INTRODUCTION

Despite the fact that survival rates for many cancers have considerably improved over the past decades, malignant disease remains a major cause of morbidity and mortality. Cancer has existed for thousands of years. It can occur in infants but is more commonly associated with increasing age. Certain cancers show an increased incidence in lower socio-economic groups, and different cancers can affect different populations. Cancer is not one disease; indeed, over 200 different cancers have been identified. In fact, there are as many cancers as there are types of human cell.

Nowhere in drug management is the nurse required to be more vigilant than in the care of the patient receiving cytotoxic drug therapy. Nurses must also have a clear grasp of the principles of cytotoxic drug therapy and the likely effects that the main drug groups will have on the patient. In this way, they will know how to advise the patient, what to look out for and what action to take if required. They must act calmly, be available at those times when they are most required by the patient and take on the roles of teacher and counsellor. Extreme care is required in correctly identifying the patient and maintaining accurate records. With additional instruction, nurses are increasingly involved in the administration of parenteral chemotherapy. The skills required are of a technical nature and call for an understanding of how the various factors interact.

AETIOLOGY

There is no known single cause of cancer, although a number of predisposing factors have been incriminated. These include:

CLASSIFICATION OF CANCERS

Cancers may be classified in different ways. They may be considered as solid tumours (e.g. lung, liver, or ‘liquid’ tumours, i.e. of the blood or lymph). Alternatively, they may be classified according to their tissue of origin (Table 19.1).

Table 19.1 Classification of tumours according to tissue of origin

SPREAD OF CANCER

Cancer spreads either by direct infiltration of adjacent tissues or by cells from the primary tumour being transported to another often distant site (or sites) in the body, where they become established and grow. These secondary deposits are known as metastases. The pathways taken by the metastasising cells include the lymphatic system, the blood, serous cavities and cerebrospinal fluid pathways. Different primary tumours tend to show preference for particular secondary sites (Box 19.1).

Some patients develop a second primary tumour.

PRESENTATION

A malignancy may be an incidental finding when some other condition is being investigated or at a routine check. It otherwise presents in many different ways, ranging from bleeding, swelling and loss of function to anaemia and general malaise depending on the type of tumour and its location. Pain tends to be a feature of more established disease when there is tissue erosion or pressure from metastases.

DIAGNOSIS AND TREATMENT OPTIONS

The diagnosis of cancer is arrived at through careful history taking, physical examination, cytological and pathological examination, and various imaging techniques. Treatment mainly takes the form of surgery, radiotherapy or chemotherapy, or combinations of these. Much will depend on the stage the cancer has reached, the condition and wishes of the patient, and the sensitivity/resistance of the tumour. Cancer cells, like other living organisms, develop resistance to toxic drugs, which may result in treatment failure.

CELL BIOLOGY

In order to appreciate how cancer chemotherapy affects cellular function, it is necessary to have a basic understanding of cell biology. Present in the nucleus of every cell is DNA, which provides the blueprint or template for the chromosomes that carry our genetic characteristics in the form of genes. Also in the nucleus is another acid, RNA, which transmits genetic instructions from the nucleus to the cytoplasm. A cell is stimulated to reproduce in response to the death of another cell. It does this by means of the cell cycle.

CELL CYCLE

The cell cycle is a continuous process during which some cells are replicating while others are resting. The cycle comprises four discrete phases of activity resulting in the production of two identical daughter cells (Fig. 19.1).

• G₁: RNA synthesis occurs in preparation for DNA synthesis

• S: DNA synthesis occurs in preparation for supplying two new cells

• G₂: RNA synthesis occurs in preparation for cell division

• M: Cell mitosis occurs (i.e. production of two new cells)

• G₀: resting phase.

Fig. 19.1 The cell life cycle.

The synthesis (S) and mitosis (M) phases are the main points of activity. The G₁ and G₂ phases occupy the gaps between these phases and allow nutrients to be gathered in to supply energy for the immediately following S and M phases, respectively.

Once the two new cells have been formed, one will mature and differentiate to become a specialised cell, while the other remains a stem cell that will go into a resting (only from replication) phase known as the G₀ phase. There it will remain until it is stimulated to undergo cell division.

Some cells therefore are ‘cycling’ and some are resting. Of those cycling, at any point in time the cells of any given tissue may be at any stage of the cycle. The time taken for the completion of the cycle varies depending on the type of tissue. Although malignant cells replicate in exactly the same way as normal cells, their cell cycle time is often shorter.

CHARACTERISTICS OF CANCER

Cancer is a problem of abnormal cell growth resulting from an interaction between the causal factor and DNA in a normal cell. The result is that normal control mechanisms are lost and the cancer cells reproduce uncontrollably, invading the surrounding tissues and eventually metastasising to sites distant from the primary tumour.

Malignant cells are therefore not new cells. They are an alteration of existing cells, a change that may have taken place as many as 15 years previously as the result of some insult or combination of effects on the body. The malignant cell behaves in a delinquent way, with no respect for the normal patterns of cell differentiation, growth and control. It is a parasite to the body and as such harms the host, which may ultimately lead to death (Fig. 19.2).

Fig. 19.2 Formation of tumour and spread of metastases.

CANCER CHEMOTHERAPY

Cancer chemotherapy is directed towards controlling abnormal cell growth and reducing the number of actively dividing cells. Cytotoxic drugs are used to kill cancer cells, but they kill healthy cells as well. All cells, whether they are normal or malignant, are in different stages of the cell cycle at any time or they may be resting (G₀ phase). Chemotherapy drugs are described as being either phase-specific, i.e. they act more powerfully in one specific phase of the cycle, or cycle-specific, i.e. they work equally well killing cells in any or all phases of the cycle. Chemotherapy drugs will not kill cells in the G₀ phase. They are also more effective when the number of cancer cells is small. It is for this reason that chemotherapy is used as adjuvant therapy, i.e. following surgery and/or radiotherapy. High individual doses of chemotherapy will kill a high percentage of cancer cells. Although healthy cells will be destroyed, they will repair themselves quickly and regrow to normal numbers far more quickly than cancer cells following chemotherapy (Fig. 19.3). Intervals between doses are needed to allow normal cells to recover. Repeat doses at intervals are needed to kill those cells that were in the resting phase and therefore protected from chemotherapy. By combining different chemotherapy drugs (e.g. in some cases using four drugs together), remission rates in many situations are hugely increased. Cancer chemotherapy is therefore at its most effective when used:

Fig. 19.3 The effect of chemotherapy on normal and cancer cells.

Table 19.2 Cancer chemotherapy regimens^a

a Consult specialist literature for details of dosage/route of administration etc. Many other regimens are quoted in the literature.

The initial letters of cytotoxic drugs may be used to represent a regimen forming an acronym. For example, CHOP stands for cyclophosphamide, doxorubicin (formerly known as hydoxyrubicin), vincristine (Oncovin) and prednisolone. Here, a proprietary name is being used as well as a change in name to form the acronym.

The timing of each pulse of treatment is critical to achieving success in eradicating the malignant cells. However, it must always be borne in mind that the patient’s normal cells, especially the rapidly dividing ones, are also being damaged. To ensure that the patient can withstand the treatment, regular haematological monitoring is essential. The tissues that are most chemosensitive are the:

CYTOTOXIC DRUGS

CYTOTOXIC DRUG GROUPS

Cytotoxic drugs fall into a number of classes, each with characteristic antitumour activity, sites of action, and toxicity:

• alkylating drugs

• antimetabolites

• cytotoxic antibiotics

• vinca alkaloids

• other antineoplastic drugs.

It is important to be aware of the metabolism and excretion characteristics, as weakened drug metabolism as a result of disease is not unusual and could result in increased toxicity. The chemotherapy of cancer is complex and should therefore be restricted to specialists in oncology. The National Institute for Health and Clinical Excellence (NICE) has examined many of these drugs and their application in specific cancers/leukaemias and has made recommendations on their use. Details can be found on the NICE website (http://www.nice.org.uk).

ALKYLATING DRUGS

These drugs are among the most widely used in cancer chemotherapy. They are phase-specific (M phase) and act by causing breaks in, and cross-linking on, the strands of DNA, resulting in inhibition of, or inaccurate, replication and finally cell death. In addition to the side effects common to many cytotoxic drugs, there are two major problems associated with use: gametogenesis is often badly affected, and prolonged use of these drugs, particularly when combined with extensive irradiation, is associated with an increased incidence of acute non-lymphocytic leukaemia.

Cyclophosphamide is used in the treatment of chronic lymphocytic leukaemia, lymphomas and some soft-tissue solid tumours. It can be given orally or by intravenous infusion, but it is inert until activated in the body by microsomal enzymes in the liver. One of the metabolites of cyclophosphamide is acrolein, which can cause haemorrhagic cystitis, a serious side effect. As a consequence, when high-dose therapy is used mesna can be given to prevent this. A high fluid intake should be maintained for 24–48 h after intravenous injection. Ifosfamide is similar to cyclophosphamide but given only by intravenous infusion.

Chlorambucil is used to treat chronic lymphocytic leukaemia, non-Hodgkin’s lymphoma, Hodgkin’s lymphoma and ovarian cancer. It is given orally and, apart from bone marrow suppression, side effects are not common, yet some patients develop a widespread rash that can lead to Stevens–Johnson syndrome or to toxic epidermal necrolysis. Lung damage has been reported.

Melphalan is used to treat multiple myeloma, ovarian adenocarcinoma, breast cancer and, by regional arterial perfusion, localised malignant melanoma. As the drug is unstable in infusion fluids, it must be administered via the port of a freely running infusion system. Busulfan is given for the palliative treatment of chronic myeloid leukaemia. Excessive myelosuppression can result in irreversible bone marrow aplasia, and so careful monitoring of blood counts is especially important.

Carmustine is used intravenously in the treatment of multiple myeloma, non-Hodgkin’s lymphoma and brain tumours. Renal damage and delayed pulmonary fibrosis can occur. Lomustine is given orally to treat Hodgkin’s lymphoma, brain or lung tumours and malignant melanoma. Bone marrow suppression can be delayed, and permanent damage can occur with prolonged use. Estramustine is a combination of estradiol and normustine used in cases of prostatic cancer responsive to other therapies. It has both an effect on cell division and a hormonal effect.

Thiotepa is mainly used to treat malignant effusions or bladder cancer when used as an intracavity drug. It has been used intravenously in the treatment of breast cancer. Treosulfan is given either orally or intravenously in the treatment of ovarian cancer. Skin pigmentation is a common side-effect, and allergic alveolitis, pulmonary fibrosis and haemorrhage cystitis can also occur rarely.

ANTIMETABOLITES

These are cycle-specific. They are substances that substitute for, or compete with, intracellular metabolites and become incorporated into the nucleic acids, DNA and RNA, preventing DNA synthesis and leading to cell death.

Methotrexate is used to treat a wide range of conditions, such as leukaemia, lymphoma, breast cancer, lung cancer, head and neck cancer, bladder cancer and osteogenic sarcoma. It acts during the S phase of cell division. It inhibits the enzyme dihydrofolate reductase, which in turn interferes with DNA production. It is a folic acid antagonist. It can be given by all main routes, including intrathecal; as a result, a wide range of doses are used. It is excreted primarily via the kidneys, therefore use is contraindicated in severe renal disease. It can cause, among other side-effects, myelosuppression, stomatitis, hepatic toxicity, photosensitivity, central nervous system symptoms, abdominal distress, rashes and genitourinary toxicity. It interacts with a significant number of drugs, leading to possible toxicity.

CALCIUM FOLINATE RESCUE FOR PATIENTS RECEIVING METHOTREXATE

Calcium folinate is chemically related to the essential coenzyme for nucleic acid synthesis. It is used to diminish the toxicity of folic acid antagonists such as methotrexate. The dose of calcium folinate will depend on the dose of methotrexate previously administered. As an example, up to 120 mg would be given in divided doses over 12–24 h by intramuscular injection, intravenous bolus or intravenous infusion. Following the initial doses, 12–15 mg intramuscularly or 15 mg is given orally every 6 h for the next 48–72 h. Steps should be taken to increase the rate of excretion of the methotrexate (e.g. by alkalinisation of the urine and maintaining the urinary output at a high level).

Fluorouracil inhibits cell division by interfering with DNA and RNA synthesis. It is usually given by intravenous infusion, or injection, to treat colon and breast cancer, as absorption after oral administration is unpredictable. In addition, it can be used locally as a topical cream to treat premalignant and malignant skin lesions. Side effects include haematological damage, gastrointestinal haemorrhage, stomatitis, diarrhoea, nausea and vomiting. Capecitabine is metabolised to fluorouracil and is given by mouth. It is used alone to treat metastatic colorectal cancer or as adjuvant treatment of advanced colon cancer following surgery. It is also used as second-line treatment of locally advanced or metastatic breast cancer, either alone or in combination with docetaxel. Tegafur, a prodrug of fluorouracil, is given orally with calcium folinate in the management of metastatic colorectal cancer.

Cytarabine acts by inhibiting pyrimidine synthesis. It is given subcutaneously, intravenously or intrathecally. It is mainly used in the induction of remission of acute myeloblastic leukaemia but can also be used in the treatment of acute lymphoblastic and acute non-lymphoblastic leukaemia. Fludarabine can be given orally, by intravenous injection or infusion, to treat advanced B-cell chronic lymphocytic leukaemia or after first-line treatment in patients with sufficient bone marrow reserves. Cladribine is given by intravenous infusion for the treatment of hairy cell leukaemia. Cytarabine, cladribine and fludarabine have potent immunosuppressive effects, therefore regular haematological monitoring is essential.

Gemcitabine is used intravenously to treat non-small cell lung cancer and pancreatic cancer. In combination with cisplatin, it is also used in the treatment of advanced bladder cancer. It may cause mild gastrointestinal side-effects, rashes, renal impairment and pulmonary toxicity. Influenza-like symptoms and haemolytic uraemic syndrome have also been reported.

Pemetrexed and raltitrexed both inhibit thymidylate transferase and other folate-dependent enzymes. Pemetrexed is given by intravenous infusion to treat unresectable malignant pleural mesothelioma, and it is also used in the treatment of locally advanced or metastatic non-small cell lung cancer that has previously been treated with chemotherapy. Raltitrexed is given intravenously for palliation of advanced colorectal cancer when fluorouracil and calcium folinate cannot be used. Common adverse effects include myelosuppression, gastrointestinal toxicity and skin disorders.

Mercaptopurine acts by interfering with synthesis of nucleic acid in proliferating cells. It is used as maintenance therapy in the treatment of acute leukaemias. Tioguanine, used in the treatment of both acute and chronic leukaemia, acts by inhibition of purine synthesis.

CYTOTOXIC ANTIBIOTICS

These are phase-specific (S phase) and act by binding to the DNA helix, inhibiting its synthesis and replication, and disrupting RNA synthesis. Many of the cytotoxic antibiotics act as radiomimetics, and therefore the concurrent use of radiotherapy should be avoided, as this may cause enhanced toxicity. Daunorubicin, doxorubicin, epirubicin and idarubicin are anthracycline antibiotics.

Doxorubicin is used in the treatment of acute leukaemia, lymphoma, soft-tissue and osteogenic sarcoma, and breast and lung cancer. It is given by intravenous injection through a freely running intravenous infusion. Extravasation can cause severe tissue damage. Supaventricular tachycardia can arise from drug administration, and cumulative doses are associated with cardiomyopathy. Above a maximum dose of 450 mg/m², symptomatic and potentially fatal heart failure is common. Account must also be taken of treatment with other cardiotoxic drugs. Electrocardiogram monitoring is required both before and after treatment. A formulation of doxorubicin inside liposomes provides a delivery system that may reduce the incidence of cardiotoxicity and lower the potential for local necrosis. However, infusion reactions, sometimes severe, can occur. Hand–foot syndrome occurs commonly with liposomal doxorubicin and may occur after two or three treatment cycles. It may be prevented by cooling hands and feet and by avoiding socks, gloves, or tight-fitting footwear for 4–7 days after treatment. Doxorubicin can also be given by intra-arterial injection and bladder instillation (bladder tumours).

Epirubicin is structurally related to doxorubicin and is used in the treatment of breast, ovarian, gastric and colorectal cancers; lymphomas; leukaemia; and multiple myeloma. A maximum cumulative dose of 0.9–1 g/m² is recommended to avoid cardio-toxicity. Like doxorubicin, it is given intravenously and by bladder instillation. Idarubicin and daunorubicin have properties similar to those of doxorubicin. Idarubicin is available as a capsule for oral ad-ministration when intravenous therapy is not practicable.

Mitoxantrone is structurally related to doxorubicin; it is used for metastatic breast cancer, non-Hodgkin’s lymphoma and adult non-lymphocytic leukaemia. It is given intravenously; myelosuppression and dose-related cardiotoxicity can occur. Cardiac exami-nations are recommended after a cumulative dose of 160 mg/m². Careful technique is essential when diluting the drug for intravenous infusion, as it is very irritant.

Bleomycin inhibits cell growth and DNA synthesis in tumour cells and is used to treat squamous cell carcinoma of the mouth, nasopharynx, oesophagus and external genitalia or skin. It can be given intra-venously, intramuscularly or by intracavity injection. It can cause increased pigmentation, particularly affecting the flexures, and subcutaneous sclerotic plaques may occur. Mucositis, Raynaud’s phenomenon and hypersensivity reactions have all been reported. The main problem with the use of bleomycin is progressive pulmonary fibrosis. This is dose-related, occurring more commonly at cumulative doses greater than 300 000 units and in the elderly. Basal lung crepitations or suspicious chest x-ray changes are an indication to stop therapy.

Dactinomycin inhibits cell proliferation by combining with DNA and interfering with RNA synthesis. It is mainly used to treat paediatric cancers; it is given intravenously through a freely running intravenous infusion. While its side effects are similar to those of doxorubicin, cardiac toxicity is not a problem. Mitomycin has an alkylating action, forming a complex with DNA in cancer cells. It is given intravenously to treat stomach, pancreatic, colonic, rectal and breast cancers and by bladder instillation for superficial bladder tumours. It causes delayed bone marrow toxicity, and therefore it is usually administered at 6-weekly intervals. Prolonged use may result in permanent bone marrow damage. It may also cause lung fibrosis and renal damage.

Only gold members can continue reading. Log In or Register to continue

Share this:

• Click to share on Twitter (Opens in new window)
• Click to share on Facebook (Opens in new window)

Related

Related posts:

1. The role of patients and carers in medicines management
2. Drug treatment of musculoskeletal and joint diseases
3. Pharmacokinetics and pharmacodynamics
4. Drug treatment of infections

Stay updated, free articles. Join our Telegram channel

Join