Prevention of colorectal cancer: systematic review of clinical studies in human volunteers; comparison with rats & mice.
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Colon Cancer Prevention, Clinical Trials in Human Volunteers
- [Man] table is a summary of dietary prevention of colorectal tumors in humans, first published in CEBP. It shows the efficacy of agents or diets to reduce Adenomatous polyp recurrence (Adeno. rec.) or ColoRectal Cancer incidence in humans (CRC incid.).
Comparison of Human Data with Animal Models Data.
- [MenRatsMice], another table, compares human data with tumor incidence in azoxymethane initiated rats and polyp number in Min mice. It was published the [Eur.J.Cancer]
See below explanations on both tables, and comments on the discrepancies between human's and rodent's studies.
--- How well do the animal models predict what happens in the clinical trials?
To answer this question we built a [MenRatsMice] table showing the effect of dietary interventions on the recurrence of colonic polyps in humans (1), compared with effects on tumors in rats (2) and in mice (3).
(1)- Human data were gathered from randomized, placebo-controlled trials directed at preventing the recurrence of colonic adenomatous polyps in human volunteers: [Man]. Data from each individual study were then summarized as "weighted mean RR/agent", by a simple-minded meta-analysis.
(2)- The mean effect in rats was extracted from the [Tumors] data base of positive studies, to which were added null and negative studies.
(3)- The mean effect in Min mice was calculated from the [Min] data base.
This [MenRatsMice] table is obviously a first approach to such a comparison, since no account was taken of the dose used, and the data presented are not homogeneous across different models. The table, none-the-less, shows that the effect of most of the diets or agents is consistent across the various models though discrepancies are seen between the effect of agents in humans and in animals as explained below.
Comments on Discrepancies
- NSAIDs strongly decrease the tumor yield in the colon of AOM-injected rats, and in the small intestine of mutant mice. This is consistent with epidemiological studies suggesting that, taken collectively, NSAIDs might decrease the colorectal cancer incidence by 45% in humans. It is also consistent with the effect of celecoxib and sulindac which decrease the polyp number in familial adenomatous polyposis patients trials. However, as detailed in Corpet and Pierre (CEBP, 2003), several independent studies (but not all) show that some NSAIDs can increase the tumor yield in the colon of mutant mice.
- Wheat bran consistently reduces carcinogenesis in animals, but has apparently no significant effect in humans, a discrepancy for insoluble fibers, already pointed out by Giovannucci.
Psyllium, a soluble fiber also called MetaMucil, decreased carcinogenesis in rats (Wilpart 1987), but increased the tumor recurrence in human volunteers (Bonithon 2000). However, both results are only supported by a single study each. An early study showed a strong promotion by psyllium of DMH-induced cancers: most psyllium-treated mice died before control mice (Toth 1984), but mortality data cannot be included in the Chemoprevention Database. In addition, most soluble fibers similar to psyllium show promoting properties in AOM-induced rats: these and Toth's data fit the human trial result.
- Fat: Rats and mice fed a high fat diet have usually more tumors than controls fed a low fat diet. In rodents, the relationship between the colon cancer incidence and the intake of fat remains true when controlled for calorie consumption. Fatty diets with high linoleic acid content, and n-6-polyunsaturated fatty acids, seem particularly consistent promoters in rodents (Zhao 1991). In contrast, neither human trials nor observation studies support fat, or linoleic acid, as tumor promoters in humans (Willet 1995
), a discrepancy already pointed out by Giovannucci.
- Caloric reduction is a strategy that seems very efficient in animals. Overnutrition could be seen as the most potent "carcinogen" in rodents (Lutz 1992
). According to Willett (2001), a positive energy balance (caloric intake versus physical activity) is the most powerful and consistent dietary influence on human carcinogenesis. No published human trial specifically tested the effect of caloric reduction. However, a side effect of interventions with low-fat diet, and with fruits and vegetables, was a modest reduction in caloric intake (Schatzkin 2000,
Beresford 2006). The lack of reduction in polyp recurrence seen in the trials summarized in the [Man] table suggests the caloric reduction was too small to reduce insulin resistance, a link between overnutrition and carcinogenesis that was speculated by Mckeown-Eyssen, 1994, and by Giovannucci, 1995.
- Veg. & Fruits: That fruits and vegetables consumption protects against colorectal cancer is a dogma supported by many epidemiological studies (Gerber 2002
; WCRF 1997), an association that may have been overstated (Michels 2000). This dogma is challenged by all the experimental studies in rats, mice and humans (see the [Man] table). Indeed, a mixture of fruits and vegetables, reproducing what people typical consume, marginally increased the tumor yield in most animal studies (VanKranen 1998
, Alink 1993, Rijnkels 1997, Rijnkels 1998), although large amounts of black raspberries or of orange juice can inhibit carcinogenesis in rats (Harris 2001, Miyagi 2000).
Conclusion: in spite of the discrepancies, the [MenRatsMice] table, and summary figures, shows that the effect of most of the diets or agents is consistent across the various models.
Explanations and NOTES to the [Man] and [MenRatsMice] tables
- Agents or diets tested in clinical trials, ranked by efficacy in humans. See the notes
below on specific agents & studies.
- Study Qual. Study Quality:
[!] ! denotes a human value not firmly established, because from a small size trial, or because the primary end point was not colon tumor.
[top] Top studies have no major flaw, according to the author of this site (see home page bottom).
[! NP], No Placebo given to controls (thus not a double-blind study);
[! EP], EndPoint: primary end-point was not Adenomatous polyp recurrence or Colorectal Cancer incidence;
[! SS], Small Study with not enough treated volunteers to yield solid data (N<99);
[! NR], No Randomization: volunteers choose their treatment;
[! WI], Weak Intervention: dietary advices were given but change was small;
[! AB], Abstract: the study has not yet been published in a peer-reviewed scientific journal.
- Gender: Female, Male or Both. The four "female" trials show no protection, while three "male" trials out of nine show some protection (non significant).
- Weighted mean/agent= attempt to estimate a single RR value for each agent in [Man] (a true meta-analysis approach would be better, but it cannot be done automatically in an Excel table). For each study, "size" was estimated by number of treated volunteers; "relevance factor" was arbitrarily set to: 1 for studies of "top" quality; between 0.3 and 0.6 for other studies; Study Weight = 'size' x 'relevance factor'. Then for each agent (e.g., aspirin), "weighted mean RR" was estimated by summing weighted RRs, and dividing the sum by the sum of weights. (if you know a better way to do a simple and rapid weighted mean, please send me a mail: see home-page bottom). Weighted mean RR was diplayed in last column of [Man], and included in first column of [MenRatsMice].
- AOM-rats, colon tumor incidence. Data come from a systematic review of positive rat's studies, pooled with null and negative published rat's studies. Data are treatment effects, averaged from all published studies, and rounded to the nearest ten. Calculation: (colorectal tumor incidence in treated group) / (incidence in control group). A percentage smaller than 1 denotes a protective effect.
- rats: No.of studies. number of independant publications whose results were pooled to yield the mean in the previous column.
- Min mice, polyp number, (small bowel): Data are treatment effects, averaged from all published studies, and rounded to the nearest ten. Calculation: (intestinal polyp number in treated group) / (intestinal polyp number in control group). A percentage smaller than 1.00 denotes a protective effect. Thus, in mice column, polyp number was used in place of tumor incidence.
- mice: No.of studies. number of independant publications whose results were pooled to yield the mean in the previous column.
NOTES for specific agents (same order as Table's lines: small RRs on top)
- Lactulose and Vitamin mixture (A+C+E): No placebo-treated controls in Roncucci's small size trial, thus not double-blind. RR and 95%C.I. were not given in the article, but calculated from table 4 p.231.
- Selenium: The top-3 double-blind studies, with lowest RRs, used Selenium supplements: Selenium thus seems the "best-choice" from this database. But these three selenium trials were not flaw-free. Colon cancer was a secondary endpoint in the selenium trial, primarily designed to reduce skin cancer (Clark 1996).
- Se,Zn,vit.C,vit.E,B-car: Colon cancer was a secondary endpoint in the SUVIMAX trial, primarily designed to reduce cardiovascular or cancer mortality. The intervention with SUVIMAX antioxidant mixture (Selenium 100 microgram, Zn 20 mg, vit.C 120 mg, vit.E 30 mg, B-carotene 6 mg) significantly reduced cancer incidence, and all-cause mortality, in men only (not in women). Digestive tract data shown in the table were extracted from top panel (men) in Fig.3 of Hercberg, 2004.
Hofstad's daily supplement was indeed a mixture containing: selenium 101 microgram, calcium 1.6 g, Vit.C 150 mg, vit.E 75 mg, beta carotene 15 mg. RR and 95%C.I. were calculated from data p.153. Hofstad's trial is placed in the Table with "Selenium & vitamin mixtures", and duplicated with calcium trials
- Sulindac sulfide: Primary endpoint in Arber's trial was change in polyp size from baseline. The decrease in median polyp size was significantly greater in exisulind 400 mg treated group (-10mm2) than in placebo-treated (-4mm2) (p=0.03). However, no difference between Intent-to-Treat populations (polyp size decrease -4 and -2 mm2), and no effect of exisulind low dose (200 mg). RR and 95%C.I. are not shown in the article. They were calculated from table 4, using "complete + partial responses" as "no polyp", and "stable + progressive diseases" as "polyps". Also, the article shows some toxicity of exisuling 400mg (increased liver enzymes and abdominal pain).
- Celecoxib: Polyp reduction shown in FAP patients (Steinbach 2000). No data yet published from large scale trials on sporadic polyps recurrence (03/2006). However, Celecoxib and Rofecoxib have been found to increase cardio-vascular risk in prospective trials (myocardial infarction).
- Sulindac shows significant protection in FAP patients (3 small-size trials), not on sporadic polyps (2 trials) (Thun 2002).
Hofstad's daily supplement was indeed a mixture containing: Calcium 1.6 g, beta carotene 15 mg, vit.C 150 mg, vit.E 75 mg and selenium 101 microgram. RR and 95%C.I. were calculated from data p.153. Hofstad's trial is placed in the Table with calcium trials and duplicated with "Selenium & Vitamin mixtures" (e.g., Hercberg's trial).
Mice: In Apc1638 mice, the low-calcium "Western Diet" increased by +175% the tumor yield (Yang 1998
). This result was not included in the table because the diet was also low in vitamin D and high in fat.
- Aspirin /polyps: Significant effect of low dose of aspirin (80 mg/d), no effect of high dose (325 mg/d) (Baron 2003). In contrast with polyp recurrence trials (Baron, Benamouzig, Gann, Sandler: mean RR, 0.85), very large scale aspirin trials show no protection of long-term aspirin on colorectal cancer incidence (Cook, Gann, Sturmer: mean RR, 1.04).
- Lactobacillus casei and Wheat bran: No placebo-treated controls in Ishikawa's small size trial, thus not double-blind. Included patients had at least 2 colorectal tumors removed before start. Both genders were included in the study, but 82% were male volunteers: line is thus labelled "M".
- Wheat bran: in addition to the lines labelled "wheat bran", two trials aimed at changing the whole diet led to an increase in fiber intake, with no change in polyp or cancer endpoint:
Beresford's interventions led to +7g and +3g/d of fiber intake in intervention groups, but no change in polyp or cancer.
- Beta-Carotene: Greenberg's 94 trial was revisited by Baron 2003, showing that B-carotene was associated with a protection (RR=0.56 95%CI= 0.35 to 0.89) in non-smokers non-drinkers. In contrast B-carotene supplements doubled the risk in smokers drinking more than 1 drink/d (RR=2.07, 95%CI= 1.39-3.08).
- Aspirin /CRC: Very large scale trials show no protection of long-term aspirin on colorectal cancer incidence (Cook, Gann, Sturmer: mean RR, 1.04), in contrast with polyp recurrence trials (Baron, Benamouzig, Gann, Sandler: mean RR, 0.85).
- Fruits and Vegetables: Disappointing that the strong health message "Five a day" was not supported by 2 large scale intervention studies: no change at all in polyp recurrence or in CRC risk in people that add 1.3 or 2 Fruits & Vegs servings per day.
Fruits & vegs. do not prevent colon carcinogenesis in rats. Thus, rat data had not been included in the chemoprevention [Tumor] table. For the [MenRatsMice] table, rat data were gathered from Alink 1993, Rijnkels 1997, Rijnkels 1998.
- Calcium & vit.D3: A very large scale trial shows no protection of long-term calcium (and vit.D3) on colorectal cancer incidence (Wactawski-Wende 2006), in contrast with polyp recurrence trials (Baron 99, Bonithon 2000, Hofstad 98: mean RR, 0.79). Thus calcium and aspirin studies show similar discrepancy between polyp recurrence trials and CRC trials results.
- Low Fat: In human volunteers, the interventions were in part, or led to, a dietary fat intake reduction (Schatzkin 2000,
The effect of fat was significant in F344 rats (Zhao 1991), but not in SD rats (not shown).
- Caloric reduction: The above cited low-fat interventions also led to a reduction in caloric intake, estimated as -18%, -10%, -4% and -5% in studies by Schatzkin,
McKeown, Beresford and
MacLennan, respectively. Caloric reduction was shown in [Man] table before 2006, then removed because redundant with Low fat lines. However, no effect of those modest caloric reductions was seen on polyps or cancers.
- Vitamin C & E: Vit.C & vit.E do not prevent colon carcinogenesis in rats. Thus, rat data had not been included in the chemoprevention [Tumor] table. For the [Man] table, rat data were obtained from a comprehensive review: G. Angres and M. Beth. Effects of dietary constituents on carcinogenesis in different tumor models: an overview from 1975 to 1988. in Cancer and Nutrition, Alfin-Slater, R.B. and Kritchevsky, D. editors. Plenum Press, NY, 337-485, 1991.
- Folic acid: B.F.Cole's abstract reports no effect of folic acid supplements taken for 3 years (RR=1.04), except a modest increase in advanced lesions risk (RR=1.31, 95%CI 0.90-1.89). The significant RR=1.44 which is reported in the "Man" table was observed after extended follow-up (duration not reported in Cole's abstract).
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Corpet DE & Taché S, 2002, Nutrition & Cancer - DE Corpet & F Pierre, 2003, Cancer Epidemiol. Biomarkers Prevention - DE Corpet & F Pierre, 2005, Eur.J.Cancer
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