© The Author 2006. Published by Oxford University Press.
ARTICLE |
Nutritional Interventions and Outcome in Patients With Cancer or Preinvasive Lesions: Systematic Review
Affiliations of authors: Department of Social Medicine (AAD, GDS, RH, GEB, JACS, RB), Division of Maxillofacial Surgery (ST), University of Bristol, Bristol, UK
Correspondence to: Steven Thomas, MD, PhD, Division of Maxillofacial Surgery, University of Bristol, Lower Maudlin St., Bristol BS1 2LY, U.K. (e-mail: steve.thomas{at}bristol.ac.uk).
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ABSTRACT |
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 TopNotes Abstract IntroductionPatients and methodsResultsDiscussionReferences |
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Background: Dietary modifications and supplements are used widely by patients with cancer and preinvasive lesions as an adjunct to standard treatment. Given the widespread use of nutritional modifications and supplements by such patients and concerns about the lack of benefit and possible harm, we conducted a systematic review of randomized controlled trials to examine the effect of nutritional interventions on patients with cancer or preinvasive lesions. Methods: We searched electronic databases and reference lists to locate all eligible trials and analyzed trial quality. Outcome measures were all-cause and cancer mortality, disease-free survival, cancer recurrence, second primary cancer, recurrence of a preinvasive lesion, or progression to cancer. Results of individual trials were combined by use of random-effects meta-analyses. Results: We identified 59 eligible trials, 25 in patients with cancer and 34 in patients with preinvasive lesions, respectively. Trial quality was generally low; only three trials (two of cancer and one of preinvasive lesions) had adequate methods for generating the allocation sequence, allocation concealment, and masking both outcome assessors and participants. The combined odds ratio (OR) for the effect of a healthy diet—given alone or with dietary supplements, weight loss, or exercise—on all-cause mortality was 0.90 (95% confidence interval [CI] = 0.46 to 1.77). There was no evidence of an association between the use of antioxidant (OR = 1.01, 95% CI = 0.88 to 1.15) or retinol (OR = 0.97, 95% CI = 0.83 to 1.13) supplements and all-cause mortality. Meta-analyses of all other outcomes did not show clear evidence of benefit or harm. Conclusions: The impact of most nutritional interventions cannot be reliably estimated because of the limited number of trials, many of which were of low quality. There is no evidence that dietary modification by cancer patients improves survival and benefits disease prognosis.
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INTRODUCTION |
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Food supplements and vitamins are widely used by patients with cancer as an adjunct to conventional treatment. The personal expenditure on dietary supplements and megavitamins by patients with cancer in the United States was estimated to be $60 million per annum in 1990 and is growing (1). Diet was one of the most frequently discussed treatments in a review of 32 Web sites for complementary and alternative medicine likely to be visited by cancer patients (2). These Web sites were selected by use of a predesigned search strategy as follows: from December 2002 to January 2003 eight popular search engines (http://www.about.com, http://www.altavista.com, http://ask.co.uk, http://search.msn.com, http://www.google.com, http://www.lycos.co.uk, http://search.aol.com, and http://www.yahoo.com) were searched for the terms "complementary" or "alternative medicine" and "cancer." Only Web sites in the English language were explored. The first 50 Web sites that appeared on each search engine were included. These were the sites most visited for this specific search query, at that point in time, according to each search engine's ranking system. Only those sites in the top 50 hits of at least three of the eight preselected search engines were included.
Concern about the dose and use of food supplements and vitamins in general has led to the introduction of a European Union Directive to tighten rules on sale of these products (3). Worries about the nature of these remedies and their possible interaction with drug regimens during cancer treatment have also been highlighted (4).
A recent narrative review (5) concluded that there was no convincing evidence that nutrition interventions are beneficial for survivors of the four major cancers—breast, colorectal, lung, and prostate. Moreover, the authors found no evidence of harm to cancer survivors. This review, however, was limited in its scope and was not systematic. Recent experience suggests that not all dietary modifications and supplements are harmless. For example, findings from two large-scale randomized controlled trials in subjects at high risk of lung cancer have suggested that 
-carotene interventions increase the incidence of lung cancer and overall mortality in smokers (6,7). A recent meta-analysis suggested that high-dose vitamin E supplements may increase all-cause mortality (8).
Given the widespread use of nutritional remedies by patients with cancer and concerns about lack of benefit and possible harm it is important that the use of these diets and supplements is supported by evidence. We therefore conducted a systematic review of randomized controlled trials that examined the effect of nutritional interventions in patients with cancer or preinvasive lesions.
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PATIENTS AND METHODS |
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Search Strategy
We carried out this review as part of a larger review that was designed to examine the role of both diet and physical activity on outcome among patients with cancer or preinvasive lesions. The search strategies and initial inclusion criteria reflect this goal. We searched for literature published through September 30, 2003, by standard systematic review methods (9,10). We searched four online databases: Cochrane Library, MEDLINE, EMBASE, and AMED. We used Medical Subject Headings (MeSH terms) and title and/or abstract words to identify the following: cancer or precancer, survivors, nutrition or physical activity, and randomized controlled trials. The search strategies were adapted for each electronic database (see Supplemental Tables 1–4, available at: http://jncicancerspectrum.oxfordjournals.org/jnci/content/vol98/issue14). We sought to identify additional publications by searching the reference lists of the relevant books, reviews, and publications that we located.
Inclusion Criteria
We considered studies to be eligible for inclusion if they reported on a randomized controlled trial, recruited patients with cancer or preinvasive lesions, and included a nutritional or physical activity intervention. We defined a patient with cancer or a preinvasive lesion as anyone who had been diagnosed with cancer (or preinvasive lesion) from the time of diagnosis through the rest of life (5). We considered a nutritional intervention to be one that altered the intake of foods or dietary constituents either directly (e.g., giving vitamin supplements) or indirectly (e.g., through nutrition education). We defined food as beverages, confectionary, ingredients in preparation of foods, and advertised dietary supplements that contained added vitamins (11). We also included micronutrients in our definition of food. We included trials that reported on one or more of the following outcomes: all-cause mortality, cancer mortality, disease-free survival, cancer recurrence, second primary cancer, number of days in hospital, recurrence of preinvasive lesions, and progression from preinvasive lesions to cancer. There were no restrictions according to language of publication, ethnicity, sex, age of the patients, or type or stage of cancer.
Exclusion Criteria
Our definition of nutritional intervention excluded interventions that were used perioperatively or in combination with chemotherapy or radiotherapy, in which outcomes were related to treatment complications and not cancer survival. We included one study that used a sip feed (a nutritional liquid taken by mouth and used to meet optimal protein and calorie requirements) at the time of radiotherapy and continued use of the feed for 12 months (12). We also excluded studies that used synthetic retinoids, vitamin analogues, herbal supplements, and polysaccharide K (a protein-bound polysaccharide that is extracted from the mycelia of the mushroom Coriolus versicolor) because they did not meet our definition of a nutritional intervention.
Trial Quality Assessment
We assessed three aspects of trial quality: generation of the allocation sequence, concealment of allocation, and masking of outcome assessors and participants to treatment allocation during the trial. We considered generation of allocation sequence and concealment of allocation to be adequate if the resulting sequences were random and if participants and enrolling investigators could not predict the assignment (9). We categorized trials stating that subjects were blinded or including an identical placebo as trials that had masked the participant to their treatment allocation. For trials that reported being double blind, we assumed that both the participants and the outcome assessors had been masked to the participant's treatment allocation.
Statistical Methods
We analyzed trials that recruited patients with cancer separately from those that recruited patients with preinvasive lesions. In trials that recruited patients with cancer at more than one anatomic site, site-specific outcome data were extracted whenever possible. The overall lack of data for any particular cancer or preinvasive lesion meant that anatomic sites were combined for all analyses. Additional cancer-specific findings were reported if data were available. When outcomes were reported at more than one time point within a trial, the outcomes nearest the end of the active intervention period were extracted. Odds ratios (ORs) were used to quantify intervention effects.
If studies had multiple intervention arms and interventions of different types (e.g., one multivitamin supplement and one dietary counseling intervention), each arm was compared with the usual treatment group (or specific placebo group) and analyzed separately. Consequently, some studies could contribute data to more than one analysis and were thus treated as separate trials when the results were pooled. When multiple interventions within a study were of the same type, data from the intervention arms were treated as one group: this method avoided the control groups being included twice in the same meta-analysis but was performed only after first comparing the results from each arm with the results from the control data arm separately to make sure that they were consistent in size and direction of effect. Factorial trials were analyzed by assuming no interaction between interventions. Random-effects meta-analysis was conducted by the method of der Simonian and Laird (9). We derived tests for heterogeneity by referring the heterogeneity statistic Q to the chi-squared distribution, and we quantified the amount of heterogeneity in each meta-analysis by use of the I2 statistic (13), which gives the percentage of variance in the meta-analysis from heterogeneity. All analyses were performed in Stata 8 (StataCorp, College Station, TX; http://www.stata.com) and Comprehensive Meta-Analysis (Biostat, Englewood, NJ; http://www.meta-analysis.com).
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RESULTS |
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The numbers of studies that we included or excluded at each stage of the review process are listed in Fig. 1; a total of 47 publications met the full inclusion criteria. Of the 22 publications reporting trials on patients with cancer (12,14–34), three reported outcome data from more than one comparison, so that 25 trials were available for analysis. DeWaard et al. (18) reported outcomes from the same trial in two different populations (Dutch and Polish), Evans et al. (20) reported outcomes for lung and colorectal cancer patients separately, and van Zandwijk et al. (34) reported outcomes for a factorial trial in which the associations of both vitamin A and N-acetylcysteine with outcome variables could be independently assessed. Seven of the 25 publications (35–59) in patients with preinvasive lesions contained trials with two (39,41,51,53,57,58) or three (46) different interventions, and one of the 25 publications reported data from two separate trials (51), resulting in 34 trials of preinvasive lesions from 25 publications. Data from four trials were reported in more than one publication: Nutritional Prevention of Cancer trial (16,19), Calcium Polyp Prevention Study (36,37), the Linxian Dysplasia Trial (45,47), and a calcium and green tea trial conducted in China (56,57). The general characteristics of the 25 cancer trials and 34 preinvasive lesion trials are summarized separately in Tables 1 and 2, respectively.
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General Characteristics of Trials that Evaluated Patients With Cancer
Eighteen of the 25 trials in patients with cancer were cancer site specific [four for skin (16,19,21,27), three for bladder (15,25,30), four for breast (12,18,33), two for head and neck (22,26), two for lung (23,32), one for cervix (24), one for leukemia (28), one for colorectum (29)] and seven of the 25 trials included multiple sites (14,17,20,31,34). Cancer stage was described in 19 of the 25 trials, of which six were in advanced disease (17,20,23,24,29). Reported duration of the interventions ranged from 4 weeks (24) to five years (21). Of those trials that reported therapeutic treatment at time of intervention (12,14,15,18,20,22–28,30–34), only one (28) began the intervention before treatment had begun.
The interventions among patients with cancer could be broadly categorized into two types: healthy diet and micronutrients. Healthy diet interventions, which were reported in eight trials (12,14,18,20,31,33), were those that advised one or more of the following: a balanced healthy diet, weight loss in overweight women, a general reduction in fat intake (as a percentage of total calories), increased intake of fiber or of fruit and vegetables, or an optimal calorie or protein diet. Micronutrient trials were predominately of antioxidants [two selenium (16,19), two -carotene (21,26), two vitamin C (17,29), one multivitamin that included an antioxidant (25), and one N-acetylcysteine (34)] or retinol (22–24,27,28,32,34), with a few vitamin B6 trials (15,30).
General Characteristics of Trials that Evaluated Patients With Preinvasive Lesions
All 34 interventions in people with preinvasive lesions were site specific: 19 colorectal (35–37,39,41,43,44,46,48–51,54), five esophageal (45,47,56,57), three mouth (53,55), three stomach (58,59), two cervical (40,52), one lung (42), and one skin (38). The duration of the interventions in trials evaluating effects associated with preinvasive lesions ranged from 4 months (42) to 6 years (45,47). The trials included the following numbers of interventions: six healthy diet (35,39,46,49,54), 14 antioxidant [seven multivitamin (41,43,45,47,48,51), six -carotene, (38,41,46,52,53,58), and one N-acetylcysteine (51)], five calcium (36,37,39,56,57), five folate (40,42,44,50,58), two retinol (53,55), one green tea (57), and one vitamin C (59). Most trials compared the nutritional intervention with placebo. However, two trials of fiber also used low-fiber supplements in the comparison groups (35,49), and seven trials used general dietary guidelines (54) or usual treatment (46,51,59), as the comparison group.
Quality of Trials
We assessed three aspects of trial quality: generation of allocation sequence, concealment of allocation, and masking of outcome assessors and participants to treatment allocation during the trial (Table 3). In 12 (48%) of 25 cancer trials and 30 (88%) of 34 preinvasive lesion trials, methods used to conceal allocation were not reported. Three trials [two cancer (21,26) and one preinvasive lesion (42)] had adequate methods for generating the allocation sequence, allocation concealment, and masking both outcome assessors and participants. In most trials, the methods used to generate the allocation sequence and conceal allocation were not reported.
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Outcomes
The following outcomes were reported in nutritional trials: 26 reported all-cause mortality [19 cancer (12,14,16–18,20,21,23,25–29,31,32,34) and seven preinvasive lesion (35,36,39,45,48,54)], 15 reported disease-free survival [six cancer (20,27,28,34) and nine preinvasive lesion (40,42,47,52,53,56,57,59)], and 11 reported cancer mortality [nine cancer (12,15,18,19,24,26,27,32) and two preinvasive lesion (38,45)]. Thirteen nutritional trials also reported cancer recurrence (12,15,16,18,22,24–27,30,32,33), and seven reported second primary cancer (18,19,21,22,26,32) in patients with cancer. Recurrence of preinvasive lesions and development of cancer from preinvasive lesions was reported in 19 (35,36,39,41,43,44,46,48–51,54,55), and seven preinvasive lesion trials (35,37,45,54,57,58). No trials reported the number of days in hospital. Supplemental Tables 5 and 6, detailing the odds ratios (95% confidence intervals [CIs]) for the effect of interventions on individual outcomes, are available at http://jncicancerspectrum.oxfordjournals.org/jnci/content/vol98/issue14.
All-Cause Mortality and Cancer-Specific Mortality in Patients With Cancer
The 19 trials reporting analyzable data on all-cause mortality included the following interventions: seven healthy diet (12,14,18,20,31), four retinol (27,28,32,34) [one retinol trial was not analyzable because all participants died (23)], two -carotene (21,26), two vitamin C (17,29), one multivitamin (25), one N-acetylcysteine (34), and one selenium (16). Eight trials reported data on cancer-specific mortality and included the following interventions: three healthy diet (12,18), one -carotene (26), one selenium (19); three retinol (24,27,32), and one vitamin B6 (15).
As shown in Fig. 2, there was little evidence that a healthy diet, given as dietary advice separately or in specific combinations with supplements, weight loss, or exercise (12,14,18,20,31), was associated with a reduction in all-cause mortality (pooled OR = 0.90, 95% CI = 0.46 to 1.77). When we combined results from the three breast cancer trials only (12,18) (results not shown in figure), the pooled odds ratio was 0.70 (95% CI = 0.26 to 1.87). Data from these three small breast cancer studies also suggested a reduction in cancer-specific mortality (pooled OR = 0.53) with healthy diet interventions, although the confidence interval was wide (95% CI = 0.16 to 1.79). There was little evidence of between-trial heterogeneity. The seven interventions (16,17,21,25,26,29,34) that included an antioxidant supplement found no evidence of an association between this intervention and all-cause mortality, compared with placebo or usual treatment (OR = 1.01, 95% CI = 0.88 to 1.15), with no heterogeneity (I2 = 0%). When we combined data from only the two skin cancer trials (16,21) (data not shown), we also obtained a similar result (pooled OR = 0.92, 95% CI = 0.70 to 1.22). Although a large selenium trial in skin cancer patients (19) showed a 41% (95% CI = 61% to 12%) reduction in cancer mortality in the intervention group, the only other trial (26) reporting the effect of antioxidants on cancer mortality found no evidence of a protective effect of -carotene on head and neck cancer mortality (OR = 1.26, 95% CI = 0.62 to 2.56). Retinol showed no evidence of effect on all-cause mortality [four trials (27,28,32,34): OR = 0.97, 95% CI = 0.83 to 1.13], cancer mortality [three trials (24,27,32)], or disease-free survival [three trials (27,28,34); data not shown in Fig. 2], compared with usual treatment.
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P = placebo; UT = usual treatment. 
Bl = bladder; Br = breast; Cer = cervix; Col = colorectal; H&N = head and neck; Leu = leukemia; Lu = lung; Oth = other (not specified in text); Ov = ovary; Sk = skin; UGI = upper gastrointestinal; Ur = urological. 
A = advanced; E = early; UC = unclear. ||One-third of control subjects were offered dietary advice, and two-thirds of control subjects were offered usual treatment. ¶In De Waard et al. (a) (Cancer Recurrence and Second Primary Cancers in Patients With Cancer
Thirteen trials reported data on cancer recurrence and included the following interventions: four healthy diet (12,18,33), four retinol (22,24,27,32), two vitamin B6 (15,30), one -carotene (26), one selenium (16), and one multivitamin (25). Seven trials reported data on second primary cancer occurrence and included the following interventions: two healthy diet (18), two -carotene (21,26), two retinol (22,32), and one selenium (19). As indicated in Fig. 3, there was considerable heterogeneity in the results of four trials, all of which included breast cancer survivors only, that examined the effect of healthy diet compared with usual treatment on cancer recurrence. Although all these trials were small, there was evidence of a protective effect (OR = 0.20, 95% CI = 0.06 to 0.65) in the largest (110 patients, 19 events) (33). There was little overall evidence of an effect of antioxidant, retinol, or vitamin B6 interventions on cancer recurrence; however, the trials estimating antioxidant effects included a diverse range of cancer sites and had widely varying results (I 2 = 86.6). Results from two trials (22,32) of the effect of retinol on second primary cancers also suggested a reduction in the risk of second primary cancers (summary OR = 0.57), although the confidence interval was wide (95% CI = 0.31 to 1.07), and a meta-analysis of three trials [one of selenium (19) and two of -carotene (21,26)]—including two of the largest interventions in the review (19,21)—provided little evidence of a reduced risk with antioxidant supplementation, compared with placebo (OR = 0.93, 95% CI = 0.69 to 1.25). When we combined data from the two large skin cancer trials (19,21) only (data not shown), we found some evidence of a small reduction in the risk of second primary cancer associated with the antioxidant intervention (pooled OR = 0.89, 95% CI = 0.62 to 1.27), although there was also evidence of between-trial heterogeneity (I 2 = 77.1 %). We found no consistent effect of healthy diet interventions on second primary cancer occurrence.
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Development of Cancer in Patients With Preinvasive Lesions
The following seven trials reported data on the development of invasive cancer from preinvasive lesions: two healthy diet (35,54), two calcium (37,57), one -carotene (58), one folate (58), and one multivitamin (45). Both healthy diet interventions included a fiber component, and the combined effect estimate suggested an increased risk of progression from colorectal adenomas to malignancy (OR = 2.64, 95% CI = 1.04 to 6.73). We combined data from the multivitamin and -carotene trials to investigate the effect of antioxidants on the development of invasive cancer from preinvasive lesions and found little evidence of reduced risk of malignant change in the esophagus or stomach (OR = 0.76, 95% CI = 0.30 to 1.92). Two trials in patients with colorectal and esophageal preinvasive lesions evaluating the effect of calcium versus placebo on the risk of developing cancer also found little evidence of effect.
Recurrence of Preinvasive Lesions
Nineteen trials reported data on the recurrence of preinvasive lesions: six healthy diet (35,39,46,49,54), two -carotene (41,46), two calcium (36,39), two folate (44,50), five multivitamin (41,43,48,51), one retinol (55), and one N-acetylcysteine (51) (Fig. 4). Three trials (41,46,51) included multiple interventions that were combined for all analyses. These were healthy diet interventions [dietary counseling to reduce fat intake and fiber supplementation (46)], and antioxidant interventions [vitamins C + E and -carotene (41) and vitamins A + C + E and N-acetylcysteine (51)]. Five healthy diet interventions (35,39,46,49,54) (all included participants with colorectal preinvasive lesions and aimed to increase fiber intake) showed little evidence of an effect on the risk of recurrence of colorectal polyps (OR = 1.03, 95% CI = 0.85 to 1.26) (I2 = 40.1%). After combining data from the two -carotene trials (41,46), four multivitamin trials (41,43,48,51), and the trial (51) containing a multivitamin arm and a N-acetylcysteine arm, there was weak evidence of a reduction in risk of colorectal polyps with these antioxidant interventions (OR = 0.63, 95% CI = 0.36 to 1.12) (I2 = 78.2%), and smaller studies reported extreme effects. Two calcium interventions (36,39) showed some evidence of a reduced risk of recurrence of colorectal polyps (OR = 0.74, 95% CI = 0.59 to 0.94). The two folate trials (44,50) were too small to allow treatment effects to be estimated with precision (OR = 0.58, 95% CI = 0.19 to 1.81).
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DISCUSSION |
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Several trials have investigated the effects of a diverse range of nutritional interventions in patients with a previous diagnosis of cancer or preinvasive lesions. These trials provide little evidence that specific interventions, or groups of interventions, have any effect, either beneficial or harmful. The impact of most nutritional interventions cannot be estimated reliably because of the limited number of trials, many of which are small and/or of low quality. However, there were enough data to exclude substantial effects of antioxidants or retinol on all-cause mortality in patients with cancer. Two trials reported an adverse effect of healthy diet on development of colorectal cancer from preinvasive lesions, although the number of events detected in the trials was small. We were able to exclude any substantial protective association between fiber interventions and recurrence of colorectal adenomas, but two trials (36,39) suggested a possible protective association between calcium and recurrence.
Our study had several limitations. Although our review was systematic and used extensive searches of several databases and inclusive search terms, it did not include unpublished results. We think it is implausible, however, that there are large unpublished trials that demonstrate a protective association between nutritional interventions and cancer. Inclusion of unpublished results in systematic reviews typically has only a modest impact on intervention effect estimates, which tend to move toward the null. We did not exclude trials on the basis of methodologic quality, but exclusion of poor-quality trials would also tend to move effect estimates toward the null (60,61). The major limitations of our review related to the limitations of the relevant literature. The diversity of the interventions and the cancers that have been studied mean that decisions on when it is appropriate to use meta-analysis to combine results are difficult. Although most of the meta-analyses that we included were cancer specific, the limited trial data on any specific nutritional intervention forced some grouping of trials from different cancer sites. However, different dietary interventions may not have equal effects, or even effects in the same direction, for different cancer types with different causes and biology. Cancer stage, timing of the intervention in relation to treatment, and the duration of the intervention varied between trials. It may be difficult to detect any effects on cancer incidence—beneficial or harmful—in trials conducted at a late stage of disease. The interventions included in our meta-analysis lasted between 4 weeks and 6 years, and the study period of many, therefore, may not have been long enough for effects to develop.
Most trials had methodologic limitations. The aspects of trial quality that have been demonstrated consistently to be associated with treatment effect estimates in randomized controlled trials are concealment of the allocation sequence and double blinding (60,61). We found that only a few trials reported the methods used to conceal allocation in sufficient detail to allow us to assess their adequacy by use of standard criteria (9). Even when allocation concealment was assessed as adequate, there is no guarantee that bias was prevented, because most concealment processes can be subverted (62). Similarly, we assumed that a trial that was reported as double-blind successfully blinded both patients and outcome assessors. In most trials reported as double-blind, no further detail on methods of blinding was given.
Although previous reviews examining the role of dietary modification and supplements in patients with cancer have been nonsystematic, they reached broadly similar conclusions to those in our study. Norman et al. (63) concluded that patients with cancer should take only moderate doses of supplements because evidence of their safety or benefit is limited. Brown et al. (5) concluded that there was no convincing evidence that nutrition interventions were beneficial among survivors of four major cancers—breast, colorectal, lung, and prostate cancer. Two previous meta-analyses (64,65) have investigated the specific role of dietary fiber and calcium on cancer incidence in people with colorectal polyps. In their review, Asano et al. (64) concluded that the apparent increased risk of colorectal cancer observed in dietary fiber trials may be due to chance because 11 of the 23 cases of colorectal cancer were diagnosed within the first year of the study, suggesting that they may have been missed by the baseline colonoscopy. The meta-analysis of calcium supplementation (65), which used the same trials and reached the same conclusions as we did in this systematic review, suggested that trial efficiency might be improved by identifying subgroups with increased susceptibility to colorectal cancer who may benefit most from calcium supplements (65).
Thus, those planning future studies face challenges. A priority should be given to large-scale, high-quality trials evaluating the most promising interventions. Unfortunately, there is little evidence from the randomized controlled trials that we have reviewed to guide the choice of either the intervention or the patient groups. The available evidence suggests that large trials of calorie and fat restriction in breast cancer and calcium in colorectal preinvasive lesions are most likely to be successful. Recent results from the Women's Intervention Nutrition Study (66)—a large-scale randomized controlled trial investigating the role of dietary fat reduction on relapse-free survival in postmenopausal women with early-stage resected breast cancer—found that women on the reduced-fat diet had a lower risk of recurrence (hazard ratio [HR] = 0.76, 95% CI = 0.60 to 0.98) than women on the standard diet; the risk was reduced further (HR = 0.58, 95% CI = 0.37 to 0.91) in those women whose cancers were estrogen receptor negative (67). A further large-scale trial that was aimed primarily at increasing vegetable intake in women diagnosed with breast cancer is currently ongoing (68). More information from a range of study types could be used to provide information for the design of randomized controlled trials: epidemiologic studies remain important for identifying potential diets associated with mortality, although studies in animal models and genetics are also critical for improving our understanding of the mechanisms of cancer biology, and, therefore, the potential relevance of interventions. Finally, identification of reliable biomarkers would improve trial efficiency.
Nutritional interventions should not be assumed to be benign. Such interventions, notably antioxidant supplementation in the primary prevention setting, have yielded unexpected adverse effects, particularly with respect to -carotene supplementation and lung cancer in smokers (6,7). As previously noted, fiber interventions with colorectal polyps have also produced a worrying, if imprecisely estimated, adverse effect. Therefore, we should not maintain the notion that nutritional interventions can be promoted because at least they will do no harm.
There is little current evidence that specific dietary interventions work, and thus we cannot recommend the widespread use of dietary modifications and supplements in cancer management. Encouraging a healthy diet is certainly important because many patients with cancer and preinvasive lesions will live a long time and may die of other diseases related to diet. Until there is more evidence that nutritional interventions improve cancer survival, clinicians should counsel their patients to consume a healthy diet but should not state that it is a priority in management of cancer itself. Clinicians need to be clear about the lack of evidence and give reliable advice, in particular on Internet sites from which many patients with cancer, and their companions, may seek information (69,70).
Evidence is lacking to support the hypothesis that dietary modification by cancer patients improves survival and benefits disease prognosis. The large personal expenditure on supplements and dietary modifications by patients with cancer demonstrates an urgent need to understand their effects on cancer outcomes. This vulnerable group of people needs to be better informed, as diet is one of the few areas of their lives where they may feel that they have some control.
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NOTES |
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Funded by a grant from the World Cancer Research Fund, who also provided assistance with protocol design and translation of research papers. The funding source had no involvement in the collection, analysis, or interpretation of the data; in the writing of the report; and in the decision to submit the paper for publication.
A. A. Davies, S. Thomas, R. Harbord, G. E. Bekkering, J. A. C. Sterne, R. Beynon, and G. Davey Smith have no conflicts of interest. The corresponding author (S. Thomas) had full access to all the data in the study and had final responsibility for the decision to submit for publication.
A. A. Davies and S. Thomas designed the review, extracted the data, interpreted the results, and drafted the article for publication. J. A. C. Sterne drafted the article for publication, advised on the study protocol, and interpreted the results. G. Davey Smith advised on the study protocol, interpreted the results, and commented on manuscript drafts. R. Harbord analyzed and interpreted the results, G. E. Bekkering assisted in data extraction, and R. Beynon retrieved the review publications and entered the extracted data. All authors commented on the final draft.
We are grateful to Professor G. McVay for translating a research article.
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Manuscript received October 19, 2005; revised April 20, 2006; accepted June 1, 2006.
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