Colorectal Cancer Case-Control Study

1.  Study Investigators

Principal Investigators: Oxford

  • Dr Raghib Ali
  • Professor Valerie Beral
  • Dr Toral Gathani

Principal Investigator: India

  • Professor Mohandas Mallath, TMH, Mumbai

Local Principal Investigators: India

  • Professor T Ganeshan, AIMS, Cochin
  • Dr Chandramohoan, RCC, Trivandarum
  • Dr Sivensan, GKMH, Coimbatore
  • Dr Chacko, CMC, Vellore
  • Dr Raghunadharao, NIMS, Hyderabad
  • Dr Loknatha, KMIO, Bangalore
  • Dr Shilin Shukla, GCRI, Ahmedebad
  • Dr Hemant Malhotra, BCC, Jaipur
  • Dr Rajiv Prasad, IGIMS, Patna
  • Dr Ravi Kannan, CCC, Silchar
  • Dr Atul Sharma, AIIMS, New Delhi

2.  Summary

Colorectal cancer (CRC) incidence rates are much lower in India than in Western countries. The high incidence of CRC in the West is attributed mainly to lifestyle factors including physical activity, smoking, and dietary factors. The lower incidence in India may be due to the large proportion of the population who are life-long vegetarians. Vegetarianism is not associated with other healthy behaviours in India which have tended to confound possible associations in Western populations. This will be the first adequately powered study in India to investigate the association. 

The overall aim of this study is to gain a better understanding of the aetiology of colorectal cancer in India and the primary objective is to investigate the association between life-long vegetarianism and the risk of CRC in India. 

Colorectal cancer (CRC) is one of the leading causes of cancer related morbidity and mortality in the world, being the third most common cancer in men (663 000 cases, 10.0% of the total) and the second most common in women (570 000 cases, 9.4% of the total) worldwide.

There is significant international variation, however, with incidence rates varying 10-fold in both sexes worldwide. The highest rates are found in the longstanding developed nations of Europe, North America & Australasia and the lowest in Middle Africa and South Asia as shown in Figures 1 and 2.

Figure 1: Estimated age-standardised incidence rates for colorectal cancer worldwide in 2008 for both sexes (rate per 100,000)

Map showing estimated age standardised rates for colorectal cancer worldwide in 2008 for both sexes

Over recent years, incidence rates have also risen rapidly in the newly-developed nations of Eastern Europe and East Asia as they increasingly adopt features of a Western lifestyle.  Migrant studies have also shown higher incidence of CRC among immigrants to the West compared to those who remained in their native, low-incidence countries, again highlighting the importance of environmental factors in colorectal carcinogenesis.

The established lifestyle risk factors for colorectal cancer include obesity, physical inactivity, smoking, a diet low in fruits, vegetables and fibre and high in red and processed meat.

Figure 2: Colorectal cancer incidence and mortality in different regions of the world [1]

chart showing colorectal cancer incidence and mortality in different regions of the world

2.1.  Colorectal cancer in India

Countries in South Asia are now undergoing many of the economic, social and demographic changes experienced in other developing regions and this epidemiological transition has already led to significant increases in the incidence of cardiovascular disease, diabetes and some cancers (e.g. breast). In contrast, the incidence of CRC has remained low. The reasons for this lower incidence in India and other South Asian countries is unclear although it is likely to be due in part to less exposure to harmful risk factors (red & processed meat) and a lower prevalence of obesity. Greater levels of physical activity in rural India and a higher intake of fibre, vegetables and legumes may also be protective. About 28% of Indians are also life-long vegetarians and this dietary pattern does, of course, have less exposure to meat and may have a greater intake of fibre than a Western diet and so may be protective. Other aspects of the South Asian diet may also be protective, with some evidence that spices commonly used in South Asian food (e.g. turmeric) have anti-carcinogenic effects.

2.2.  Studies on vegetarianism and meat intake in the West

There have been a number of studies (both cohort and case-control and meta-analyses) in the West looking at the association between vegetarianism and CRC with conflicting results. Some have shown vegetarianism to be protective and others, harmful. 

The World Cancer Research Fund meta-analysis in 2007 reported that red and processed meats are ‘convincing’ causes of colorectal cancer and many other studies have found similar results.

2.3.  Vegetarianism in India

Importantly, it is almost exclusively for religious reasons that Indians are vegetarian, and vegetarianism is not known to be associated with other healthy behaviours which have been thought to have confounded possible associations between vegetarian and cancer in Western populations.  Also vegetarians in India have generally not eaten meat since birth whereas many vegetarians in the West adopted vegetarianism in adulthood and as CRC is thought to have an induction period of 20-30 years from ‘first hit’ to development of CRC, this may weaken the association seen in Western populations.

As the incidence if CRC in India is low, there have been very few studies investigating the importance of various risk factors. Only three small case-control studies have been conducted but all had significant limitations or were underpowered for a meaningful analysis of dietary and non-dietary risk factors.

The first hospital-based case-control study on colorectal cancer in India was conducted at the Tata Memorial hospital in Mumbai that recruited 203 CRC cases and 1628 hospital controls. Data was collected on chewing, smoking, alcohol habits and dietary habits. The results indicated no significant excess risk for chewers, smokers and alcohol drinkers compared to those without the habits. However, they did report that cabbage eaters had a 50% reduction in risk among both sexes when compared to non-cabbage eaters. Sprout eaters also had a 30-50% reduction in risk and those who ate fresh fish had a 40-70% reduction in risk compared to those who didn’t. Conversely, men who ate ‘dry fish’ compared to those who didn’t were 1.6 times more likely to develop CRC and female meat eaters had a 2.4 fold excess risk compared to non-meat eaters. Dark green leafy vegetables did not show any protective effects for colorectal cancer in this study. However the results from this study cannot be seen as reliable due to the use of an FFQ which cannot record diet accurately in a retrospective study.

The second study specifically looking at the association of diet and colorectal cancer in India was undertaken in the Malabar region of Kerala. It was a hospital based case-control study that enrolled 108 cases and 324 controls. The information was collated using a food frequency questionnaire for commonly consumed dietary items in the region. A strong association was found between colorectal cancer and tapioca (a starch extracted from the root of a plant (OR = 2.7; p = 0.001)), beef (OR = 4.25; p = 0.000) and pungent spices (OR = 9.62, p = 0.018). Fruits and vegetables showed strong inverse associations (OR = 0.15; p = 0.002) as did fish consumption. Finally heavy consumption of sugar (OR = 2.80) and tobacco use (OR = 8.79) showed a significant increase in risk. Again, this study had the same limitations as the first.

The third study was conducted in Chennai and primarily focused on associations with polymorphisms in the MTHFR gene and was under-powered for any analysis of dietary risk factors.

The only study which looked specifically at the association between LLV and CRC was again from Tata Memorial Hospital in Mumbai but this was a retrospective analysis of an existing nutrition clinic’s database of 8, 877 patients, of whom 796 had CRC. The results showed colorectal cancer to be inversely associated with LLV when compared to three different control groups (non colorectal cancer patients, patients with benign disorders and patients with tobacco related cancers) odds ratio of 0.71; 95% CI of 0.59-0.85 and a p-value of <0.001 after being adjusted for age, affluence, diabetes, gender and BMI.

This will be the first study in India which is being designed and powered to look specifically at the association between lifelong vegetarianism and colorectal cancer.

3.  Aims

The overall aim of this study is to gain a better understanding of the aetiology of colorectal cancer in India and the primary research question which we aim to answer using a case-control study is:

What is the association between life-long vegetarianism and the risk of colorectal cancer in India?

4.  Methods

  • The study design is an interviewer administered questionnaire based case-control study taking place in all twelve of the INDOX collaborating centres in India.
  • Data analysis will take place in both Oxford and India.
  • Anticipated duration of study is 24 months from the commencement of patient recruitment including the pilot phase of the study.

This study will begin recruiting patients in India in Spring 2011.