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.

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.

Patient management

Clinical assessment

Tumour marker	Indicative cancer
CA125	Ovarian cancer, although non-specific
α-Fetoprotein (AFP)	Testicular tumour
β-Human chorionic gonadotrophin (β-HCG)	Testicular tumour
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

Three main options are available for the treatment of patients with solid tumours: surgery, radiotherapy and chemotherapy. Targeted and biological therapies are at present minor modalities, and it is hoped that these will be employed more as their effectiveness improves. Each treatment may play a number of roles, either alone or in combination, depending on the disease, stage and grade.

Role of surgery

Surgery can be curative when solid tumours are confined to one primary anatomical site or region as in localised disease. It can also be used to remove isolated metastatic masses with curative intent in rare circumstances or to deal with anatomical consequences of a tumour as a palliative procedure, such as relief of bowel obstruction by defunctioning colostomy. Surgical techniques may be used to support chemotherapy administration when given by continuous infusion or by the intraperitoneal route. Surgery may also play a role in diagnosis through tissue biopsy or in staging to ascertain the extent of tumour involvement such as in ovarian cancer. In the latter, it may also be used to debulk or reduce the size of the tumour to effect pain relief or to improve the effectiveness of subsequent radiation or chemotherapy. However, with more widespread disease, systemic treatment becomes necessary, with chemotherapy playing a major role

Role of radiotherapy

Radiotherapy can be used to cure cancer, reduce the symptoms of the tumour, reduce the size of the tumour ready for surgery or to prevent re-occurrence of the tumour after surgical removal. It can be used alone or in combination with surgery and/or chemotherapy. A full exposition of the role of radiotherapy is beyond the scope of this chapter, which concentrates on the role of systemic agents. However, the combination of radiotherapy and systemic treatment is becoming increasingly employed as research shows the benefit to disease control and long-term survival, for example, in carcinoma of the uterine cervix (Green et al., 2009).

Systemic therapy

This encompasses cytotoxic chemotherapy, hormonal, biological and targeted therapies, but the term does not usually encompass the modalities of nutritional, complementary, alternative, or other ‘holistic’ interventions, even if employed within a conventional medical environment.

Cytotoxic chemotherapy

Chemotherapy regimen

Although chemotherapy is sometimes administered as a single agent, it is more usual to combine two or more drugs to achieve additive or synergistic effects. Generally, drugs used in combination should have established efficacy as single agents, different mechanisms of action and differing toxicity profiles to allow their use at optimal doses.

Chemotherapy scheduling

As chemotherapy does not specifically target malignant cells, any actively proliferating normal cell will be at potential risk of damage, in particular the cells of the bone marrow. This causes a fall in the white blood cell count and with many cytotoxic drugs, the white blood count is at its lowest level (nadir) around 10 days after treatment. Recovery generally occurs by day 20 post-treatment, and therefore chemotherapy treatment is usually repeated every 3–4 weeks. With agents such as mitomycin and lomustine, haematological recovery may be delayed for 42–50 days following treatment, in which case the interval between treatment cycles needs to be increased. In most cases, a course of treatment will comprise a maximum of six cycles of chemotherapy, although in some less common cancers such as sarcomas and in paediatrics, the regime may continue with a much longer period of adjuvant or consolidation therapy.

Figure 52.3 demonstrates the tumour cell kill for each cycle of chemotherapy together with the healthy normal cell kill. Chemotherapy works in situations where the healthy normal cells recover faster or more completely from the effects of chemotherapy compared to the tumour cells. This allows the tumour cells to be progressively killed off, whilst not having a detrimental effect on the patient.

Fig. 52.3 The effect of chemotherapy on tumour mass and healthy cells.

Chemotherapy dose

The dose of most chemotherapy agents is calculated using the patient’s body surface area (BSA) and is usually given in the form of milligrams per square meter. Body surface area may be calculated from the height and weight of the patient using a nomogram and may need to be recalculated for subsequent cycles of chemotherapy if the patient experiences significant weight changes. Table 52.4 gives an example of a chemotherapy regimen used in breast cancer. The reliability of body surface area as a predictor of the effective safe dose is diminished for patients who are either very thin (cachectic) or grossly overweight (morbidly obese) since it does not then reflect a reasonable estimate of lean body mass.

Table 52.4 Example of a chemotherapy regimen FEC–T (Fluorouracil, epirubicin, cyclophosphamide, docetaxel (Taxotere®)) for breast cancer

Indication	Adjuvant Breast Cancer
Length of cycle	21 days
No. of cycles	3 cycles of FEC followed by 3 cycles of Taxotere® (Docetaxel)
FEC
Fluorouracil	IVB	500 mg/m² day 1
Epirubicin	IVB	100 mg/m² day 1
Cyclophosphamide	IVB	500 mg/m² day 1
T
Docetaxel	IVI over 1 h	100 mg/m² day 1

IVB, i.v. bolus; IVI, i.v. infusion.

Adjuvant chemotherapy

Adjuvant chemotherapy means literally ‘additional treatment’ and is usually given after surgery or radiotherapy when all detectable disease has been removed, but where there remains a statistical risk of relapse due to undetectable disease. Adjuvant therapy is, therefore, used to increase the likelihood of cure. Only patients whose cancers have a high or intermediate risk of recurrence tend to be selected for adjuvant chemotherapy since it is not desirable to expose patients whose disease may already have been cured by surgery or radiotherapy to the toxicity of chemotherapy treatment.

In colorectal cancer, for example, adjuvant chemotherapy provides significant disease-free survival benefit by reducing the recurrence rate and also increases overall survival. This indicates the curative role of chemotherapy in the adjuvant setting (Sargent et al., 2009). Similarly, in breast cancer, adjuvant treatment has been shown to increase recurrence-free survival (Levine and Whelan, 2006), and trials are underway to determine which agents and in what combination further improvements in overall survival will be obtained. A recent trial has shown that three-weekly AC/T (doxorubicin, cyclophosphamide, docetaxel [Taxotere®]) is significantly inferior to CEF (cyclophosphamide, epirubicin, 5-flourouricil) or EC/T (epirubicin, cyclophosphamide, docetaxel [Taxotere®]) in terms of recurrence-free survival (Burnell et al., 2010). This is important, as standard treatment choices should move to the superior regimen.

Neo-adjuvant chemotherapy

In neo-adjuvant chemotherapy, chemotherapy is given before local therapy, often preoperatively, to reduce tumour size and facilitate surgical removal. Neo-adjuvant chemotherapy has been of particular value in cases of breast cancer, non-small-cell lung cancer, advanced head and neck cancer, and bone tumours. In Ewings sarcoma, it allows limb-sparing surgery as an alternative to amputation. It also improves survival with reduced morbidity in osteosarcoma.

Synchronous chemoradiation

In several cancers, chemotherapy alongside radical radiotherapy is now established. Agents such as cisplatin are commonly used as a ‘radiosensitiser’ in head and neck, oesophageal and cervical cancers. The use of cetuximab in combination with radiotherapy for a certain type of head and neck cancer is also recommended (National Institute for Health and Clinical Excellence, 2008). Although common, the use of the term ‘radiosensitiser’ in this context is somewhat inaccurate and is distinct from the ‘true’ radiosensitising drugs such as nimorazole, which interact at a chemical level with very short-lived radiation-induced free radicals, and the effect is better termed ‘combined modality therapy’.

Adverse effects of cytotoxic drugs

Most cytotoxic drugs have been developed because of their effect on dividing cells. Consequently and as previously mentioned under chemotherapy scheduling, proliferating normal tissue such as bone marrow is at risk. Myelosuppression is frequently the dose-limiting toxicity with these compounds. Neutropenia and thrombocytopenia place patients at risk of life-threatening infection and bleeding, respectively.

The other acute adverse effects occurring most frequently include nausea and vomiting, mucositis, anorexia and alopecia. Individual drugs will also give rise to specific adverse effects, some of which may not be reversible on stopping treatment. Cardiotoxicity, nephrotoxicity and pulmonary toxicity, which are specific to the chemotherapeutic agent or class, may depend on cumulative drug exposure, the schedule of administration and previous therapy. Long-term side effects include infertility due to suppression of ovarian and testicular function and occasionally the induction of a second malignancy.

Chemotherapy-specific adjunctive treatments

Both ifosfamide and cyclophosphamide are metabolised to the inactive acrolein which is responsible for bladder toxicity. The co-administration of mesna, a sulphydryl-containing compound which binds to acrolein, has reduced the incidence of haemorrhagic cystitis associated with intravenous regimens of ifosfamide and high-dose cyclophosphamide.

Calcium leucovorin or folinic acid is a reduced form of folic acid and is in effect an ‘antidote’ to the cytotoxic methotrexate. Folinic acid is effectively used as a form of ‘rescue’ when high doses of intravenous methotrexate are used to limit the exposure to methotrexate to a defined period of time.

Targeted therapies

In recent years, there has been an increased understanding of biochemical signalling pathways involved in the growth and progression of tumours. This has allowed the development of therapies targeted specifically at the cell receptors involved. A number of these are described. As they are targeted at tumour cells, they suppress disease without inflicting the non-selective toxic effects of cytotoxic chemotherapy on the patient.

Epidermal growth factor receptor

The epidermal growth factor receptor (EGFR) is a transmembrane protein with an intracellular tyrosine kinase domain. Extracellular binding of the epidermal growth factor receptor induces tyrosine phosphorylation which activates signal cascade pathways. These ultimately lead to cellular proliferation and metastasis. Epidermal growth factor receptor expression is low in normal tissues, and overexpression is associated with a variety of tumours including non-small-cell lung cancer, colon, and head and neck.

Inhibitors of epidermal growth factor receptor (also known as human epidermal growth factor receptor type 1 [HER1]) include:

• Small molecules such as the orally administered erlotinib used in the treatment of non-small-cell lung cancer and imatinib used in the treatment of gastro-intestinal stromal tumours (GIST) which specifically inhibit tyrosine kinase.

• Monoclonal antibodies such as cetuximab which binds to the epidermal growth factor receptor. Cetuximab has demonstrated synergy when given in combination with irinotecan chemotherapy, offering prolonged survival in selected patients with metastatic colorectal cancer.

Vascular endothelial growth factor receptor

Angiogenesis is the formation of new blood vessels on which tumour growth depends. Vascular endothelial growth factor (VEGF) is key in angiogenesis and its overexpression has been associated with increased vasculature, aggressive disease and poor prognosis. The monoclonal antibody bevacizumab inhibits VEGF, thereby reducing new blood vessel growth and interstitial pressure within the tumour, allowing improved chemotherapy access. Studies have demonstrated meaningful survival benefits when bevacizumab is administered in conjunction with chemotherapy in patients with advanced or metastatic colorectal cancer (Hurwitz et al., 2004).

Human epidermal growth factor receptor type 2

Overexpression of human epidermal growth factor receptor 2 (HER2) is associated with a particularly aggressive form of breast cancer (about 20% cases are HER2 positive) linked with a poor prognosis. Trastuzumab, a humanised monoclonal antibody, specifically targets human epidermal growth factor receptor 2 and is only effective in patients with elevated levels. It is used widely in metastatic and early breast cancer (National Institute for Health and Clinical Excellence, 2002, 2006a). The use of trastuzumab in other cancers that express human epidermal growth factor receptor 2 is also under investigation. Trastuzumab has also been licensed for use in human epidermal growth factor receptor 2 positive gastric cancer.

Capecitabine

Although capecitabine does not target a particular receptor, it is mentioned in this section, as it preferentially targets tumour cells.

Capecitabine is a fluoropyrimidine carbamate precursor of 5-fluorouracil (5FU). Given orally, it is converted via enzyme pathways to 5-fluorouracil. As these enzymes are found in higher concentrations in tumour cells, treatment is effectively targeted. Capecitabine has been shown to be at least as effective as intravenous 5-fluorouracil (Twelves et al., 2008), and it is widely used in practice. This is of a particular benefit where the total regimen can then be given orally rather than intravenously.

Management of patients receiving cytotoxic chemotherapy

Prescription verification

Over recent years, there has been considerable effort to improve the quality and safety of chemotherapy services for adult patients (National Chemotherapy Advisory Group, 2009). In particular, the importance of all chemotherapy prescriptions being checked by appropriately trained and competent pharmacists is now recognised. A checklist of key points an authorised pharmacist must undertake to verify any prescription for systemic anti-cancer therapy prior to preparation and release has been determined (British Oncology Pharmacy Association, 2010) and is presented in Box 52.2.

Box 52.2 Standards for chemotherapy prescription verification (British Oncology Pharmacy Association, 2010)

1. Check prescriber’s details and signature are present and confirm they are authorised to prescribe SACT

2. Ensure regimen has been through local approval processes, for example, clinical governance and financial approval and/or is included on a list of locally approved regimens

3. On the first cycle, check the regimen is the intended treatment as documented in a treatment plan, in the clinical notes or in the electronic record

4. Check regimen is appropriate for patient’s diagnosis, medical history, performance status and chemotherapy history (using the treatment plan, clinical notes or electronic record)

5. Check there are no known drug interactions (including with food) or conflicts with patient allergies and other medication(s)

6. Check that the timing of administration is appropriate, that is the interval since last treatment

7. Check patient demographics (age, height and weight) have been correctly recorded on prescription

8. Check body surface area (BSA) is correctly calculated, taking into account recent weight. Note there should be local agreement for frequency of monitoring and checking patient’s weight

9. Check all dose calculations and dose units are correct and have been calculated correctly according to the protocol and any other relevant local guidance, for example, dose rounding/banding

10. Check cumulative dose and maximum individual dose as appropriate

11. Check reason for and consistency of any dose adjustments, for example, reduction(s) or escalations and ensure reason is documented

12. Check method of administration is appropriate

13. Check laboratory values, FBC, U&Es and LFTs are within accepted limits if appropriate

14. Check doses are appropriate with respect to renal and hepatic function and any experienced toxicities

15. Check other essential tests have been undertaken if appropriate

16. Check supportive care is prescribed and it is appropriate for the patient and regimen

17. Sign and date prescription as a record of verification

SAT, Systemic anticancer therapy

Cumulative dosing

The use of doxorubicin is limited by a dose-dependent cardiomyopathy. A number of other factors have been implicated, including treatment schedule, patient age and pre-existing cardiac disease, but dose is the most important. The maximum recommended cumulative dose is 550 or 400 mg/m² for patients who have received radiotherapy to the mediastinum. Therefore treatment should be monitored closely to make sure the cumulative dose is not exceeded throughout the patient’s lifetime. All other anthracycline antibiotics also have a lifetime cumulative dose limit.

Dose modification or delay

Appropriate investigations must be carried out before each treatment to ensure that patients are fit for chemotherapy. In particular, the patient’s haematological, renal and hepatic function should be investigated. For some cytotoxic drugs, it may be necessary to adjust the dose, or even stop treatment, in the presence of renal or hepatic impairment to ensure that delayed excretion or reduced metabolism does not result in excess toxicity. Therefore, the individual summary of product characteristics (SPC) for the chemotherapy agent should be consulted and can be found at http://www.medicines.org.uk.

If the bone marrow does not recover sufficiently between cycles of treatment, then a dose reduction or a delay in treatment may be necessary. In general, patients with a neurophil below 1 × 10⁹/L or a platelet count below 100 × 10⁹/L should not be given myelosuppressive cytotoxics at full doses.

Drug interactions

Prescriptions for cancer chemotherapy are often complex, sometimes involving combinations of both parenteral and oral cytotoxic drugs, intravenous fluids and other supportive therapies. The potential for drug interactions to arise is considerable. However, care is required when assessing the clinical significance of potential drug interactions. A documented interaction does not necessarily imply that drugs should not be used together but can necessitate close monitoring of the patient.

Patient information and counselling

All patients must be provided with information about their treatment, including any anticipated side effects. Patients should be encouraged by health professionals to ask questions about their treatment.

Patients must understand the different medication, the specific role of each medicine and duration of treatment. Duration of treatment is particularly important to prevent highly potent medicines from being inadvertently continued beyond their intended course.

Symptom control

Nausea and vomiting

Chemotherapy-induced nausea and vomiting (CINV) is one of the most frequently experienced side effects encountered by chemotherapy patients and is considered to be the most distressing. In extreme cases, poor symptom control can result in patients refusing further treatment.

In selecting an appropriate anti-emetic regimen, relevant factors include the emetogenic potential of the chemotherapy drugs prescribed, the putative mechanism(s) of inducing emesis, and the likely onset and duration of symptoms. Individual patient characteristics also have to be taken into consideration. For example, predisposing factors which increase a patient’s susceptibility to emesis following chemotherapy treatment are:

• Poor control with prior chemotherapy.

• Female sex.

• Younger age <50 years.

• A current or prior history of low chronic alcohol intake.

• History of sickness: pregnancy/travelling/surgery.

• Anxiety.

• Smoking.

• Radiation to gastro-intestinal tract, liver or brain.

• Other medications: various medications can cause nausea and vomiting such as anaesthetic agents, anti-depressants, anti-microbials, anti-fungals, iron, levodopa, carbidopa, NSAIDs.

Differences in the severity of emesis can also occur between patients receiving the same type of chemotherapy and even between treatment cycles in the same patient; however, modern drug treatment can successfully control CINV for the majority of patients.

The 5-hydroxytryptamine type 3 (5HT₃) receptor antagonists, which include dolasetron, granisetron, ondansetron, palonosetron and tropisetron, have become the standard management of acute CINV when treating patients with moderately emetogenic chemotherapy regimens. For highly emetogenic chemotherapy regimens such as those including cisplatinum, the use of the NK₁ inhibitor, aprepitant, together with a 5HT₃ antagonist is becoming the gold standard. These agents are most effective in dealing with acute emesis (less than 24 h duration) when combined with a potent steroid such as dexamethasone.

It is important to achieve optimal control of nausea and vomiting at the outset to avoid subsequent anticipatory symptoms which can prove very difficult to treat.

The route of administration for anti-emetics is an important consideration. With intravenous chemotherapy, it may be simpler to administer all treatments by the intravenous route. Alternatives to the oral route may be useful when vomiting occurs and include the rectal and buccal route.

Pain control

Drug therapy remains the cornerstone of effective pain management but it is often undertreated, thus highlighting the importance of regular patient assessment and appropriate dose or drug treatment changes. For example, patients experiencing intolerable side effects to morphine may be transferred to oxycodone or transdermal fentanyl skin patches. Analgesia should be prescribed both regularly and for breakthrough pain, and stimulant laxatives should be prescribed to prevent constipation. Combinations of analgesics which have synergistic activity, for example, opiates plus NSAIDs, can be highly effective whilst minimising dose-related side effects of each agent.

The route of administration is also important. When patients are unable to manage oral medication, it is important to assess the use of alternative routes such as the rectal, subcutaneous, epidural and transdermal routes.

Bone marrow suppression

Myelosuppression following chemotherapy is common, and for some patients profound. The risk of systemic infection can be reduced by good oral hygiene and mouth care using antiseptic mouthwashes and anti-fungal prophylaxis. Patients must be advised to immediately report symptoms of infection and bruising. Platelet transfusions may be required, but fever or other evidence of infection occurring in a neutropenic patient when the neutrophil count is less than 1.0 × 10⁹/L must be aggressively treated with broad-spectrum intravenous antibiotics to prevent overwhelming infection.

The duration and depth of neutropenia can be dramatically reduced by the administration of G-CSF which stimulate neutrophil production and, in cases of severe neutropenia, effectively rescue the patient. Once the patient’s neutrophil count has recovered sufficiently, their use may be safely discontinued. These agents may also be used prophylactically in patients with a high risk of febrile neutropenia before receiving chemotherapy.

Blood transfusions are commonly required by patients at some stage of their treatment due to anaemia. Alternatively, erythropoietin may be useful in some patients receiving chemotherapy to shorten the period of anaemia and improve the patient’s quality of life where blood transfusions are not possible.

Extravasation

Extreme care must be taken when administering cytotoxic drugs parenterally because of the dangers of extravasation. Extravasation, which is the accidental leakage of an intravenous drug into the surrounding tissue, can cause pain, erythema and severe local necrosis, resulting in permanent tissue damage. The patient must be asked to immediately report any pain or a stinging sensation at the injection site since the degree of damage is determined by the amount of drug extravasated and the speed at which it is detected. If extravasation is suspected, the administration of further chemotherapy must stop and remedial treatment must commence as soon as possible. The effectiveness of such therapy varies according to the agent extravasated.

Inpatient or outpatient treatment

The majority of patients receive chemotherapy in the outpatient clinic or day-care setting, where cytotoxics are administered mainly by short intravenous infusion at 3- or 4-week intervals. Other treatments include monoclonal antibodies, which usually require close monitoring of the patient for several hours in case of anaphylactic reactions. More complex treatments, such as cisplatinum-containing regimens which require prehydration with intravenous fluids, need the patient to attend all day.

Currently, inpatient treatment of chemotherapy only occurs for the small minority of treatments, and this number is declining further as novel ways of administering long infusions are being developed.

Domiciliary treatment

Oral cytotoxic drugs can safely be taken at home so long as the patient is informed and able to monitor side effects. Availability of a 24-h helpline is essential for these patients should they encounter problems whilst on treatment (National Chemotherapy Advisory Group, 2009). In the future, administration of intravenous treatments, such as the monoclonal antibody trastuzumab, may be carried out more frequently in the home setting, particularly when safety permits and where patient preference becomes an influential factor.

Monitoring anti-cancer therapy

As well as desirable outcomes, treatment with chemotherapy may result in a variety of undesirable outcomes; both require careful monitoring.

Toxicity

The toxicity resulting from treatment is routinely assessed following each cycle of chemotherapy, and may result in therapy being modified on subsequent cycles, for example, a dose reduction, a delay in treatment or, in some cases, an alternative treatment. A number of international rating scales are available for rating predictable acute reactions arising from chemotherapy, including that of the National Cancer Institute Common Toxicity Criteria (for an example, see Table 52.5). Standardising the assessment of treatment-related toxicity in this way allows comparison to be made between published reports of clinical trials.

Table 52.5 National Cancer Institute common toxicity criteria for anaemia (haemoglobin) (Cancer Therapy Evaluation Program, 1998)

Response to treatment

Throughout treatment, the response to therapy is closely monitored, noting changes in performance status, symptoms and objective measurements of the tumour. This may necessitate repeating some or all of the initial staging investigations. Should the initial treatment prove ineffective, an alternative can then be considered without delay. Assessment of response should be formally documented before proceeding to further therapy.

Definitions of response

These have been standardised by the WHO:

• Complete response or remission (CR). Disappearance of all recognisable tumour masses and/or biochemical changes directly related to the tumour and resolution of symptoms determined by two observations at least a month apart.

• Partial response (PR). Decrease by 50% or more in all tumour masses, measured by the product of the longest × the widest perpendicular diameters for at least a month.

• Stable disease (SD) or no change (NC). Changes smaller than those described above for PR or less than for progressive disease for at least a month.

• Progressive disease (PD). Occurrence of any new lesion or increase in the longest × widest perpendicular diameters of measurable disease by at least 25%.

Again, this allows comparison of results between different reported studies. An update of the WHO guidelines has been published (Therasse et al., 2000) called RECIST or Response Evaluation Criteria in Solid Tumours. To avoid confusion, it is important to stipulate in trial protocols which system will be used. Although clinical response indicates tumour sensitivity, it may not necessarily predict long-term survival nor does it measure other benefits such as quality of life.

Case studies

Case 52.1

Mrs BH, a 53-year-old post-menopausal mother of two teenage children, has recently completed six cycles of FEC(100)-T (5-fluorouracil, epirubicin, cyclophosphamide, docetaxel) as adjuvant chemotherapy for her node-positive early breast cancer. She tolerated her chemotherapy well and did not require any dose reductions or delays.

Her receptor status at diagnosis was oestrogen receptor positive and progestogen receptor negative (ER+/PR–); she was also HER2 positive.

Her oncologist has recommended that she commences adjuvant treatment with trastuzumab.

Questions

1. What treatment regimen for trastuzumab should be followed?

2. What side effects of trastuzumab should Mrs BH be informed about when giving consent for treatment?

3. What other treatments should be considered for this patient?

Answers

1. Trastuzumab targets the epidermal growth factor receptor (EGFR) and is indicated for the treatment of early breast cancer overexpressing HER2 following surgery, chemotherapy (neo-adjuvant or adjuvant) and radiotherapy if applicable as recommended by National Institute for Health and Clinical Excellence (2006a). The product license for trastuzumab recommends the dosing schedule used in the HERA study (Piccart-Gebhart et al., 2005), that is loading dose of 8 mg/kg body weight, followed by 6 mg/kg body weight 3 weeks later and then 6 mg/kg repeated at three-weekly intervals administered as infusions over approximately 90 min. This is continued for 12 months, stopping sooner if disease reoccurs.

2. The most common side effects experienced by patients are infusion related, such as fever and chills, usually following the first or second treatment. Patients should be closely monitored for at least 6 h after the start of the first infusion and if the treatment has been well tolerated, for 2 h after the start of subsequent infusions. If a reaction occurs, the infusion should be stopped, appropriate symptomatic treatment administered and treatment recommenced at a slower rate only when the symptoms have subsided. Trastuzumab has been associated with cardiotoxicity and patients who have previously received anthracyclines are at increased risk. All patients should have their cardiac function closely monitored at baseline and every 3 months during the period that they are being treated with trastuzumab (National Institute for Health and Clinical Excellence, 2006a). There was an approximate 5% increase in the number of patients with a significant change in cardiac function in the HERA study (Piccart-Gebhart et al., 2005).

3. In view of her receptor status, this patient should be offered hormonal treatment. Depending on the perceived level of risk of recurrence as estimated using a model such as the Nottingham Prognostic Index (Galea et al., 1992), she should be offered either 5 years’ treatment with an aromatase inhibitor or planned sequential treatment with tamoxifen switching to an aromatase inhibitor after 2–3 years’ therapy. The long-term effect on cardiovascular health (tamoxifen) or bone health (aromatase inhibitors) together with the expected level of benefits should be used to guide choice of treatment. Further information can be found in national guidance for the early management of breast cancer with hormonal treatments (National Institute for Health and Clinical Excellence, 2006a).