Cancer not a single disease: it has multiple causes and as many treatments

With time, cancer has increasingly come to be understood as a lifestyle and an environmental disease with several causal pathways

By Shreeshan Venkatesh
Published: Thursday 31 May 2018

Cancer is among the most perplexing of ailments that has tormented humans for much of our civilisation. The earliest known mention of cancer comes from Egyptian texts dating back to about 5,000 years in which the removal of eight tumours is described.

Evolutionarily, cancer finds its basis much earlier in history—right back to the times of our early metazoan ancestors who first experienced a differentiation of cells and tissues based on functionality. The great variety of anatomical designs in the animal world owes this differentiation and organisation at the cellular level. Organ and tissue construction, to the extent visible in the living world, would be virtually impossible without the versatility and autonomy of cellular structures. Cells have the ability to continue to grow and divide much after all the organs in a body are fully developed. This ability makes it possible for cells to maintain organs, replace dead cells and repair any wounds or damage to existing tissues. While this ability is critical in the maintenance of life and in the evolutionary process, the versatility and autonomy of cellular structures are also responsible for the prevalence of cancer.

Genomes are susceptible to structural alterations which could force cells to behave in an irregular fashion. Alterations in the way cells divide and proliferate can lead to the creation of large populations of mutated cells that do not obey the rules of normal growth and maintenance. These clusters of rebellion are what we call cancers.

With time, cancer has increasingly come to be understood as a lifestyle and an environmental disease with several causal pathways. According to the World Health Organization’s (WHO) World Cancer Report published in 2014, over 14 million new cases of cancer were registered in 2012 alone, of which 165,000 had been diagnosed in children under the age of 14. A study published in The Lancet in April, 2017, says that cancer was 13 per cent more common in the 0-14 age group in 2001-10 than it was in the 1980s. The study shows that leukaemia is the most common cancer in children under 15, making up almost a third of childhood cancer cases. Tumours of the central nervous system ranked second (20 per cent of the cases) and lymphomas accounted for 12 per cent of the cases. In children younger than five years, a third of the cases were embryonal tumours, such as neuroblastoma, retinoblastoma, nephroblastoma or hepatoblastoma. Denis Henshaw, emeritus professor at the School of Chemistry in University of Bristol, the UK, and former scientific director of Children with Cancer, a UK-based charity, says that exposure of children to external factors such as pesticides, air pollution and dietary habits may have a bearing on the increase in childhood cancers.

In India, the Indian Council of Medical Research (ICMR) in 2016 revised its estimates of cancer patients for 2020 by 30 per cent. The current estimate is 1.73 million new cases as compared to the 2013 estimate of 1.32 million new cases annually by 2020. The data shows a significant rise in the incidence rates of lung, colon, rectum and prostate cancers among men. Among women, lungs, breast, ovary and corpus uteri cancers are becoming common. Breast cancer, for instance, is the leading form of cancer at 19 of the 27 cancer registries.

Soumya Swaminathan, newly-appointed deputy director general, WHO, director general, ICMR, says the higher numbers reflect improving cancer detection rates, age-related cancers due to increasing life expectancy and higher exposure to cancer-related risk factors. The reports, however, do not explain why the incidence rate of the same cancer is different in different parts of the country. For instance, the annual percentage change in uterine cancer cases in Bengaluru is the highest (5.5), while it is 3.6 in Delhi. It does not even explain why the same kind of diet causes two different types of cancer. For example, the diet of communities in Mizoram and Nagaland is rich in fermented food and smoked meat and fish. Consumption of tobacco and chewing betel nut is also high among these communities. But while stomach cancers are high among Mizo men and women, Nagaland records a high incidence of nasopharynx cancer (which extends from the base of skull to the upper surface of the soft palate).

Consumption of smoked meat has been linked to higher incidence of stomach cancer in the Northeastern states

Cancer triggers

Diet and nutrition: It has been estimated that up to 30 per cent of all cancers in the developed world and 20 per cent in the developing world are linked to diet. However, studies have yet to prove conclusively that specific dietary components cause cancer. While certain foods show an association with a change in cancer risk, direct causation has yet to be proven.

Still, one of the most closely-studied correlations is the one between meat consumption and cancer. Over a hundred studies from around the world have reported the link between meat intake and the likelihood of developing cancer. While the exact pathway of cause and effect still remains unclear, a possible role of carcinogenic components of meat such as N-nitroso compounds, heterocyclic amines or polycyclic aromatic hydrocarbons has been of great interest.

Interestingly, not all types of meat have been found to be equally culpable when it comes to cancer. A meta-analyses from early 2015, published in the International Journal of Cancer found that beef had the highest positive correlation with colorectal and colon cancer followed by lamb, whereas pork and poultry consumption consistently showed no association with the likelihood of developing cancer.

A research analysis in 2016 investigated the links between nutrition and the development of 16 different types of cancers, including breast, lung, esophageal, gastric, renal and prostrate. While cancer might have a correlation with meat intake, other factors such as physical activity and obesity have been found to be the other factors that are linked to both diet and cancer development.

According to the American Cancer Society, there is strong evidence of a link between being overweight or obese and having a higher risk of endometrial cancer (cancer of the lining of the uterus). This has been linked to accumulation of belly fat which increases estrogen levels. Other studies have shown that men who are overweight may have a lower risk of prostate cancer overall, but a higher risk of prostate cancers that are likely to be fatal.

Surprisingly, certain food types have anti-cancer properties too. Cruciferous vegetables such as broccoli, cauliflower, cabbage and radish have been found to contain sulphur-containing group of chemicals call glucosinolates. These break down into biologically active compounds, which have been found to prevent several cancers including those of the bladder, breast, liver, lung and stomach. Several recent studies have shown reduced risks of prostate, colorectal, lung and breast cancers associated with the high intake of these vegetables.

Antioxidants are important for cancer prevention as they help neutralise free radicals that damage cells. However, the research to support “the-more-is-better” is not proven fully. For example, we don’t know how long antioxidants have to be consumed for benefits. This is important considering that cancers develop over many decades. As foods high in antioxidants offer other benefits too, it is good to consume as much as possible through natural sources like colourful vegetables.

Tobacco and alcohol: In 1761, English clinician John Hill first proposed a link between tobacco smoke and cancer. Today, we know that consumption of tobacco products is intrinsically linked with cancer. Tobacco smoke contains more than 7,000 chemical compounds, many of which are established carcinogens. Broad classes of carcinogens in tobacco smoke include polycyclic aromatic hydrocarbons, N-nitrosamines and aromatic amines, together with a range of tobacco-specific toxins, including volatile aldehydes and phenolic amines. Tobacco smoke, being a mixture of gases and tiny particulate matter, can reach the minute pathways of the alveoli, deep in the lungs. Components such as nicotine are then carried through the body by blood, exposing different tissues to varying levels of carcinogens.

Tobacco components have been found to contribute to the formation of cancerous tumours through multiple mechanisms including DNA binding and mutations, inflammation, oxidative stress and epigenetic changes. Causal associations between tobacco smoking and at least 14 different types of cancers have been established by epidemiological studies.

Smokeless tobacco is not much better either. It contains more than 3,000 chemical compounds, including at least 28 known carcinogens (many of which are the same as those found in smoking tobacco). Even though tobacco has been unequivocally found as a leading cause of cancer, worldwide consumption has been consistently high. According to WHO, at least 1.3 billion people around the world use some form of tobacco and approximately 6 million people die every year due to tobacco-related ailments. Currently, over 80 per cent of tobacco users reside in medium and low income countries (see ‘Anti-tobacco campaign in India’,).

If tobacco were to be the villain in the cancer story, its side-kick would undoubtedly have to be alcohol. The association between alcohol and cancer was first observed in the early 20th century. The suspected correlation was grounded soon after, as it was noted that heavy drinkers had a far higher risk of developing head and neck cancers than those who abstained from drinking due to religious reasons.

Following these early observations, thousands of studies have explored the link between alcoholic beverages and the risk of cancer. The studies have found definitive causal links between alcohol consumption and cancers of the oral cavity, pharynx, larynx, oesophagus, liver, colorectum and breasts. Although evidence of biological pathways is yet to be found, there is a positive correlation between alcohol consumption and prostate cancers. Evidence points to a synergistic impact of smoking and drinking on the risk of several types of cancer, including those of the oral cavity, pharynx, larynx and oesophagus. The highest risk of cancer is apparently to those who are heavy consumers of both tobacco and alcohol.

Tobacco smoke contains more than 7,000 chemical compounds, many of which are established carcinogens

Alcoholic beverages have been found to contain several carcinogenic compounds including ethanol, acetaldehyde, aflatoxins and ethyl carbamate. Scientists are now beginning to piece together the puzzle. Studies have established ethanol as the most harmful carcinogen in alcoholic beverages, with other compounds increasing the risk of cancer. Acetaldehyde, the primary metabolic state of ethanol, is strongly associated with cellular and genetic corruption. Oxidative stress—the condition of elevated levels of reactive oxygen species that cause molecular damage to vital structures and functions within cells—was identified as an important step in the pathway to cancer in the early 2000s. More recently, studies have thrown some light on how alcohol could be linked to aberrant patterns of DNA methylation, an important mechanism for the transcription of genes, leading to higher likelihood of developing cancer. According to the World Cancer Report, 337,400 deaths and over 8.6 million disability-adjusted life years were lost due to alcohol-related cancers in 2010 alone. Liver and breast cancers were found to be the most common type of malignancy associated with drinking among men and women respectively.

Toxins: Since the beginning, human civilisation has depended on the modification of nature for survival. But along with convenience, industrial progress has increasingly brought us in contact with novel substances and new compounds, many of which have been found to interfere with basic cellular and genetic functions. There are thousands of known and suspected carcinogens that play a part in daily human life. Take air pollution for instance. In the past three decades of the 20th century, several prominent studies have found an increased cancer risk associated with urban air pollutants. In 2010, the International Agency for Research on Cancer (IARC) said about 223,000 lung cancer deaths were directly linked to air pollution. In 2013, WHO declared air pollution carcinogenic. Since then, studies have pointed at an even higher cancer burden of air pollution. It has been found that the major contributor to increased cancer risk is particulate matter present in ambient air pollutants, especially PM 2.5, which has been found to contain a higher proportion of mutagenic compounds. A 2017 study from the University of Illinois revealed that air pollution had contributed to a 10 per cent rise in cancer diagnoses in counties across the US between 2006 and 2010. Particulate matter generated in the mining, construction and textiles sectors, among other important industries, have been highlighted several times in past research as contributing to cancer risks of labourers in these sectors. Even a majority of the pesticides used for agricultural and residential purposes have been found to contain chemicals linked with cancer. A 2010 report produced by the UK-based organisation, CHEMTrust, has tabled over 70 components of pesticides linked with 16 different types of cancer. In the past five years, the number of cancers for which there is epidemiological evidence of being linked with pesticide exposure has increased to 28. Of these, the strongest associations have been found to be with cancers of the brain, bladder, kidney, liver, breast and blood.

The pervasion of carcinogenic agents does not end there. Recent studies have increasingly revealed the presence of several cancer-causing compounds in commonly-used household substances, most notably in cleaning liquids and certain cosmetic products. In June 2015, a global collective of medical researchers attempted to address longstanding concerns of chemical exposure in everyday life. Scientists chose 85 commonly encountered chemicals out of thousands and found that 50 of these supported key cancer-related mechanisms. It is estimated that up to 20 per cent of cancer cases can be linked to environmental exposures of toxins. While the study provoked sensational headlines in the media, it remains a launching pad for further research. A more recent study, published in 2016, looked at chemicals used in making consumer products in indoor dust in US households and found that 90 per cent of the houses had dust which contained 10 chemicals suspected to be harmful to human health, specifically by interfering with endocrine and reproductive functions. Hydrofluorocarbons, commonly found in household dust, has been linked to renal and testicular cancers.

Cancer prevention and treatment

Cancer is not a single disease, and neither can it be treated as one. Conventional treatment of cancer involves a combination of surgery, radiation therapy and site-specific drugs, the strength and duration of which are decided depending on various variables like the site, the stage of the cancer, it’s rate of development and environmental factors. Newer methods such as hormone therapy and stem cell transplants have now emerged as valuable additions to the conventional treatment options, especially in treating specific kinds of cancer such as breast cancer and some types of blood cancers.

The wide scope of the disease and its steadily increasing global burden has placed the onus largely on private research and the development of new treatments and drugs. What this has meant is that pharmaceutical companies rely on sales and pricing strategies to generate R&D costs for any new medication. According to industry estimates, it costs about $1.2 bn to release a new drug in the market.

However, a 2011 study published in the BioSocieties estimated the median R&D cost for a pharmaceutical company to be around $56 million per drug, just 4.6 per cent of the industry estimate. Still, a free market system has given pharma companies the freedom to decide on the pricing of drugs.

While private R&D has contributed to enhancing drug effectiveness and novel treatments, the free hand given to companies to quote their price on patented drugs is having an unexpected outcome. The pricing of cancer drugs is largely seen to be spiraling out of control and is reaching a point of unsustainability. A 2015 study by the National Bureau of Economic Research, a US-based non-profit research organisation, revealed that cancer drug prices had increased by 10 per cent annually between 1995 and 2013. The rising prices of cancer drugs has seen the global cost of cancer treatment inch towards the $1 trillion mark. Among high-income countries, European countries—where public healthcare is the norm—are beginning to feel the heat of high cancer drug pricing. The most telling example comes from the UK where the Cancer Drug Fund, a subsidiary of the National Health Service, was overhauled in 2016 after it cost the government 1.27 billion Pounds from two years of overspending on cancer drugs. On the other end of the spectrum, recent economic instability in Europe also saw pharma companies effectively hold countries to ransom. In 2011, Roche, the world’s largest cancer drug manufacturer, stopped supplying hospitals in Greece with cancer drugs because of unpaid bills.

The problem of high pricing is hitting low-income and developing countries the most. According to a 2015 estimate, India had only one oncologist per 1,600 new patients of cancer. Besides this, setting up a cancer treatment facility is expensive, costing upwards of Rs 100 crore. Treatment costs can go up to Rs 20 lakh a year. In comparison, India’s GDP per capita is just above Rs 1 lakh, putting cancer care far out of the reach of the Indian public.

India’s priority has been to increase access to medication by managing the patents and costs of life-saving drugs. One of the ways of achieving this has been by relying on generic manufacturers to make cheaper drugs. According to Oxfam, generic cancer drugs in India can cost anywhere between half to one-thirtieth of the costs at which the same drugs are available in high-income countries. Unsurprisingly, public and official support for generic life-saving drugs has been strong in the country much to the annoyance of big pharma. In 2012, the Indian Patent Office issued a compulsory license on a drug thereby allowing generic drug manufacturer Natco Pharma to manufacture a generic version Bayer’s kidney and liver cancer drug, Nexavar. Natco launched the product at just 3 per cent of Nexavar’s cost. In 2013, the Supreme Court rejected a patent application by Novartis for Gleevec, a preferred drug to treat chronic myeloid leukaemia, after a seven year court battle. The rejection of the patent was on the grounds that it failed to improve the original molecule sufficiently. The judgement threw open the production of Gleevec to Indian generic manufacturers. In January 2013, the Union Health Ministry recommended the compulsory licensing of the patents on three anti-cancer drugs—dasatinib, trastuzumab and ixabepilone—to the Department of Industrial Policy and Promotion.

While the steps taken in India has raked up considerable controversy and has contributed to mounting pressure from the US regarding intellectual property, the need to delink R&D costs from the final product costs to increase access drugs is being widely acknowledged now. Even within the industry, there is huge variation in the way different companies are dealing with the need to balance their pricing strategies so as to stay relevant in developing countries while also not giving up on revenue.

One high profile example is Roche, which has established a differential pricing mechanism for low- and medium-income countries. In the Philippines, Roche has experimented with a tiered pricing system based on individual ability to pay for the crucial breast cancer drug, herceptin. In India, it adopted a different strategy. It partnered with Emcure pharmaceuticals to repackage and sell the drug. Generic manufacturers have not only won the the right to produce biosimilar drugs, they have also got the nod from the US Food and Drug Administration to explore the possibility of importing life-saving drugs.


Some of the measures taken by the government and the judiciary

India is undoubtedly a major node on the map of the global tobacco epidemic. India is the second largest nation in the world in terms of both tobacco production and consumption, after China. In the face of the epidemic though, the Indian government and judiciary have taken aggressive control measures including taxation, legal recourse, penalties and major awareness drives. A January 2017 report by the WHO picked out India for praise for its anti-tobacco initiatives.

TAXATION: Over the past decade the Indian government has pursued a steep year-on increase in taxes on tobacco products, specifically cigarettes. Still, taxation of cigarettes at 43 per cent is much lower than the WHO recommended 75 per cent.

Even more startling is that in India, cigarettes account for just a fraction of the consumption with beedis being the most common form. Unfortunately, being popular as the poor man’s cigarette, beedis are taxed at just 7 per cent. The WHO-Bloomberg report on tobacco estimates that raising taxes of beedis to 40 per cent and that of cigarettes to 78 per cent would save close to 20 million lives and contribute about Rs 18,000 crores in tax revenue.

LEGISLATION: India’s first national level anti-tobacco legislation was the Cigarettes Act of 1975 which mandated health warnings on cigarette packets and advertisements. Since the passage of the Cigarettes and Other Tobacco Products Act (COTPA) in 2003, smoking is banned in public places. Additionally, it prohibits advertisements of tobacco products on mass media. Sale to minors and shops within 100 yards of educational institutes have been prohibited. Most major public places, including hubs of transport such as bus stands and railway stations are now smoke free.

Some states have also passed state and regional legislation controlling or banning the sale and consumption of cigarettes/tobacco products in all public areas, thus expanding the mandate of the COPTA.

EDUCATION AND AWARENESS: While enforcing control was one one of the objectives of the COPTA, another major objective was to educate and spread awareness among the Indian public of the evils of tobacco consumption. The biggest step in this direction is arguably in the pictorial and labelled warnings on tobacco packs.

As per the latest ruling, health warnings must cover 85 per cent of the front and back panels of the packaging and must be rotated every 12 months. The act also mandates the indication of nicotine and tar contents, although this has scarcely been implemented.

The Union Ministry of Information and Broadcasting has been mandatorily publishing anti-tobacco advertisements and short films on all modes of mass communication radio, television, print and in cinema halls. Since 2005, specific health warnings have been incorporated in movies during smoking scenes.

The article was first published in State of India's Health 2018: Body Burden

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