Principles of the surgical management of cancer

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6 Principles of the surgical management of cancer

The biology of cancer

A neoplasm or new growth consists of a mass of transformed cells that does not respond in a normal way to growth regulatory systems. These transformed cells serve no useful function and proliferate in an atypical and uncontrolled way to form a benign or malignant neoplasm. In normal tissues, cell replication and death are equally balanced and under tight regulatory control. However, when a cancer arises, this is generally due to genomic abnormalities that either increase cell replication or inhibit cell death (Fig. 6.1). The mechanisms by which this abnormal growth activity is induced (carcinogenesis) are complex and can be influenced in many ways: for example, inherited genetic make-up, residential environment, exposure to ionizing radiation or carcinogens, viral infection, diet, lifestyle and hormonal imbalances. These cellular insults give rise to alterations in the genomic DNA (mutations) and it is these mutations that lead to cancer. Mutations can lead to disruption of the cell replication cycle at any point and lead to either activation or over-expression of oncogenes, or the inactivation of tumour suppressor genes, or a combination of the two (Table 6.1). Defining which genes have been mutated in the primary and metastatic cancers may ultimately help predict prognosis. For example the amplification and over expression of C-erbB-2 oncogene can give an indication of the aggressiveness of breast cancer. Scientists have now been able to sequence the entire human genome. This will allow identification of new genes and hence proteins involved in the formation of cancer that will eventually lead to a greater understanding of the development of cancer, and new treatments.

Table 6.1 Examples of gene mutations that can lead to cancer formation

Gene Point of action in cell cycle
p16, CDK4, Rb Cell cycle check point
MSH2, MLH1 DNA replication and repair
p53, fas Apoptosis
E cadherin Cellular adhesion
erb-A Cellular differentiation
Ki-ras, erb-B Regulatory kinases
TGF-β Growth factors

Changes within the cellular genome occur frequently and do not necessarily result in cancer. Natural protective mechanisms repair errors in DNA replication; similarly, immune surveillance, simple wastage (i.e. loss of cells from the surface) and programmed cell death (apoptosis) destroy mutant cells before they proliferate. For persistence of growth and hence cancer formation, these protective mechanisms must break down (e.g. failure of mismatch repair due to mutations in genes such as MLHI and MSH2, or failure of apoptosis). The host’s internal environment may also have a role in the ‘promotion’ of tumour growth. Good examples are the ‘hormone-dependent’ cancers of the breast, prostate and endometrium, which require a ‘correct’ balance of hormonal secretion from the endocrine glands of the host for their continued growth. The natural history of a tumour is also related to its growth rate, which in turn is determined by the balance between cell division and cell death. Some tumours are slow-growing (e.g. prostate) and years may pass before deposits reach a size that threatens normal organ function. Others grow rapidly as a result of a high rate of cell proliferation, and some expand rapidly (despite a relatively normal rate of cell proliferation) if cell death is slow to occur.

The adenoma–carcinoma progression

Neoplasms may be benign or malignant; the essential difference is the capacity to invade and metastasize. The cells of benign tumours do not invade surrounding tissues but remain as a local conglomerate. Malignant tumours are invasive and their cells can directly invade adjacent tissues or enter blood and lymphatic channels, to be deposited at remote sites. This malignant genotype develops as a result of the progressive acquisition of cancer mutations (by point mutation, chromosomal loss or translocation). This progressive accumulation of mutations may lead to the formation of cancer stem cells. In a similar manner to other stem cells these cancer stem cells are pleuripotent (i.e. have the ability to give rise to more than one cell type). It is proposed they produce cells that form the epithelial, structural, and vascular components needed for cancer formation. However the cells arising from a cancer stem cell lack the normal response to the normal cell cycle controls and are, therefore, tumour forming. Such cancer stem cells could explain why cancers can relapse or metastasize. The acquisition of the malignant phenotype can be recognized histologically as a tumour develops from a benign adenoma through to a dysplastic lesion, and finally into an invasive carcinoma (Fig. 6.2). The concept of tumour progression from a benign to malignant phenotype provides the rationale behind screening and early detection programmes; i.e. if benign or pre-invasive lesions are removed, this will prevent invasive disease.

Invasion and metastasis

Benign tumours rarely threaten life but may cause a variety of cosmetic or functional abnormalities. In contrast, malignant tumours invade and relentlessly replace normal tissues, destroying supporting structures and disturbing function; they can spread to distant tissues (metastasize), eventually causing death. Metastases are cancer deposits similar in cell type to the original cancer found at remote (secondary) sites in the body.

The process of invasion and metastasis is complex (Fig. 6.3) and is dependent on the biology of the tumour. For metastases to occur it would appear that further mutations need to occur in the cancer cells. These extra mutations can be called the metastatic signature. Some tumours metastasize earlier in their clinical course than others. This variation may depend on the tissue of origin of the primary tumour, but can also vary widely according to the phenotype of individual tumours. For example, cancer of the breast is thought to metastasize early, and micrometastases are often present but not detectable when the patient first presents. Some patients with apparently localized colorectal cancer are cured by radical surgery, but others receiving the same treatment deteriorate rapidly with metastatic disease.

The mechanisms that control invasion and metastasis are obscure (Fig. 6.4). Local pressure effects from the expanding tumour and the increased motility of tumour cells may play a role in local invasion. Malignant cells secrete a number of factors that may determine their biological behaviour and promote growth at both primary and metastatic sites. The matrix metalloproteinases (MMPs) are endoproteinases with enzymatic activity directed against components of the extracellular matrix. Their action facilitates tumour cell invasion and metastasis by degrading extracellular collagens, laminins and proteoglycans. Other proteases, such as urokinase, plasminogen-activating factor and the cathepsins, are also involved in metastasis formation. Clumps of cancer cells can then embolize to distant tissues and form metastases. The location for the development of metastases could be a simple mechanical property with organs that have fine capillary beds, such as liver and lung, trapping circulating malignant cells which then develop into metastases. The survival of metastatic deposits depends on angiogenesis, which is mediated by an imbalance between positive and negative regulatory molecules released by the tumour cells and surrounding normal cells. Negative factors, such as angiostatin or endostatin, will inhibit new vessel formation. Positive factors, such as vascular endothelial growth factors or fibroblast growth factors, will enhance metastasis. Cancer cells also secrete prostaglandins, which can induce osteolysis and may promote the development of skeletal deposits.

Natural history and estimate of cure

Calculations based on an exponential model of tumour growth suggest that three-quarters of the lifespan of a tumour is spent in a ‘pre-clinical’ or occult stage, and that the clinical manifestations of the disease are limited to the final quarter. For cure, every malignant cell must be eradicated. There should be no recurrent tumour during the patient’s lifetime, or evidence of residual tumour at death. This rigid definition of cure is rarely attainable. Instead, a normal duration of life without further clinical evidence of disease is generally accepted as evidence of cure, even though microscopic deposits of tumour may still be present.

Measuring and comparing the outcome(s) of cancer treatment can be a difficult exercise. Cancer survival data is not normally distributed but skewed with many events happening early in the study period. Survival data is generally expressed as a time from a predefined starting point (e.g. time of surgery) to a similarly defined end point (e.g. disease relapse). Other time points may also be used and so a careful and precise definition of the time period used is essential. In addition, not all patients will have experienced the defined end point by the end of the study period. This phenomenon is known as censoring and mean survival time will be unknown for a subset of the study group. Other confounding factors such as age and the stage of disease also need to be considered. Hence special methods of data interpretation are required. These various statistical methods of cancer data interpretation and comparison are termed survival analysis.

Measures used in survival analysis include, survival and hazard probabilities, Kaplan–Meier equations and graphs (Fig 6.5), Cox’s proportional hazard models, univariate and multivariate analysis. Survival is the probability that a subject survives from the starting point to the end point of the study period. Hazard is the probability that the subject has a specified event at one particular moment in time. ‘Cure’ rates of individual cancers are assessed by survival rates at various times after treatment. Conventionally, 5- and 10-year intervals are used. Cure rates vary according to the aggressiveness of the disease and the success of treatment. In some patients with cancer (e.g. stomach and lung), metastases grow rapidly and cause death within a few years of clinical presentation. In others (e.g. cancer of the breast and melanoma), many years may elapse before metastatic spread becomes evident and, even when metastases have occurred, life may be long. It is for this reason that 5-year survival rates cannot provide a satisfactory estimate of cure for all tumours.

The management of patients with cancer

The goals of treating cancer can be broadly grouped as follows: prevention, cure and palliation. Prevention seeks to modify behaviour to prevent cancer formation. For example, the avoidance of smoking or direct sunlight may prevent the formation of lung or skin cancer. Taking a small dose of aspirin on a regular basis may protect against colorectal cancer (chemoprevention). When a cancer has formed, treatment is aimed at cure for early-stage disease. When a cancer is locally advanced or has metastasized, the chance of cure reduces. In cancers that are felt to be incurable, treatment is then aimed at palliation of troublesome symptoms.

Screening

If cancer can be detected before it causes symptoms, then it is generally smaller, has less chance of having metastasized and is therefore more amenable to cure. Detecting benign lesions with malignant potential, pre-invasive cancer, and invasive malignancy before it becomes symptomatic is called screening (Fig. 6.6). Screening is expensive and its effectiveness in relation to cost must be critically evaluated before routine use (EBM 6.1). Screening is most effective when targeted at specific risk groups and when the screening test has a high level of acceptability to the target population. For successful screening, the test used must be able to detect the cancer at a stage when earlier treatment will lead to fewer deaths from the cancer. In any given population, the likelihood of a cancer being present is generally low (< 1%); hence, the test must be sensitive in order to detect these relatively rare lesions. The test must also be specific (i.e. have a low false-positive rate); otherwise, individuals will undergo unnecessary investigation or even inappropriate treatment. Finally, the proposed treatment of a cancer patient detected by a screening programme must be effective. In the UK, cervical cytology is offered to women on a 3-yearly basis until the age of 60, and mammographic screening (Fig. 6.7) is offered to women between 50 and 64 years on a 3-yearly basis. Other tumour types that might be amenable to screening are listed with their relevant screening tests in Table 6.2.

image

Fig. 6.6 Cervical cytology.

A group of severely dyskaryotic squamous cells in a ThinPrep liquid-based cytology preparation

(Courtesy of Dr A.R.W. Williams, Senior Lecturer/Honorary Consultant in Pathology, University of Edinburgh).