209
210
211
212
213
214
215
216
217
218
DISCUSSION
Our systematic review summarized nutritional interventions in survivors of colorectal
adenomas and cancer since 2006 to evaluate the effects on colorectal adenoma and cancer
recurrence. We identified eight completed and two on-going RCTs in colorectal adenoma
survivors but only one on-going RCT in CRC survivors. Four folic acid RCTs in colorectal
adenoma survivors showed no significant effect on colorectal adenoma recurrence (p>0.05)
when meta-analysed. The remaining RCTs in colorectal adenoma survivors were too limited
and heterogeneous to enable conclusions to be draw about their effect. However, the
ongoing RCT in CRC survivors in remission is to our knowledge, the first RCT in this
population that examines the effect of diet separately from physical activity.
We identified a different range of nutritional interventions than reported in the WCRF/AICR
systematic review. 6 This was largely due to our focus on CRC survivors in remission and the
inclusion of biomarkers of pre-cancerous cell or tumour progression, which we considered a
realistic outcome given the timeframe for cancer development. Our meta-analysis on the
association between folic acid and colorectal adenoma recurrence confirmed the findings of
three recently published systematic reviews that found no significant association between
folic acid and overall adenoma recurrence.29-31 Two of the four completed non-folic acid
RCTs that we identified (phytoestrogen/insoluble fibre and anti-oxidants) demonstrated a
reduced risk of recurrence, warranting additional larger-scale studies to replicate the
results. However, the WCRF/AICR review identified six anti-oxidant RCTs that when meta-
analysed, showed no significant effect on colorectal adenoma recurrence (OR: 0.63; 95% CI:
0.36-1.12) with high heterogeneity between studies (I2=78.2).6 In fact, the WCRF/AICR
12
219
220
221
222
223
224
225
226
227
228
229
230
231
232
233
234
235
236
237
238
239
240
advise against dietary supplement intake for both primary cancer prevention and for cancer
survivors.2
Our systematic review identified one completed GTE RCT,23 that reported a reduction in
colorectal adenoma recurrence but the statistical significance was lost when an intention-
to-treat analysis was performed. In animal studies, GTE has been shown to reduce the
number and growth rate of colorectal adenomas in the Apcmin mouse, a model for colorectal
adenoma development.32-33 However, excluding the RCTs identified in the current review,
evidence in humans is still limited to observational studies examining the link with primary
CRC prevention with a recent Cochrane narrative review reporting that the evidence was
too limited and conflicting to base recommendations on.34 Studies have also been
undertaken in Asia where baseline green tea consumption is high.34,35 The ongoing GTE RCT
we identified is Germany,26 excludes patients with moderate or high green tea consumption
and will provide the highest quality evidence to date to support any effect of green tea
consumption on colorectal adenoma recurrence in a European population.
Interestingly, all completed studies we identified involved dietary supplementation
interventions. However, the effect of supplements can be highly confounded by the lifestyle
habits of intervention subjects and more specifically the intake of the assessed nutrient in
their diet.36 Additionally, the effect of the supplement may differ depending on the dosage
and timing of the intervention. Folic acid has been reported to impair carcinogenesis in pre-
cancerous cells but promote it in established cancer cells in animal studies.37 These factors
could collectedly explain the difference in the direction of the effect between studies (see
Figure 2), particularly if some of the subjects had undetected colorectal carcinomas.
13
241
242
243
244
245
246
247
248
249
250
251
252
253
254
255
256
257
258
259
260
261
262
Our review had a number of limitations. First, only one researcher was involved in the
search process so eligible studies may have been missed. Similarly, the assessment of risk of
bias was made by one researcher; another researcher may have evaluated the studies
differently. These limitations were partially circumvented by consulting a second researcher
(GKP) at regular intervals for guidance on any areas of uncertainty. Despite the search of
grey literature, it is also possible that unpublished studies, which are frequent in cancer,
were not identified.38 Additionally, we did not exclude studies based on methodological
quality as we expected this criterion would severely limit the search results. Our meta-
analysis used summary statistics rather than individual level data thus we relying on the
accurate statistical analysis and reporting of the primary data by the original researchers.
Finally, our focus on RCTs may have limited our search results through not being the most
widely used study design in CRC survivors. Although meta-analyses of RCTs are generally
ranked as the highest level of clinical evidence, the WCRF/AICR39 and others40 regard
epidemiology, particularly longitudinal prospective cohort studies, as a more relevant study
design for identifying the aetiology of a disease. However, two recent reviews8,9 that
included observational research in their search criteria, failed to identify any observational
studies in CRC survivors in remission suggesting that research in this population is limited
across all study designs.
Our review had a number of strengths. The focus on CRC survivors in remission and
colorectal adenoma survivors is highly relevant in the context of public health given the
increase in the number of CRC survivors living beyond five years3 but also the high incidence
of CRC.1 A systematic approach to identify trials and critically assess their risk of bias was
used and the search strategy employed a comprehensive, well researched list of search
14
263
264
265
266
267
268
269
270
271
272
273
274
275
276
277
278
279
280
281
282
283
284
285
terms and included four key databases (Medline, Embase, Scopus, Web of Science ) and the
Cochrane Library. The inclusion of ongoing RCTs in our search criteria was another strength
as it highlighted the only RCT in CRC survivors in remission and other highly relevant ongoing
RCTs that were not included in previous reviews. By highlighting the paucity of RCTs in CRC
survivors, our review underlined the need for additional primary research in this population.
This is highly relevant in the context of the more abundant research that is available for
other types of cancer, most notably breast and prostate.12
Future research is warranted in CRC survivors in remission focusing on food-based
interventions as most research to date has investigated vitamin, mineral and other types of
supplementation in colorectal adenoma survivors. Dietary factors that are linked with
modified primary CRC risk could form the basis of future RCTs in CRC survivors to confirm
whether the same factors are associated with CRC recurrence. This concept forms the basis
of the ongoing RCT we identified in CRC survivors which aims to reduce red meat
consumption (and refined grains) in CRC survivors in remission.28 We also identified an as
yet unpublished RCT that involves reducing red meat and eliminating processed meat
consumption in colorectal adenoma survivors (ISRCTN: 03320951) which assesses
compliance and if successful, a RCT assessing colorectal adenoma recurrence will follow.
Additionally, since isolating the effects of specific foods or nutrients is challenging due to
their interaction with other dietary components, this could be circumvented through
investigating the effects of healthy dietary patterns in a RCT design in CRC survivors. In
prospective cohort studies, Westernized dietary patterns have been associated with an
increased risk of primary colorectal cancer in the general population41-42 and poorer disease
free survivals in CRC survivors recruited during chemotherapy.43
15
286
287
288
289
290
291
292
293
294
295
296
297
298
299
300
301
302
303
304
305
306
307
308
In conclusion, there is currently insufficient evidence that dietary interventions modify CRC
recurrence in CRC survivors or adenoma recurrence in colorectal adenoma survivors.
Although our systematic review identified one ongoing RCT in CRC survivors in remission,
overall it highlighted the need for further research especially in CRC survivors in remission.
The results from such research will provide valuable information to evaluate whether
dietary factors relevant to primary CRC prevention have a similar effect on CRC recurrence.
16
309
310
311
312
313
314
REFERENCES
1. Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Maxwell et al. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer 2010; 127: 2893-2917
2. Allemani C, Weir HK, Carreira H, Harewood R, Spika D, Wang X-S et al. Global surveillance of cancer survival 1995–2009: analysis of individual data for 25 676 887 patients from 279 population-based registries in 67 countries (CONCORD-2). Lancet 2014; 385: 977-1010
3. Scholefield JH, Steele RJ. Guidelines for follow up after resection of colorectal cancer. Gut 2002; 51(Suppl V): v3–v5
4. World Cancer Research Fund/American Institute for Cancer Research. Food, nutrition, physical activity and the prevention of cancer: a global perspective. American Institute for Cancer Research: Washington, USA, 2007.
5. Rock CL, Doyle C, Demark-Wahnefried W, Meyerhardt J, Courneya KS, Schwartz Al et al. Nutrition and Physical Activity Guidelines for Cancer Survivors. CA Cancer J Clin 2012; 62: 242-274
6. Bekkering T, Beynon R, Davey Smith G, Davies A, Harbord R, Sterne J et al. A systematic review of randomized controlled trials investigating the effect of nutritional and physical activity interventions on cancer survival, updated report World Cancer Research Fund Available at: www.dietandcancerreport.org/cancer_resource_center/downloads/SLR/Cancer_survivors_SLR.pdf (accessed: 28 March 2014)
7. World Cancer Research Fund / American Institute for Cancer Research. Continuous Update Project Report. Food, Nutrition, Physical Activity, and the Prevention of Colorectal Cancer. American Institute for Cancer Research: Washington, USA, 2011.
8. Vrieling A , Kampman E. The role of body mass index, physical activity, and diet in colorectal cancer recurrence and survival: a review of the literature. Am J Clin Nutr 2010; 92: 471-479
9. van Meer S, Leufkens AM, Bueno-de-Musquita HB, van Duijnhovan FJB¸ van Oijen MGH, Siersema PD. Role of dietary factors in survival and mortality of colorectal cancer: a systematic review. Nutr Rev 2013; 71: 631-641
10. Pekmezi D, Demark-Wahnefried W. Updated evidence in support of diet and exercise interventions in cancer survivors. Acta Oncol 2011; 50: 167-178
11. Davies N, Thomas R, Batehup L. Advising Cancer Survivors About Lifestyle: A Selective Review of the Evidence. Available at: www.ncsi.org.uk/wp-content/uploads/Lifestyle-Review.pdf (accessed 28 March 2014).
12. Davies NJ, Batehup L, Thomas R. The role of diet and physical activity in breast, colorectal and prostate cancer survivorship: a review of the literature. Br J Cancer 2011; 05: S52-S73
13. Leslie A, Carey FA, Pratt NR, Steele RJ. The colorectal adenoma-carcinoma sequence. Br J Surg 2002; 89: 845-60
14. Velicier CM, Ulrich CM. Vitamin and Mineral Supplement Use Among US Adults After Cancer Diagnosis: A Systematic Review J Clin Oncol, 2008; 26: 665-67
15. Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gotzsche PC Ioannidis JP et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration. Ann Intern Med 2009; 151: W-65-W-94
16. Higgins JPT, Green S. Cochrane handbook for systematic reviews of interventions version 5.1. 0 [updated March 2011]. Available at: http://handbook.cochrane.org/ (accessed: 28 March 2014)
17. Review Manager (RevMan). [Computer Programme].Version 5.3. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration 2014
18. Cole BF, Baron JA, Sandler RS, Haile RW, Ahnen DG, Bresalier RS et al. Folic acid for the prevention of colorectal adenomas: a randomized clinical trial. JAMA 2007; 297: 2351-2359
19. Logan RFA, Grainge MJ, Shepherd VC, Armitage NC, Muir KR. Aspirin and Folic Acid for the Prevention of Recurrent Colorectal Adenomas. Gastroenterology 2008; 134: 29-38
17
315
316317318319320321322323324325326327328329330331332333334335336337338339340341342343344345346347348349350351352353354355356357358359360361362
20. Jaszewski R, Misra S, Tobi M, Ullah N, Naumoff JA, Kucuk O et al. Folic acid supplementation inhibits recurrence of colorectal adenomas: A randomized chemoprevention trial. World J Gastroenterol 2008; 14: 4492-4498
21. Wu K, Platz EA, Willett WC, Fuchs CS, Selhub J, Rosner BA et al. A randomized trial on folic acid supplementation and risk of recurrent colorectal adenoma. Am J Clin Nutr 2009; 90: 1623-1631
22. Bonelli L, Puntoni M, Gatteschi B, Massa P, Missale G, Munizzi F et al. Antioxidant supplement and long-term reduction of recurrent adenomas of the large bowel. A double-blind randomized trial. J Gastroenterol 2013; 48: 698-705
23. Shimizu M, Fukutomi Y, Ninomiya M, Nagura K, Kato T, Araki H et al. Green tea extracts for the prevention of metachronous colorectal adenomas: a pilot study. Cancer Epidemiol Biomarkers Prev 2008; 17: 3020-3025
24. Limburg PJ, Mahoney MR, Allen Ziegler KL, Sontag SJ, Schoen RE, Benya R et al. Randomized phase II trial of sulindac, atorvastatin, and prebiotic dietary fiber for colorectal cancer chemoprevention. Cancer Prev Res 2011; 4: 259-269
25. Principi M, Leo AD, Pricci M, Scavo MP, Guido R, Tanzi S et al. Phytoestrogens/insoluble fibers and colonic estrogen receptor β: Randomized, double-blind, placebo-controlled study. World J Gastroenterol 2013; 19: 4325-4333
26. Stingl JC, Ettrich T, Muche R, Wiedom M, Brockmöller J, Seeringer A et al. Protocol for MInimizing the Risk of Metachronous Adenomas of the CoLorectum with Green Tea Extract (MIRACLE): A randomised controlled trial of green tea extract versus placebo for nutriprevention of metachronous colon adenomas in the elderly population. BMC Cancer 2011; 11: 360
27. Hull MA, Sandell AC, Montgomery AA, Logan RFA, Clifford GM, Rees CJ et al. A randomized controlled trial of eicosapentaenoic acid and/or aspirin for colorectal adenoma prevention during colonoscopic surveillance in the NHS Bowel Cancer Screening Programme (The seAFOod Polyp Prevention Trial): study protocol for a randomized controlled trial. Trials 2013; 14: 237
28. Ho JWC, Lee AM, MacFarlane DJ, Fong DYT, Leung S, Cerin E et al. Study protocol for "moving Bright, Eating smart" - A phase 2 clinical trial on the acceptability and feasibility of a diet and physical activity intervention to prevent recurrence in colorectal cancer survivors BMC Public Health 2013; 13: 487
29. Carroll C, Cooper K, Papaioannou D, Hind D, Tappenden P, Pilgrim H et al. Meta-analysis: folic acid in the chemoprevention of colorectal adenomas and colorectal cancer Aliment Pharmacol Ther 2010; 31: 708-718
30. Figueirdo JC, Mott LA, Giovannucci E, Wu K, Cole B, Grainge MJ et al. Folic acid and prevention of colorectal adenomas: a combined analysis of randomized clinical trials Int J Cancer 2011; 129: 192-203
31. Fife J, Raniga S, Hider PN, Frizelle FA. Folic acid supplementation and colorectal cancer risk: a meta-analysis. Colorectal Dis 2010; 13: 132-137
32. Ju J, Hong J, Zhou JN, Pan Z, Bose M, Liao J et al. Inhibition of intestinal tumorigenesis in Apcmin/+ mice by (-)-epigallocatechin-3-gallate, the major catechin in green tea. Cancer Res 2005; 65: 10623-10631
33. Issa AY, Volate SR, Muga SJ, Nitcheva D, Smith T, Wargovich MJ. Green tea selectively targets initial stages of intestinal carcinogenesis in the AOM-Apcmin mouse model. Carcinogenesis 2007; 28: 1978-1984.
34. Boehm K, Borrelli F, Ernst E, Habacher G, Hung SK, Milazzo S et al. Green tea (Camellias sinensis) for the prevention of cancer Cochrane Database Syst Rev doi: 10.1002/14651858.CD005004.pub2.
35. Sun, CL, Yuan JM, Koh WP, Yu MC. Green tea, black tea and colorectal cancer risk: a meta-analysis of epidemiological studies. Carcinogenesis 2006; 27: 1301-1309
36. Martinez ME, Jacobs ET, Baron JA, Marshall JR, Byers T. Dietary Supplements and Cancer Prevention: Balancing Potential Benefits Against Proven Harms. J Natl Cancer Inst 2012; 104: 732-73
18
363364365366367368369370371372373374375376377378379380381382383384385386387388389390391392393394395396397398399400401402403404405406407408409410
37. Kim YI. Folate and Carcinogenesis: Evidence, mechanisms and implications. J Nutr Biochem 1999; 10: 66-88
38. Egger M, Juni P, Bartlett C, Holenstein F, Sterne J. How important are comprehensive literature searches and the assessment of trial quality in systematic reviews? Executive Summary. Health Technol Assess 2003; 7: 1
39. WCRF/IARC Systematic Literature Review Specification Manual (version 15) (no date) Available at: http://www.dietandcancerreport.org/cancer_resource_center/downloads/SLR_Manual.pdf (accessed 28 April 2014)
40. Greenhalgh T. How to read a paper: getting your bearings (deciding what the paper is about) BMJ 1997; 315: 234-246
41. Fung T, Hu FB, Fuchs C, Giovannucci E, Hunter DJ, Stampfer MJ et al. Major dietary patterns and the risk of colorectal cancer in women Arch Intern Med 2003; 163: 309-314
42. Wu K, Hu FB, Fuchs C, Rimm EB, Willett WC, Giovannucci E. Dietary patterns and risk of colon cancer and adenoma in a cohort of men (United States). Cancer Causes Control 2004; 15: 853-862.
43. Meyerhardt JA, Niedzwiecki D, Hollis D, Saltz LB, Hu FB, Mayer RJ et al. Association of Dietary Patterns with Cancer Recurrence and Survival in Patients with Stage II Colon Cancer JAMA 2007; 298: 754-764
19
411412413414415416417418419420421422423424425426427
TABLES AND FIGURES
Figure 1. Flow chart of the search and selection process for articles included in the systematic review of randomized controlled trials investigating the effects of nutritional interventions in survivors of colorectal cancer and colorectal adenomas.
20
982 studies found Medline: n=273Embase: n=396Scopus: n=187Web of Science: n=41Cochrane: n=85
609 unique citations identified following de-duping
373 duplicates removed
590 articles excluded after title/abstract screening
11 articles included in review
11 articles excluded for following reasons:not randomized controlled trials (n=5); combined with physical activity (n=2); no control (n=2); other (n=2)
3 additional completed RCTs identified from review papers bibliography search (n=2) and research registers (n=1)
4 studies included in meta-analysis
19 full-text articles screened
428
429
430
431
432
433
434
435
436
437
438
439
440
441442443
Table 1. Characteristics of included trials for the systematic review of randomized controlled trials (RCT) of dietary interventions in survivors of colorectal cancer (CRC) and colorectal adenomas.First author (Year)
Nutritional Factor Investigated
Setting (Population; Country; Age) Outcome Sample size Treatment Follow Up Results
Completed TrialsCole et al. (2007)17
Folic Acid History of colorectal adenomas but not FAP or HNPCC; in USA or Canada (9 centres); aged 21-80 years (average 57 years of age in both groups).
Primary: colorectal adenoma recurrence; secondary: advanced lesion and adenoma multiplicity.
Total randomized: 1021. folic acid only (no aspirin): 170; placebo only (no aspirin): 169
1 mg folic acid or placebo 1xday.
3 years and 6 or 8 years
RR= 1.20; 95% CI: 0.95-1.51
Jaszewski et al. (2008)19
Folic acid History of colorectal adenomas but not FAP or HNPCC; USA (1 centre); aged 18-80 years (average 60 and 62 years in intervention and placebo groups respectively).
Colorectal adenoma recurrence.
Total randomized: 177; folic acid: 80; placebo: 97
5 mg folic acid or placebo 1xday.
3 years RR= 0.44; 95% CI: 0.24-0.83
Logan et al. (2008)18
Folic acid History of colorectal adenomas; UK (9 centres) and Denmark (1 centre); < 75 years (average 58 years in both groups).
Primary: colorectal adenoma recurrence or cancers; secondary: colorectal adenoma multiplicity and advanced colorectal adenomas.
Total randomized: 945; folic acid only (no aspirin): 234; placebo only (no aspirin): 233
0.5 mg folic acid or placebo 1xday.
3 years RR= 1.10; 95% CI: 0.81-1.49
Wu et al. (2009)²º
Folic Acid History of colorectal adenomas; US (2 cohorts); average age: 65 years (intervention group) and 66 years (placebo group).
Primary: colorectal adenoma recurrence; secondary: colorectal adenoma by site and stage and multiplicity of colorectal adenomas.
Total randomized: 672; intervention: 338; placebo: 334
1 mg folic acid or placebo 1xday.
5 years, 4 months
Adjusted RR= 0.86; 95% CI: 0.65-1.15
Bonelli et al. (2012)21
Multi-vitamin and mineral supplement
History of colorectal adenomas but not FAP or HNPCC; Italy (3 centres); aged 25-75 years (average: 58 years in intervention group and 37 years in placebo group).
Colorectal adenoma recurrence.
Total randomized: 411; intervention: 200; placebo: 211
200 µg selenium, 30 mg zinc, 2 mg vitamin A, 180mg vitamin E or placebo 1xday.
4 years Adjusted HR: 0.61; 95% CI: 0.41-0.92
21
Limburg et al. (2011)23
Prebiotic dietary fibre
History of previously resected colon cancer or advanced colorectal adenoma; USA (10 centres); > 40 years (average - 58 years).
Primary : percentage change in rectal ACF; secondary: changes in proliferation and apoptosis
Total randomized: 88; prebiotic dietary fibre: 20; Control: 22. (Other groups – NSAID and statin)
ORAF TI Synergy 1 (prebiotic dietary fibre) 2xday or control: maltodextrin, 2xday.
6 months Median value (range) of %∆ACF: (-3.6% (-88% to 83%) versus -10% (-100% to 117%), (p=0.92) – dietary fibre v control group.
Principi et al. (2013)24
Phytoestrogens and insoluble fibre
History of previous endoscopic polypectomy; Italy (1 centre); no age restriction in men but women had to be post-menopausal.
Primary: change in estrogen receptor expression (ERα and ERβ); secondary: epithelial proliferation and apoptosis.
Total randomized: 60; intervention: 30; placebo: 30;
750 mg insoluble and indigestible oat fibre, 50 mg flaxseed dry extract and 175 mg milk thistle extract 2xday.
2 months Significant increase in ER-β protein (0.822 ± 0.08 v 0.768 ± 0.10; p=0.04). No significant increase in any other estrogen receptor proteins or mRNA, markers of or proliferation.
Shimizu et al. (2008)22
GTE History of colorectal adenomas; Japan (4 centres); aged 20-80 years (average: 62 and 63 years in intervention and placebo groups respectively)
Colorectal adenoma recurrence
Total randomized: 136; intervention: 68; Control: 65.
GTE tablets 3xday or no supplement. One tablet of GTE (500 mg) contained 52.5mg EGCG, 12.3 mg epicatechin, 34.6 mg epigallocatechin, 11.1 mg epicatechin gallate and 15.7 mg caffeine.
12 months RR= 0.49; 95% CI: 0.24- 0.99 N.B. intention-to-treat analysis (data not provided) was insignificant.
Ongoing TrialsReference Nutritional
Factor Investigated`
Setting (Population; Age; Country) Outcome Sample size Treatment Follow Up Results
22
Stingl et al. (2011)25
GTE History of colorectal adenomas; Germany; aged 50-80 years;
Primary: colorectal adenoma recurrence; secondary: subtypes of colorectal adenomas, frequency of carcinoma, genetic and biochemical biomarkers for colorectal adenoma recurrence.
Total randomized: 2,534 to be split equally between placebo and intervention.
GTE containing 150 mg of EGCG supplement v placebo.
3 years N/A
Ho et al. (2012)27
Reduction in consumption of red and processed meat and refined grains
CRC patients within one year of completion of cancer treatment; Hong Kong; >18 years of age.
Primary: decreased western-pattern diet and increased physical activity; secondary: compliance and health benefits including quality of life.
Total randomized: 222; 4 equal intervention groups.
i) dietary intervention: reduce red meat and processed meat to < 5 portions weekly and refined grains to 2 portions x day; ii) physical activity intervention: first 6 months – 30 mins/5 days a week; following 6 months – 60 mins/5 days a week; iii) diet and activity intervention (combination of both) and iv) usual care.
1 year and 2 years
N/A
Hull26 EPA Patients with a history of colorectal adenomas; UK; 60-73 years.
Primary : colorectal adenoma recurrence; secondary: adverse events, number of advanced colorectal adenomas, downgrading of high risk status, number of advanced colorectal adenomas, location of colorectal adenomas, total number of colorectal adenomas.
Total randomized: 904. 4 groups
Group 1: 1 g EPA 2xday and 300 mg aspirin 1xday; Group 2: 1 g EPA 2xday and aspirin placebo 1xday; Group 3: EPA placebo 2xday plus 300 mg aspirin1xday; Group 4: EPA placebo 2xday plus aspirin placebo 1xday
12 months N/A
Abbreviations: FAP, familial adenomatous polyposis; HNPCC, hereditary nonpolyposis colorectal cancer; RR, relative risk; CI, confidence intervals; HR: hazard ratio; ACF, aberrant crypt foci; NSAID, nonsteroidal anti-inflammatory drugs; ER, estrogen receptor; mRNA, messenger RNA; GTE, green tea extract; EGCG, epigallocatechin gallate; EPA, eicosapentaenoic acid.
23
444445446
24
447
Figure 2. Risk of adenoma recurrence with folic acid supplementation based on RevMan
results16.
25
448
449
450451
452
453
454
Figure S1. Search strategy for the Medline database for the systematic review of
randomized controlled trials investigating the effects of nutritional interventions in survivors
of colorectal cancer and colorectal adenomas conducted in January 2014.
1. colorectal cancer*.tw.2. colorectal neoplasm.tw.3. exp Colorectal Neoplasms/4. exp Colonic Polyps/5. 1 or 2 or 3 or 46. exp Intestine, Large/7. large intestine.tw.8. colorect*.tw.9. rect*.tw.10. colon*.tw.11. 6 or 7 or 8 or 9 or 1012. exp Carcinoma/13. carcinoma*.tw.14. exp Adenomatous Polyps/15. cancer*.tw.16. polyp*.tw.17. tum?r*.tw.18. lesion*.tw.19. adenocarcinoma*.tw.20. exp Adenocarcinoma/21. exp Adenoma/22. adenoma*.tw.23. exp Precancerous Conditions/24. 12 or 13 or 14 or 15 or 16 or 17 or 18 or 19 or 20 or 21 or 22 or 2325. 11 and 2426. 5 or 2527. surviv*.tw.28. exp Survivors/29. exp Recurrence/30. recurr*.tw.31. 27 or 28 or 29 or 3032. nutr*.tw.33. exp Diet Therapy/34. diet*.tw.35. exp Food/36. food*.tw.37. exp Beverages/38. beverage*.tw.39. alcohol*.tw.40. supplement*.tw.
26
455
456
457
458
459460461462463464465466467468469470471472473474475476477478479480481482483484485486487488489490491492493494495496497498499
41. antioxidant*.tw.42. exp Antioxidants/43. micronutrient*.tw.44. exp Trace Elements/45. exp Vitamins/46. vitamin*.tw.47. 32 or 33 or 34 or 35 or 36 or 37 or 38 or 39 or 40 or 41 or 42 or 43 or 44 or 45 or 4648. 26 and 31 and 4749. limit 48 to (humans and randomized controlled trial and last 8 years)
27
500501502503504505506507508
Supplementary Table 1 Risk of bias of each study in detail
Random Sequence Generation (selection bias)
Allocation Concealment (Selection Bias)
Blinding of Participants and Personnel (performance bias)
Blinding of outcome assessment (detection bias)
Incomplete outcome data (attrition bias)
Selective reporting (reporting bias)
Other bias
Cole et al. (2007)17
Computer-generated in blocks of 6.
Treatment assignments were concealed from participants and study staff except for the pharmacists. Placebo tablets were identical in appearance to folic acid tablets.
See above. Placebo tablets were identical in appearance to folic acid tablets.
Treatment study staff except for the pharmacists. No information on how this was done.
Drop outs reported: Phase 1: died (n=34), lost to follow up (n=9). Phase 2: died (n=16), lost to follow up (n=31).
After randomization, there was limited separate reporting on the outcome of the six sub-groups. The reasons for these omissions are thought to be that the author was focusing on the placebo or folic acid group (with our without the two different doses of aspirin) as a whole.
Power calculations were performed and sufficient sample numbers acquired.
Jaszewski et al. (2008)19
Randomization was performed using a "stratified randomization block". No other information was provided.
Selected assignment was made in advance and recorded in sealed envelopes, numbered consecutively.
Unspecified. Unspecified. No consort flow diagram. 139 eligible subjects randomized. 94 completed the 3 year analysis. 43 dropped out - unrelated deaths (n=28), relocation (n=15). Very high level of deaths despite excluding for co-morbidities. Analysis on 49 (intervention) and 45 (control). In drop-out subjects, there was no statistically significant difference in key demographics. Not clear how many were in each group at baseline as numbers in chart incorrect.
Recurrent adenomas reported as mean number rather than relative risk. Data from paper cannot therefore be used in meta-analysis.
Inconsistencies in baseline data provided. No power calculations were performed.
28
509
Logan et al. (2008)18
Computer-generated randomized list with a block size of 8, with randomization stratified by centre.
The researchers and all clinical staff involved with patient recruitment were blind to this treatment allocation schedule. All trial medication was bottled, labelled and supplied from the central trial pharmacy and dispensed to patients through regional pharmacies at each participating centre.
Aspirin and folic acid placebo were identical in appearance to active treatments. Study participants, clinical staff involved with patient surveillance and investigators at the coordinating centre were all blind to treatment. Only trial pharmacists had knowledge of treatment.
No further information provided
Drop out data provided and largely balanced across two groups. Folate only intervention - 19 drop outs at stage 1 - died (n=4), lost to follow up (n=5), poor health (n=6), patients refused (n=4). 54 drop outs at stage 2 - withdrew from both medication arms (n=42), withdrew from aspirin only (n=11), withdrew from folic acid only (n=1); Placebo Intervention - 29 drop outs at stage 1 - died (n=7), lost to follow up (n=7), poor health (n=7), patient refused (n=8). 46 drop outs at stage 2 - withdrew from both medication arms (n=25), withdrew from aspirin only (n=21).
Apparently free of selective outcome reporting - all stated outcomes reported.
Power calculations provided but required sample size not met.
Wu et al. (2009)20
Random number generator
No information provided. No blinding of participants because the control group received no placebo supplement.
Drop out figures were provided and reasons for drop out reported. Difference in drop out figures between groups: n=41 discontinued folic acid intervention v n=62 in intervention group. Similar numbers in final analysis cohorts (n=237 in folic acid intervention and n=238 in cohort). Although number of subjects excluded from analysis were similar in both groups it was not
Apparently free of selective outcome reporting - all stated outcomes reported.
No inclusion of power calculations.
29
explained how these related to drop out figures. Baseline characteristics of participants included in the final analysis were similar to all randomly assigned participants. In the 194 participants who did not receive an endoscopy, characteristics such as age or severity of adenoma at baseline, that may have affected the likelihood of a follow up, did not differ significantly at baseline.
Bonelli et al. (2012)21
No further information provided than randomization lists stratified by centre were provided by the pharmaceutical company.
Each centre received a random list where the assigned treatment was indicated by the label numbers of the bottles containing the pills with no reference to their contents. The active compound and the placebo had an identical appearance and that the bottles and pills contained no reference to their contents.
Double blinded but no further information
States that the trial was double blinded but no further information about blinding of personnel was provided.
All drop outs reported: intervention (n=36): refused follow up colonoscopy (n=29), died (n=6), cancer (n=1); control (n=45): refused follow up colonoscopy (n=35), died (n=9), cancer (n=1).
Apparently free of selective outcome reporting - all stated outcomes reported.
Power calculations provided but required sample size not met. No collection of information on confounding factors at baseline.
Limburg et al. (2011)23
"Dynamic allocation procedure".
No information provided. Some interventions were delivered as tablets and some as powder. Also different daily dosages used.
No information provided. Low drop-out rate and drop out reasons provided: lost to follow up (n=3), withdrew consent (n=2), medical contraindications (n=1), other (n=2).
Apparently free of selective outcome reporting - all stated outcomes reported.
Power calculations provided but required sample size not met.
Principi et al. (2013)24
Computer generated.
Unspecified. States that the patients and investigators were blinded
States that both LI and intensity staining were calculated by two independent observers in a blinded fashion without
Much higher percentage withdrawal in intervention than control group. 7 out of 30 patients withdrew from the intervention group (4
Apparently free of selective outcome reporting - all stated outcomes reported.
Power calculations provided but required sample size
30
to assignment without providing any further information.
providing any further information.
withdrew consent before T60 colonoscopy and 3 were lost to T60 colonoscopy). 3 out of 30 patients withdrew from the control group (3 withdrew consent before T60 colonoscopy).
not met.
Shimizu et al. (2008)22
Not described. Unspecified. No blinding of participants because the control group received no placebo supplement.
States that endoscopists were blinded to the study group but no further information provided.
8 patients were lost to follow up in intervention arm only as they could not be reached from the day after the initiation of the trial. No intention to treat analysis included. Author refers to it in the discussion and states that the results were insignificant.
Apparently free of selective outcome reporting - all stated outcomes reported.
Power calculations not provided.
31
510