Environmental factors

Increasingly, lifestyle factors play a large part in the development of many cancers. Cigarette smoking has been identified as the single most important cause of preventable disease and premature death in the UK. The beneficial effect of stopping smoking on the cumulative risk of death from lung cancer reduces with increasing age (Doll et al., 2004). Smoking causes about 90% of lung cancer deaths, and the link between tobacco and cancer was established more than 50 years ago.

The most important lifestyle factor for bowel cancer is diet, while cervical cancer is primarily linked to sexual behaviour through the transmissible agent human papilloma virus (HPV) and secondarily to smoking.

Table 52.1 lists a number of other factors which have been associated with cancer development.

Table 52.1 A–K of factors associated with specific cancer sites: An empirical basis for recommending lifestyle changes (Jankowski and Boulton, 2005)

Genetic factors

A number of rare tumours are known to be associated with an inherited predisposition, where an individual is born with a marked susceptibility to cancer. This is due to the inheritance of a single genetic mutation which may be sufficient to greatly increase the risk of one or more types of cancer. Examples include the paediatric malignancies, Wilms’ tumour of the kidney and bilateral retinoblastoma, a rare cancer of the eye. Some common cancers such as breast, ovarian and colorectal cancer may also show a tendency to occur in families, but these represent a small proportion of the overall presentation of common cancers where identifiable risk factors are relevant in only 5–10% of cases, although when the genetic factor is present the cancers tend to have their onset at a younger age (Garber and Offit, 2005).

Screening

Screening programmes aim to detect pre-malignant changes or early-stage cancer in asymptomatic individuals in the general population to provide earlier and thus more effective treatment. Any screening test must be simple, reliable, highly specific (to exclude healthy individuals) and highly sensitive (detection: 90–95%). For a screening programme to be effective in reducing morbidity and mortality, there must also be an available, effective, safe and economically viable treatment that can be applied to the abnormalities detected by the screening test. Screening is well established for cancers of the breast, cervix and, more recently, bowel. Population screening for prostate cancer using the prostate-specific antigen (PSA) blood test remains more controversial due to the lack of specificity and sensitivity of the test, and to the limited evidence on the viability and effectiveness of the treatment options in early-stage disease. It is currently not recommended for use in screening programmes in the UK but is used in the USA. The evidence base for ovarian cancer screening using the blood test CA125 and pelvic ultrasound is evolving through clinical trials.

Prevention

The strong association between cancer risk and lifestyle factors means there is great potential for the primary prevention of cancer through:

Chemoprevention

Chemoprevention is the prevention of cancer by using medication. The most common example is tamoxifen (pre-menopausal women) or an aromatase inhibitor (post-menopausal women) prescribed daily for 5 years to reduce the risk of developing breast cancer in high-risk women. However, these treatments are not without their side effects, such as menopausal symptoms and increased risk of thromboembolic events. Therefore, the risk-benefit ratio to each patient needs to be carefully assessed.

Another potential future development is the effect of aspirin as a chemopreventive agent for colorectal cancer. Maximal effect requires long-term use of high-dose aspirin that may increase the risk of gastro-intestinal bleeding. Non-steroidal anti-inflammatory drugs (NSAIDs) and selective cyclooxygenase-2 (COX-2) inhibitors may also be candidates for chemoprevention. However, the regular use of these drugs may also cause gastro-intestinal bleeding and increase the risk of cardiovascular events (Herszényi et al., 2008)

Oncogenes

Oncogenes are where the normal gene, called a proto-oncogene, mutates and is then expressed at inappropriately high levels, therefore increasing the function of that gene. Examples of proto-oncogenes are genes that encode growth factors, signal transducers and transcription factors.

Tumour suppressor genes

Tumour suppressor genes are normal genes which have a protective effect against oncogenes, and are also known as ‘anti-oncogenes’. The tumour suppressor gene’s normal function is usually to control the cell cycle or act as a check point in division. When this function becomes lost due to mutations affecting both copies of the gene in a potentially malignant cell, other genetic mutations have a greater likelihood of progressing to cancer. An example is the TP53 gene which codes for the suppressor protein product p53.

The p53 protein acts as a regulator of cell growth and proliferation and controls passage from G1 to S phase in cell division (see Fig. 52.1). Agents which damage DNA cause p53 to accumulate. This accumulation of p53 switches off replication in the cell, arresting the cell cycle and allowing time to repair. If repair fails, p53 may trigger cell suicide by apoptosis. Thus, p53 controls and halts the proliferation of abnormal cell growth.

Fig. 52.1 Normal cell cycle.

The cancer cell

Cancer cells differ from normal cells in that they function differently. Inherently unstable, they may display different protein or enzyme content and chromosomal abnormalities (such as translocations or deletions) which may be associated with differences in their susceptibility to chemotherapy or radiotherapy. The changes in internal structure and function lead to changes in their appearance which are visible under light microscopy, for example, larger and more varied appearance of the cell nuclei, and loss of the appearances of specialised cell function such as gland formation. This allows them to be easily detected, particularly when these lead to changes in the way clusters of cells form structures as a group and relate to normal cells in a tissue or organ.

Tumour growth

A solid tumour represents a population of dividing and non-dividing cells. The time it takes for a tumour mass to double is known as the doubling time. The latter will vary depending on the type of tumour but for most solid tumours it is about 2–3 months. In most solid tumours, the growth rate is very rapid initially (exponential growth) and then slows as the tumour increases in size and age, a pattern described as Gompertzian growth (see Fig. 52.2). The growth fraction is the percentage of actively dividing cells in the tumour, and this decreases with increasing tumour size.

Fig. 52.2 Example of Gompertzian growth of cancer cells.

This pattern of tumour growth kinetics has implications for chemotherapy treatment. Generally, chemotherapy is most successful when the number of tumour cells is low and the growth fraction high, which is the situation in the very early stages of cancer.

Tumour spread

As a primary tumour grows, it both pushes the normal surrounding cells aside and invades between them into normal tissue. It is this property of invasion that characterises a malignant tumour and leads to distant spread of the disease, since the abnormal cells often infiltrate through the walls of blood vessels and the lymphatic system. Malignant cells are then released from the infiltrating cluster of tumour cells and are transported by the blood or lymphatic fluid to other organs of the body where they can subsequently form secondary cancers or metastases. The pattern of spread tends to be predictable for different tumour types, influenced by the anatomy of the primary site and by differences in the local factors affecting the viability of malignant calls when they become deposited elsewhere. For example, breast cancer usually metastasises to the lymph nodes under the arm, lungs and central nervous system, while prostate cancer tends to metastasise to bone. Generally, when the primary is first detected, the larger the tumour mass the more likely that it has metastasised to other sites.

Clinical assessment

Treatment