Solid tumours

52 Solid tumours



N. Wood, A. Lamont




Key points



• Cancer involves a group of relatively normal cells dividing without the controls that usually prevent the cells from growing beyond their usual size, site and nutritional base.

• Cancer is now considered a long-term illness with many subgroups.

• Cancer is a collective term for several diseases each with its own characteristics and natural history according to where it has started. Even for a single site of origin, such as breast cancer, major biological and histological differences can be shown.

• Before treatment, patients must be carefully ‘staged’ to establish the type and extent of disease.

• Depending on the stage of disease, the aim of treatment may be cure, prolongation of survival or symptom control.

• Cytotoxic chemotherapy is the main treatment for disseminated disease.

• Treatment options depend not only on the ‘gold standard’ of treatment but also patient factors and preferences.

• Targeted medical therapies are becoming more common, generally have fewer side effects and are given over a longer term than conventional chemotherapy.

The term ‘cancer’ is used to describe more than 200 different diseases, including those affecting discrete organs (solid tumours) and haematological malignancies (which are not localised in the same way). Whereas some tumours are benign and may be harmless, this chapter will focus on the management of patients with solid malignancies which require some form of treatment. Treatment is generally carried out in specialised cancer centres, cancer units or for some agents, in the patient’s home. Therapy may include surgery, radiotherapy, chemotherapy and biological or targeted therapy as single modalities or in combination. Care of the cancer patient demands a broad range of services involving a multidisciplinary team working across the hospital, community and hospice network.



Epidemiology


Cancer is a common disease, and more than one in three people will develop some form of cancer in their lifetime. Although more than a quarter of a million people develop cancer each year in the UK, it is predominantly a disease of the elderly, with 74% of new cases diagnosed in people aged over 60 years. Of all deaths in the UK, one in four is due to cancer. The most common single cause of death (22%) is lung cancer, which is potentially preventable by a reduction in tobacco smoking.


Prostate cancer is now the most common cancer in men (24%) followed by lung (15%) and bowel (14%) cancer. In women, breast cancer is the most common (31%) followed by bowel (12%) then lung (12%). However, there are regional variations. From 1979 to 2008, mortality rates from cancer fell by 20% (Cancer Research UK, 2010).



Aetiology


The causes of cancer may be categorised as either environmental or genetic, although these may be interrelated and the causes of some cancers may be multifactorial.



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)







































Factor Associated cancer
Alcohol consumption >3 units a day Most squamous cancers, especially bladder and oesophagus
Body mass index >25 and certainly >30 All solid cancers
Cigarette smoking at any level (even passive smoking) Bladder, lung, head and neck, oesophagus and oropharyngeal cancers
Diet, especially one that is high in fat All solid cancers
Exercising <30 min a day All solid cancers
Family history of cancer (in at least one first-degree relative and at least three people in two or more generations) Inherited cancer syndromes, including breast, colorectal, diffuse gastric, ovarian, prostate and uterine cancers
Genital and sexual health (sexually transmitted infections) Cervical cancer
Health-promoting drugs that may decrease global cancer risks (but need a careful risk/benefit analysis) Colonic adenomas can be treated with low-dose aspirin but can have serious side effects
Hormone replacement therapy linked with breast cancer
Intense sunburn Melanoma
Job-related factors Lung cancer (exposure to asbestos and particulates), skin cancer (contact with arsenic)
Known disease associations Colorectal cancer has predisposing mucosal pathology – adenomas, coeliac disease, ulcerative colitis


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 and prevention



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:


• Avoiding tobacco use, especially exposure to cigarette smoke

• Moderate alcohol consumption

• Healthier eating

• Limiting exposure to sunlight and artificial tanning UV exposure

• Encouraging physical exercise

• Maintaining a healthy body weight

• Maintaining adequate protection from asbestos fibres, radon and other occupational and environmental risk factors.


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)



Cancer at the cellular level


Cancer arises from the changes in genes that regulate cell growth. For a normal cell to transform into a cancer cell, genetic changes must occur to the genes that regulate cell growth and differentiation. The nature of the genetic change may be a single point change to a DNA nucleotide, or the complete loss/gain of an entire chromosome. However, the most important factor is that a gene which regulates cell growth and/or differentiation must be altered to allow the cell to grow in an uncontrolled manner. Most cancers require a series of genetic mutations in a cell before an invasive tumour results.



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.


image

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.


image

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.



Patient management



Clinical assessment



Presentation


The clinical features of cancer vary with tumour type. Generally, patients most commonly present with non-specific complaints which include weight loss, unexplained anaemia, malaise, lethargy or pain, or they may have a specific localising symptom such as bleeding from an identifiable site, a non-healing ulcer, a minor symptom such as a cough or hoarseness not resolving in the usual way or the presence of a painful or painless lump. In general, solid tumours are first clinically detectable when there are approximately 108–109 tumour cells present in a tumour mass in the range of 1–10 g. The patient is usually in the terminal stages of the disease when there are 1012 cells present and a tumour burden of around 1 kg. A tumour may be detected by chance during a routine physical examination or by screening or through identification of early symptoms. However, if this does not occur or these symptoms are not present or not recognised, then the disease at presentation is commonly at a stage where there is a high risk that metastatic spread has already occurred at a microscopic level even if that is not clinically detectable.


Before treatment, each patient must undergo a thorough assessment to establish diagnosis, stage of disease and general fitness level. These factors will influence the choice of treatment and give a guide to prognosis.



Diagnosis


An accurate diagnosis is usually made from a tissue sample taken from a suspected primary or secondary tumour, according to the initial clinical investigations. This sampling procedure, biopsy, may be obtained by an open operation, or less invasively by endoscopy. Such samples may be obtained, for example, during bronchoscopy when lung cancer is suspected or, as in the case of a patient presenting with a breast lump, aspiration through a fine needle.


Malignant tumours vary in their sensitivity to chemotherapy. For example, there are two major groups of lung cancer: small-cell and non-small-cell lung cancer. Each of these groups is treated with different combinations of surgery, radiotherapy and chemotherapy drugs. Therefore, precise histopathology is important.



Tumour markers


Tumour markers are usually proteins associated with a malignancy and are clinically useful to:


• Diagnose a specific tumour

• Monitor response to treatment

• Estimate prognosis

• Detect recurrent disease

• Screen a healthy population or a high risk population for the presence of cancer.

They may be detected in a solid tumour, in circulating tumour cells in peripheral blood, in lymph nodes, in bone marrow or in other body fluids. A number of the tumour markers are presented in Table 52.2.


Table 52.2 Examples of tumour markers used in detection, diagnosis and monitoring





























Tumour marker Indicative cancer
CA125 Ovarian cancer, although non-specific
α-Fetoprotein (AFP) Testicular tumour
β-Human chorionic gonadotrophin (β-HCG)
5-Hydroxyindole acetic acid (5HIAA) Carcinoid tumours
Thyroglobulin Thyroid cancer
α-Fetoprotein Hepatocellular carcinoma
Prostate-specific antigen Prostate cancer
Human chorionic gonadotropin Gestational trophoblastic tumours


Staging investigations


Since the cancer is often disseminated at the time of presentation, it is vital that patients undergo thorough staging investigations to establish the extent and nature of disease. This will determine the most appropriate treatment offered to the patient. Baseline investigations range from clinical examination, blood tests, liver function tests, diagnostic imaging such as chest and skeletal X-rays, ultrasound, computed tomography (CT), magnetic resonance imaging (MRI) and positron emission tomography (PET), depending on the disease type and likely pattern of spread. Clinical guidelines for staging and management of malignancies of the various body systems have been produced at local and national level in most developed countries, with relatively minor variations according to local custom and practice (e.g. NICE in UK, see http://www.nice.org.uk/ for guidance and NCI in USA, see http://www.cancer.gov/ for guidance).



Staging classification


Staging is essentially a measure of how far a tumour has progressed in its development at the time of diagnosis, while grading is a measure of how aggressive its behaviour is likely to be in future based on the microscopic appearance of the cells of the tumour. Both measures are relevant to the patient and clinical team in planning the management.


Most tumours are classified according to the TNM (tumour–nodes–metastases) system where T (0–4) indicates the size of the primary tumour, N (0–3) the extent of lymph node involvement and M (0–1) the presence or absence of distant metastases. Each solid tumour site has a specific grading and staging classification such as Dukes staging in colorectal cancer (Cancer Research UK, 2009) and Gleason scoring for grading prostate cancer (Berney, 2007).



Performance status


The patient’s general level of fitness (performance status) at the time of diagnosis is often a surprisingly reliable indicator of prognosis independent of disease-related factors, and will help determine if they are likely to withstand intensive chemotherapy; this therefore influences the choice of treatment. A number of physical rating scales have been devised to assess performance status, including the Karnofsky performance index (Karnofsky and Burchenal, 1949) and the World Health Organization (WHO) performance scale (Box 52.1).



Box 52.1 Performance status scales


Karnofsky performance index


100 Normal, no complaints, no evidence of disease


90 Able to carry on normal activity, minor signs or symptoms of disease


80 Normal activity with effort, some signs or symptoms of disease


70 Cares for self, unable to carry on normal activity or do active work


60 Requires occasional assistance but is able to care for most of own needs


50 Requires considerable assistance and frequent medical care


40 Disabled, requires special care and assistance


30 Severely disabled, hospitalisation is indicated, although death is not imminent


20 Very sick, hospitalisation necessary, active supportive treatment is necessary


10 Moribund, fatal processes progressing rapidly


WHO performance scale


0. Able to carry out all normal activity without restriction

1. Restricted in physically strenuous activity but ambulatory and able to carry out light work

2. Ambulatory and capable of all self-care but unable to carry out any work; up and about more than 50% of waking hours

3. Capable of only limited self-care; confined to bed more than 50% of waking hours

4. Completely disabled; cannot carry on any self-care; totally confined to bed or chair


Prognostic factors


These are factors that can predict how the disease is likely to behave and determine an outcome in individual patients. For example, Table 52.3 lists prognostic factors in patients with colorectal cancer.


Table 52.3 Prognostic factors in patients with colorectal cancer


















Favourable Unfavourable
Good performance status Presence of nodal involvement
No penetration of the tumour through the bowel wall Presence of distant metastases
Absence of nodal involvement Bowel obstruction and bowel perforation
Absence of distant metastases  


Treatment



Treatment goals


After the diagnosis of cancer has been confirmed and the extent of disease fully investigated, the goals of treatment have to be considered. Depending on stage of disease, the goal can be the following (and may change throughout treatment):


• Cure – Patients are said to be ‘cured’ of cancer when they are completely disease free and have a normal life expectancy. The smaller the tumour bulk when treatment is given, the greater the potential of achieving cure. A common measure of ‘cure’ is the 5-year disease-free survival rate

• Prolong survival while maintaining patient quality of life

• Provide palliative care with relief of symptoms such as pain.

Childhood malignancies, choriocarcinoma and testicular tumours in adults are most responsive to chemotherapy and these patients are frequently cured, even with advanced disease. However, for most patients treated with chemotherapy, cure is less likely and treatment will be given to maximise the probability of cure, prolong survival or be purely palliative. The decision is influenced by factors such as the extent of the disease as well as co-existing symptoms and concurrent medical conditions, performance status and, importantly, the patient’s wishes. The possibility of medium-to long-term survival justifies aggressive treatment but with palliative therapy it is particularly important that the toxicity of treatment is carefully weighed against the potential benefits.



Treatment guidelines


Consensus on the best approach to managing each particular type of cancer is continually evolving, based on the evidence from clinical research most reliably in the form of randomised controlled trials. National guidelines aim to promote equity for patients and ensure a consistent treatment approach taking account of the boundaries of affordability for the healthcare system. In the absence of clinical consensus, patients should be encouraged to participate in clinical trials.



Treatment methods

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Jun 18, 2016 | Posted by in PHARMACY | Comments Off on Solid tumours

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