Cancer affects many people in the EU. Therapeutic advances mean that people with many different types of cancer now live longer and have a better quality of life. And research continues; pharmaceutical companies are investigating new medicines and novel therapies, such as gene therapy to reduce the toll of cancer on patients and families.
Cancer is a disorder in which there is unregulated multiplication of cells in the body. The resulting cell mass, called a tumour, may eventually develop its own blood system and begin to invade neighbouring organs. Some cancers, known as ‘malignant’, shed cells into the blood or lymph and these cells become trapped in small blood vessels in organs such as the liver, lung or brain, where they form secondary tumours called metastases. These can often be more serious than the primary tumour. In late disease, solid tumours release substances that depress appetite and cause weight loss and often lead to death from overwhelming infection, such as pneumonia.
Tumours can develop in any organ. Depending on where they arise, they pose very different medical and management problems. Some can be treated medically, but many are hard to cure except through surgical or radiological intervention. Advances in medical research have made many more tumours treatable, and today many people with cancer live longer than previously, with a better quality of life.
Cancer can affect any of us, and there can be few families that do not have a relative or friend who has some form of cancer. It affects one in two men and more than one in three women at some time in their lives, though some types of tumour are much less common than others.
In the EU, the commonest form in women is breast cancer, followed by colorectal (bowel), lung, ovarian and uterine cancer. In men, prostate cancer is the most common, followed by lung, colorectal and bladder cancer. In 2012. epidemiologists from the Dutch Scientific Society, Erasmus University Rotterdam, and the International Agency for Research on Cancer, Lyon, undertook country comparisons to calculate disability-adjusted life-years (DALYs) and to estimate the global burden of cancer in 2008. Worldwide, an estimated 169,3 million years of healthy life were lost because of cancer in this year. Colorectal, lung, breast, and prostate cancers were the main contributors to total DALYs in most world regions and caused 18 to50 per cent of the total cancer burden. The researchers estimated an additional burden of 25 per cent from infection-related cancers (liver, stomach, and cervical) in sub-Saharan Africa, and 27 per cent in eastern Asia.
Survival rates for many cancers are poorer in economically developing countries than in developed countries largely because of lack of availability of early detection and treatment services. For example, overall five-year childhood cancer survival rates are around 75 percent in Europe and North America, compared to three-year survival rates of only 48 to 62 percent in Central American countries.
In contrast to economically developed countries, the three most commonly diagnosed cancers in economically developing countries are cancers of the lung, stomach, and liver in men, and cancers of the breast, cervix uteri, and stomach in women. In developing countries, two of the three leading cancers in men (stomach and liver) and in women (cervix and stomach) are related to infection. In both economically developed and developing countries, the three most common cancer sites are also the three leading causes of cancer death.
Approximately 15 per cent of all cancers worldwide are infection-related, with the percentage of cancers related to infection about three times higher in developing than in developed countries. The burden of cancer is increasing in developing countries as deaths from infectious diseases and childhood mortality decline and more people live to older ages when cancer most frequently occurs. This cancer burden is also increasing as people in the developing countries adopt western lifestyles such as cigarette smoking, higher consumption of saturated fat and calorie-dense foods.
It is not possible to detail here all the available treatments for cancer, many of whose side effects are well known. Radiotherapy, surgery and chemotherapy are all used for treatment, depending on the tumour type. There are several classes of chemotherapy agents and it is common for oncologists to use combinations of several, to maximise effectiveness. Some can make the recipients feel very unwell, causing nausea and loss of hair, and depress the immune system, leaving them vulnerable to infection.
Other side-effects include loss of fertility, as well as liver or cardiac damage. Medicines used for hormone-dependent tumours (e.g. breast and prostate cancer)are generally better tolerated than the older alkylating agents. In general, cancer treatment requires a large number of medicines to destroy a tumour, e.g. cytotoxic and cytostatic compounds; to compensate for the harmful effects of chemotherapy, e.g. antiemetics, analgesics and folinates; to control cancer-related complications, e.g. factors to grow red and white blood cells; and also including artificial intravenous nutrition.
Radiotherapy may be helpful in reducing the size of a tumour before surgical removal, or to eliminate any cells remaining after surgery. Chemotherapy used for this purpose is termed ‘adjuvant therapy’. The disadvantages of radiotherapy mainly arise from the unavoidable irradiation of surrounding healthy tissue or organs - the intestines, the bone marrow and kidneys are particularly sensitive. The shortcomings of chemotherapeutics, apart from their toxicity, relate mainly to lack of efficacy. Many tumours are very responsive to chemotherapy initially, but the impact on survival still remains small in many cases and complete cures are difficult to achieve. Hence there is a big need for less toxic and more curative forms of medication for most solid tumours.
|Alkylating agents||Ovarian cancer; small-cell lung cancer; brain tumours; breast cancer; testicular cancer; cervical cancer; bladder cancer; malignant glioma|
|Anti-metabolites||Colorectal cancer; bladder cancer; pancreatic cancer, non small-cell lung cancer; breast cancer; lung cancer; ovarian cancer; head & neck cancers|
|Topoisomerase inhibitors||Testicular cancer; small-cell lung cancer; colorectal cancer; ovarian cancer|
|Cytotoxic antibiotics||Testicular cancer; uterine cancer; rhabdomyosarcoma; breast cancer; ovarian cancer; stomach cancer; lung cancer; colorectal cancer; bladder cancer|
|Microtubule disruptors||Breast cancer; non small-cell lung cancer; ovarian cancer; small-cell lung cancer; head & neck cancers, leukaemias|
|Hormonal agents||Breast cancer; prostate cancer|
|Aromatase inhibitors||Breast cancer|
|Monoclonal antibodies||Breast cancer; colorectal cancer; head & neck cancer|
|Other agents, i.e. interferons||Kaposi’s sarcoma; melanoma; gastro-entero-pancreatic cancers; breast cancer|
Breast cancer is often treatable with surgery followed by radiotherapy or chemotherapy. For the majority whose breast tumours are dependent on steroids for growth, steroid receptor blockers can prevent recurrence and the development of metastases. For advanced breast cancer, different aromatase inhibitors are in use. Adjuvant therapy for postmenopausal women with hormone-receptor positive breast cancer should include an aromatase inhibitor, in order to lower the risk of tumour recurrence. In advanced metastatic breast cancer, microtubule disruptors may also be considered. A monoclonal antibody (mAb) has also been shown to improve survival in advanced breast cancer where the tumour is herceptin receptor (HER2) positive.
Tyrosine kinase inhibitors make up another class of new medicines for treating breast cancer. One compound inhibits the tyrosine kinase associated with cell proliferation, tissue invasion and metastasis. It is being studied further for its potential in treating metastases that have spread to the brain.
Colorectal cancer (CRC) is a type of cancer in which chemotherapy has had only moderate success, partly because the disease is often not detected until an advanced stage. Surgery is still the primary therapy and makes up the treatment of about 50 per cent of patients. A first-line therapy with medicines tends to be a combination of a fluoropyrimidine, a folate and a platinum compound. The combination of 5-FU, folinic acid and oxaliplatin is often known as the FOLFOX regimen.
New monoclonal antiodies are among the agents being used as new therapies for CRC. One is directed against EGF receptor. Another mAb acts by making tumour cells self-destruct through a natural process known as programmed cell death (apoptosis). The compound is also being studied to see whether, in combination with the FOLFOX regimen, it can reduce the risk of a relapse in people with no evidence of disease after curative surgery for CRC.
Lung cancer is the leading cause of cancer deaths worldwide - each year more than one million people die of the disease. It is a form of cancer which can be very difficult to treat, particularly ‘small cell’ lung cancer, in which average survival from diagnosis is approximately one year. Platinum compounds, anti-metabolites and microtubule disruptors and topoisomerase inhibitors are often used for chemotherapy, usually in combination, and side-effects can limit therapy.
Another promising class of medicines that may help to extend survival are the kinase inhibitors. These inhibit enzymes involved in key cell functions and their effects vary according to which enzymes they inhibit. Many, but not all, of them are given orally. One compound has already shown a survival benefit in non-small lung cell cancer (NSCLC) and is indicated for use in advanced disease where chemotherapy has failed. Another multi-kinase inhibitor targets an even wider range of enzymes.
In 2013, a compound has been approved by the US Food and Drug Administration as first line therapy to treat patients with non small cell lung cancer (NSCLC) which shows a particular epidermal growth factor receptor (EGFR)-mutation. The medicine acts as a selective inhibitor of the tyrosine-kinase domain of the EGFR-1. NSCLC-cells need this protein to grow and divide. In the future, targeted therapies will help to treat patients more specifically with the appropriate medicine.
Ovarian cancer is less common than lung cancer, but it is still a significant cause of death. If platinum-based therapy is unsuccessful, there is only a limited choice of second-line medicines and new therapies, e.g. topoisomerase inhibitors, are therefore being sought. Five-year survival rates are still below 30 per cent.
Pancreatic cancer is another condition which is difficult to treat. Most tumours are carcinomas that originate in the exocrine duct cells or digestive enzyme-producing cells. The survival rate for all stages of pancreatic tumours is poor, with most studies showing a five-year survival rate of less than five per cent. About 220,000 people worldwide are diagnosed each year with pancreatic cancer, with 60,000 new cases in Europe and 30,000 in the US.
An anti-metabolite and a microtubule inhibitor have been the main chemotherapy agents used, often together with radiotherapy, but response rates are not encouraging. Meanwhile, small molecule EGF-receptor-tyrosine kinase inhibitors have been authorized as they were shown to significantly prolong survival in advanced pancreatic cancer. A high-affinity anti-CEA antibody has been awarded orphan drug designation by the European and US Medicines Agencies which is also being tested in imaging metastatic colorectal cancer.
Prostate cancer has a much better prognosis than pancreatic cancer. While a tumour confined within the prostate itself is usually treated by surgery (radical prostatectomy) or radiation therapy, about half of all cases have already metastasised by the time they are discovered and require additional treatment.
This usually involves therapy with hormonal agents such as gonadotrophin releasing hormone (GnRH) agonists or anti-androgens. These compounds inhibit the activity of male hormones, such as testosterone, that help drive tumour growth. Many of these drugs act by functionally disrupting the androgen receptor (AR), a transcriptional regulator of cell proliferation, but tumours eventually become resistant to the treatment by expressing higher levels of the AR.
In 2010, the U.S. Food and Drug Administration (FDA) approved the first therapeutic cellular immunotherapy to treat metastatic hormone refractory prostate cancer. While referred to as a therapeutic vaccine, the treatment is an immunostimulant. A course of therapy consists of three basic steps: A patient's own white blood cells are extracted. The blood product is incubated with a fusion protein. The activated blood product is re-infused into the patient to cause an immune response against prostate cancer cells carrying a specific antigen. Treatment repeats three courses over the span of a month, with two weeks between successive courses.
Other tumour types are less common. However, the need to improve chemotherapy is just as acute. For example, alkylating agent implants for malignant glioma have increased the therapeutic options available for tumours of the brain. Positive developments in kidney cancer include the introduction of a blocker of angiogenesis (blood vessel growth) and a tyrosine kinase inhibitor. Furthermore, a tyrosine kinase inhibitor has been authorised for use in gastrointestinal stromal tumours.
Supportive treatment is also needed to ensure that chemotherapy works most productively. Erythropoietic growth factor has been registered for its ability to counteract the anaemia that may develop with some existing chemotherapy agents. Vomiting is also a problem with many chemotherapy regimens, and new anti-emetics have been authorized. There are also new analgesic compounds to relieve cancer patients from pain.
The new cancer immunotherapy approaches aim at combating cancer by stimulating the body's own immune cells. The tumour and its environment suppress the ability of cancer patients to develop an effective anti-tumour immune response and in this way protect both tumour growth and survival.
Latest cancer immunotherapies have demonstrated surprising clinical benefit, even for end-stage patients with difficult-to-treat tumours such as prostate and non-small cell lungcancer. Researchers hope that, unlike conventional cancer therapies, clinical responses to cancer immunotherapy tend to be durable, sometimes resulting in much better long term survival and absence of resistance or recurrences.