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SG - Clinical Cancer Research Studies

by Sandra Goodman PhD(more info)

listed in seminars, originally published in issue 160 - July 2009

Clinical Cancer Research Studies

KEY and COLLEAGUES, Cancer Epidemiology Unit, Nuffield Department of Clinical Medicine, University of Oxford, Oxford OX3 7LF,[1] Health Sciences Research Institute, Warwick Medical School, University of Warwick, Coventry CV4 7AL[2] and The Edgar National Centre for Diabetes Research and the Department of Human Nutrition, University of Otago, PO Box 56, Dunedin, New Zealand[3] studied cancer risk among meat eaters, non-meat eaters who ate fish (fish eaters) and vegetarians.

Few prospective studies have examined cancer incidence among vegetarians.
The author pooled the analysis of data from two prospective studies in the United Kingdom, namely the Oxford Vegetarian Study (Appleby et al, 1999) and the EPIC-Oxford cohort (Davey et al, 2003).

In the Oxford Vegetarian Study, participants were recruited throughout the United Kingdom between 1980 and 1984 (Thorogood et al, 1994). Vegetarian participants were recruited through advertisements, the news media and word of mouth, and non-vegetarian participants were recruited as friends and relatives of the vegetarian participants. A semi-quantitative food frequency questionnaire was completed at the time of recruitment, and information was collected on smoking and exercise habits, alcohol drinking, social class, weight and height and reproductive factors in women. In total, 11 140 participants were recruited.

The EPIC-Oxford cohort was recruited throughout the United Kingdom between 1993 and 1999 (Davey et al, 2003). Two methods of recruitment, namely general practice (GP) recruitment and postal recruitment were used.

Postal recruitment was designed to recruit as many vegetarians and vegans as possible. The main questionnaire was mailed directly to all members of The Vegetarian Society of the United Kingdom and to all surviving participants in the Oxford Vegetarian Study.

Respondents were invited to give names and addresses of their relatives and friends who might also be interested in receiving a questionnaire. In addition, a short questionnaire was distributed to all members of The Vegan Society, enclosed in health/diet-interest magazines, and displayed on health food shop counters.

The main questionnaire was then mailed to all those who returned a short questionnaire. A total of 7423 participants were recruited by the GP method and 58 042 participants by the postal method. The main questionnaire included a food frequency questionnaire and information on smoking and exercise habits, alcohol drinking, social class, weight and height and reproductive factors in women.

The diet group was classified into three categories, namely meat eaters, fish eaters (participants who did not eat meat but did eat fish) and vegetarians (participants who did not eat meat or fish). Wherever a participant could not be categorised for a given factor (usually because the appropriate section of the questionnaire was left unanswered or incomplete) they were allocated to an 'unknown' category for the analysis.

The authors studied 61,566 British men and women, comprising 32,403 meat eaters, 8,562 non-meat eaters who did eat fish (‘fish eaters’) and 20,601 vegetarians. After an average follow-up of 12.2 years, there were 3,350 incident cancers of which 2,204 were among meat eaters, 317 among fish eaters and 829 among vegetarians. Relative risks (RRs) were estimated by Cox regression, stratified by sex and recruitment protocol and adjusted for age, smoking, alcohol, body mass index, physical activity level and, for women only, parity and oral contraceptive use.

One-third of the participants were vegetarians and three-quarters were women. The mean age at recruitment was lower in the fish eaters and vegetarians than in the meat eaters. Smoking rates were low overall, with only 14.4% of meat eaters, 11.2% of fish eaters and 11.4% of vegetarians reporting that they were smokers at the time of recruitment.

The median BMI was 1.5 kg m-2 lower in vegetarians than in meat eaters, and the median alcohol consumption was 1.0 g per day lower in vegetarians than in meat eaters. Fish eaters had similar mean BMI to the vegetarians and had similar alcohol consumption to the meat eaters.

The proportions of men and women who reported a relatively high level of physical activity were higher among fish eaters and vegetarians than among meat eaters. The proportion of women who were nulliparous at recruitment was higher among fish eaters and vegetarians than among meat eaters, and the proportion of women who had ever used oral contraceptives was lower among fish eaters and vegetarians than among meat eaters.

There was significant heterogeneity in cancer risk between groups for the following four cancer sites:
  • Stomach cancer, RRs (compared with meat eaters) of 0.29 (95% CI: 0.07–1.20) in fish eaters and 0.36 (0.16–0.78) in vegetarians, P for heterogeneity=0.007;
  • Ovarian cancer, RRs of 0.37 (0.18–0.77) in fish eaters and 0.69 (0.45–1.07) in vegetarians, P for heterogeneity=0.007;
  • Bladder cancer, RRs of 0.81 (0.36–1.81) in fish eaters and 0.47 (0.25–0.89) in vegetarians, P for heterogeneity=0.05; and
  • Cancers of the lymphatic and haematopoietic tissues, RRs of 0.85 (0.56–1.29) in fish eaters and 0.55 (0.39–0.78) in vegetarians, P for heterogeneity=0.002.
  • The RRs for all malignant neoplasms were 0.82 (0.73–0.93) in fish eaters and 0.88 (0.81–0.96) in vegetarians (P for heterogeneity=0.001).
For the other cancer sites examined, there was no significant heterogeneity between the three dietary groups, but the RR for cancer of the cervix was significantly higher in vegetarians than in meat eaters (2.08 (1.05–4.12)) and the RR for prostate cancer was significantly lower in fish eaters than in meat eaters (0.57 (0.33–0.99)). The RRs for all malignant neoplasms were 0.82 (0.73–0.93) among fish eaters and 0.88 (0.81–0.96) among vegetarians (P for heterogeneity between the dietary groups=0.001).

The aim of this report is descriptive, and we did not have strong previous hypotheses as to which cancers might show differences in risk between the dietary groups. Therefore, these results should be interpreted cautiously, and for each significant finding we simply give a brief comment in relation to previous evidence and plausibility.

The first results from EPIC-Oxford suggested that the incidence of breast cancer did not differ significantly between vegetarians and non-vegetarians (Travis et al, 2008), that the incidence of colorectal cancer was higher in vegetarians than in meat eaters, that the incidence of lung cancer was lower in fish eaters than in meat eaters, and that the risk for all malignant cancers was lower in fish eaters and possibly lower in vegetarians than in meat eaters (Key et al, 2009).

Stomach cancer risk differed significantly between the dietary groups, and was significantly lower in the vegetarians than in the meat eaters, with a similar (non-significantly) low risk among the fish eaters. This observation was based on only 49 cases of stomach cancer. Previous research has suggested that processed meat may increase the risk for stomach cancer, perhaps due to the presence of N-nitroso compounds (Forman and Burley, 2006). Therefore, it is plausible that a meat-free diet could be associated with a reduction in the risk for stomach cancer. There is also some evidence that a high intake of fruit and vegetables might reduce the risk for stomach cancer, but the data are not consistent (Forman and Burley, 2006) and, although on average vegetarians eat more fruit and vegetables than meat eaters, the difference in intake is modest (Key et al, 2009).

The risk for cancer of the cervix was significantly higher among vegetarians than among meat eaters, with a similar (non-significantly) high risk among the fish eaters. The principal cause of cervical cancer is human papillomavirus. Dietary factors have been suspected of influencing risk, but no firm conclusions have been drawn (García-Closas et al, 2005). The increased risks observed in non-meat eaters were based on only 50 cases overall and might be due to non-dietary factors, such as differences in attendance for cervical cancer screening, or to chance.

The risk for ovarian cancer differed significantly between the dietary groups, and was significantly lower among fish eaters than among meat eaters. In a review, Schulz et al (2004) concluded that high meat consumption may be associated with an increased risk of ovarian cancer. The likely mechanism for such an effect is not clear, and the differences in the risk for ovarian cancer, which we observed, could be due to chance or due to differences in reproductive factors beyond the simple categories of parity and oral contraceptive use for which we were able to adjust.

Prostate cancer risk did not differ significantly between the dietary groups, although there was a significantly lower risk among fish eaters compared with meat eaters.

We did not observe any significant difference in the incidence of colorectal cancer between the dietary groups.

The results presented in this study are simply descriptive of the incidence of cancer in fish eaters and vegetarians relative to meat eaters. More detailed analyses of individual cancer sites are needed to explore, for example, whether the differences observed might be linked to particular types of meat or to other dietary or lifestyle characteristics of non-meat eaters that were not adjusted for in the current analysis.

A potential weakness of this type of study is the accuracy of the assessment of vegetarian status. The diet group was assigned on the basis of the answer to four questions, asking specifically about whether participants ever ate meat, fish, dairy products and eggs. When the diet group in EPIC-Oxford was assigned on the basis of answers to the same four questions in a follow-up questionnaire 5 years later, 85% of the vegetarians were allocated to the same diet group as at the time of recruitment (Key et al, 2009), suggesting that the assessment of vegetarian status is accurate and stable over at least several years, and may be a substantially more stable dietary characteristic than epidemiological estimates of nutrient intakes.

IN CONCLUSION, this study suggests that the incidence of all malignant neoplasms combined may be lower among both fish eaters and vegetarians than among meat eaters. The most striking finding was the relatively low risk for cancers of the lymphatic and haematopoietic tissues among vegetarians.

Conflict of interest TJK is a member of the Vegetarian Society. The other authors declare no conflict of interest.

The incidence of some cancers may be lower in fish eaters and vegetarians than in meat eaters.

TJ Key,[1] PN Appleby,[1] EA Spencer,[1] RC Travis,[1], NE Allen,[1] M Thorogood[2] and JI Mann[3]. Cancer incidence in British vegetarians. British Journal of Cancer 101: 192–197. 2009. doi:10.1038/sj.bjc.6605098

Influence of a Diet Very High in Vegetables, Fruit, and Fiber and Low in Fat on Prognosis

Following Treatment for Breast Cancer: The Women’s Healthy Eating and Living (WHEL) Randomized Trial JAMA. 2007;298(3):289-298

Considerable evidence from preclinical studies indicates that plant-derived foods contain anticarcinogens. A comprehensive review of the literature found that a diet high in vegetables and fruit probably decreases breast cancer risk and that a diet high in total fat possibly increases risk.
However, evidence of an association between a diet high in vegetables and fruit and low in total fat and prevention of cancer progression has been mixed in epidemiological studies

An interim analysis of data from the Women’s Intervention Nutrition Study (WINS), which assessed the effect of a dietary intervention designed to reduce fat intake on relapse-free survival in breast cancer patients, 18 found that the intervention was associated with a marginally statistically significant improvement in relapse-free survival. To our knowledge, no other clinical trials investigating dietary change and breast cancer survival have been reported.

The Women’s Healthy Eating and Living (WHEL) Study was a randomized trial assessing whether a dietary pattern very high in vegetables, fruit, and fiber and low in fat reduces the risks of recurrent and new primary breast cancer and all-cause mortality among women with previously treated early stage breast cancer.

DIETARY ASSESSMENT. Dietary intake was assessed by sets of 4 prescheduled 24-hour dietary recalls conducted by telephone on random days over a 3-week period, stratified for weekend vs weekdays.20 These dietary recalls were scheduled for all participants at baseline, 1 year, 4 years, and 6 years and on 50% random samples at 6, 24, and 36 months.

The study was based on the recommendations of a national committee of experts called to respond to a 1993 challenge grant from a private philanthropist who believed that the role of diet in preventing cancer progression deserved scientific study to enable cancer survivors to make decisions without having “to rely on folklore, rumor and hearsay.”

Context Evidence is lacking that a dietary pattern high in vegetables, fruit, and fiber and low in total fat can influence breast cancer recurrence or survival.

OBJECTIVE To assess whether a major increase in vegetable, fruit, and fiber intake and a decrease in dietary fat intake reduces the risk of recurrent and new primary breast cancer and all-cause mortality among women with previously treated early stage breast cancer.

DESIGN, SETTING AND PARTICIPANTS Multi-institutional randomized controlled trial of dietary change in 3088 women previously treated for early stage breast cancer who were 18 to 70 years old at diagnosis. Women were enrolled between 1995 and 2000 and followed up through June 1, 2006.

INTERVENTION The intervention group (n=1537) was randomly assigned to receive a telephone counseling program supplemented with cooking classes and newsletters that promoted daily targets of 5 vegetable servings plus 16 oz of vegetable juice; 3 fruit servings; 30 g of fiber; and 15% to 20% of energy intake from fat. The comparison group (n=1551) was provided with print materials describing the “5-A-Day” dietary guidelines.

Main Outcome Measures Invasive breast cancer event (recurrence or new primary) or death from any cause.

From comparable dietary patterns at baseline, a conservative imputation analysis showed that the intervention group achieved and maintained the following statistically significant differences vs the comparison group through 4 years: servings of vegetables, _65%; fruit,_25%; fiber,_30%, and energy intake from fat, −13%. Plasma carotenoid concentrations validated changes in fruit and vegetable intake. Throughout the study, women in both groups received similar clinical care.

Over the mean 7.3-year follow-up, 256 women in the intervention group (16.7%) vs 262 in the comparison group (16.9%) experienced an invasive breast cancer event (adjusted hazard ratio, 0.96; 95% confidence interval, 0.80-1.14; P=.63), and 155 intervention group women (10.1%) vs 160 comparison group women (10.3%) died (adjusted hazard ratio,  0.91; 95% confidence interval, 0.72-1.15; P=.43).

No significant interactions were observed between diet group and baseline demographics, characteristics of the original tumor, baseline dietary pattern, or breast cancer treatment.

We suggest caution in applying our findings to groups of women other than those represented in our study, which was confined to women who had already completed initial therapy for breast cancer and excluded women with diagnoses after age 70 years and those with stage 1 tumors smaller than 1 cm. Also, only 14% of our study population was self-identified as from African American, Hispanic, and Asian American racial/ethnic groups.

Our finding that reducing dietary fat intake did not benefit breast cancer outcomes appears at odds with the interim analyses from the Women's Intervention Nutrition Study (WINS), which concluded that reducing dietary fat intake was marginally associated with longer relapse-free survival of breast cancer patients, an effect most noted in the subgroup with estrogen-negative tumors. However, differential follow-up between intervention and comparison groups may have influenced the WINS finding.4

The absence of an observed effect on breast cancer events or all-cause mortality over a 7.3-year follow-up period in this study does not rule out the possibility of improved longer-term survivorship within this cohort. We did not explore the possibility that increased exercise and weight loss might benefit breast cancer survivors. Finally, our study did not address whether consuming the high–vegetable/fruit/fiber and low-fat diet of our study intervention early in life would alter risk of primary breast cancer.

In conclusion, during a mean 7.3-year follow-up, we found no evidence that adoption of a dietary pattern very high in vegetables, fruit, and fiber and low in fat vs a 5-a-day fruit and vegetable diet prevents breast cancer recurrence or death among women with previously treated early stage breast cancer.

Among survivors of early stage breast cancer, adoption of a diet that was very high in vegetables, fruit, and fiber and low in fat did not reduce additional breast cancer events or mortality during a 7.3-year follow-up period.

Influence of a Diet Very High in Vegetables, Fruit, and Fiber and Low in Fat on Prognosis
Following Treatment for Breast Cancer: The Women’s Healthy Eating and Living (WHEL) Randomized Trial JAMA. 2007;298(3):289-298

John P. Pierce, PhD, Loki Natarajan, PhD, Bette J. Caan, DrPh, Barbara A. Parker, MD, E. Robert Greenberg, MD, Shirley W. Flatt, MS, Cheryl L. Rock, PhD, RD, Sheila Kealey, MPH, Wael K. Al-Delaimy, MD, PhD, Wayne A. Bardwell, PhD, Robert W. Carlson, MD, Jennifer A. Emond, MS, Susan Faerber, BA ,Ellen B. Gold, PhD, Richard A. Hajek, PhD, Kathryn Hollenbach, PhD, Lovell A. Jones, PhD, Njeri Karanja, PhD, Lisa Madlensky, PhD, James Marshall, PhD, Vicky A. Newman, MS, RD, Cheryl Ritenbaugh, PhD, MPH, Cynthia A. Thomson, PhD, Linda Wasserman, MD, PhD, Marcia L. Stefanick, phd
JAMA. 2007;298(3):289-298

Combined impact of health behaviours and mortality in men and women: the EPIC-Norfolk prospective population study.
KHAW and COLLEAGUES,  Department of Public Health and Primary Care, Institute of Public Health, University of Cambridge School of Clinical Medicine, Cambridge, United Kingdom.  quantified the potential impact of 4 health behaviours upon mortality of healthy men and women.

: There is overwhelming evidence that behavioural factors influence health, but their combined impact on the general population is less well documented. The authors aimed to quantify the potential combined impact of four health behaviours on mortality in men and women living in the general community.

: The authors examined the prospective relationship between lifestyle and mortality in a prospective population study of 20,244 men and women aged 45-79 years with no known cardiovascular disease or cancer at baseline survey in 1993-1997, living in the general community in the United Kingdom, and followed up to 2006. Participants scored one point for each health behaviour for a total score ranging from zero to four:
  • Current non-smoking
  • Not physically inactive
  • Moderate alcohol intake (1-14 units a week)
  • Plasma vitamin C >50 mmol/l indicating fruit and vegetable intake of at least five servings a day.
RESULTS: After an average 11 y follow-up, the age-, sex-, body mass-, and social class-adjusted relative risks (95% confidence intervals) for all-cause mortality(1,987 deaths) for men and women who had three, two, one, and zero compared to four health behaviours were respectively:
1.39 (1.21-1.60)
1.95 (1.70--2.25)
2.52 (2.13-3.00)
4.04 (2.95-5.54) p < 0.001 trend.
The relationships were consistent in subgroups stratified by sex, age, body mass index, and social class, and after excluding deaths within 2 years. The trends were strongest for cardiovascular causes. The mortality risk for those with four compared to zero health behaviours was equivalent to being 14 y younger in chronological age.

: Four health behaviours combined predict a 4-fold difference in total mortality in men and women, with an estimated impact equivalent to 14 years in chronological age.

Khaw KT,  Wareham N,  Bingham S,  Welch A,  Luben R and Day N. Combined impact of health behaviours and mortality in men and women: the EPIC-Norfolk prospective population study.[see comment][erratum appears in PLoS Med. 18;5(3):e70]. Mar 2008. Comment in: PLoS Med.;5(1):e15; PMID: 18184034. Jan 8 2008. Source  PLoS Medicine / Public Library of Science.  5(1):e12, Jan 8 2008.  Source: NLM. PMC2174962.

: The results of this study ought to be made known far and wide. By not smoking, by ingesting 5 servings of fruit and vegetables per day, by not being physically inactive and having a moderate alcohol intake, there is a 4-fold (400%) decrease in risk of dying compared to individuals not undertaking any of these 4 behaviours, which is equivalent to being 14 years younger in age.


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About Sandra Goodman PhD

Sandra Goodman PhD, Co-founder and Editor of Positive Health, trained as a Molecular Biology scientist in Agricultural Biotechnology in Canada and the USS, focusing upon health issues since the 1980s in the UK. Author of 4 books, including Nutrition and Cancer: State-of-the-Art, Vitamin C – The Master Nutrient, Germanium: The Health and Life Enhancer and numerous articles, Dr Goodman was the lead author of the Consensus Document Nutritional and LifeStyle Guidelines for People with Cancer and compiled the Cancer and Nutrition Database for the Bristol Cancer Help Centre in 1993. Dr Goodman is passionate about making available to all people, particularly those with cancer, clinical expertise in Nutrition and Complementary Therapies. She has been a member of the Therapy Advisory Panel of the Penny Brohn Cancer Care, Scientific Expert Committee member of the Alliance for Natural Health and Patron of the Avalon Complementary Medicine Trust in Wells, Somerset.

Dr Goodman and long-term partner Mike Howell seek individuals with vision, resources, and organization to continue and expand the Positive Health PH Online legacy beyond the first 25 years, with facilities for training, fund alternative cancer research, and promote holistic organizations internationally. Read about Dr Goodman and purchase Nutrition and Cancer: State-of-the-Art.  She may be contacted privately for Research, Lectures and Editorial services via:   and

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