Recall the cell cycle in Chapter 2. Re-read this and determine which normal cells in the body are rapidly and continually dividing. Think about what specific impact this might have on the patient undergoing cytotoxic therapy.

NMC Domain 3: 3.2

There are hundreds of cytotoxic drugs, grouped together according to their biochemical nature (Table 10.1). We also classify the drugs in terms of how they act on the cell. Most cytotoxic drugs disrupt the cell cycle by damaging the DNA or affect mitosis and are classified into groups depending on which part of the cell cycle they affect:

• Cell cycle non-specific drugs kill cells whether in the cycle or resting, i.e. all phases: G0, G1, G2, S and M phases.

• Cell cycle non-phase-specific drugs only kill cells that are active in the cell cycle, i.e. G1, G2, S and M phases, but not G0.

• Cell cycle phase-specific drugs kill cells that are in a particular phase of the cell cycle, i.e. only cells in G1 phase.

Table 10.1 Biochemical classification of cytotoxic drugs

Groups of cytotoxics	Examples of drugs
Antimiotic antibiotics	Doxorubicin Epirubicin
Anthracyclines	Mitomycin C
Non-anthracyclines	Methotrexate 5-Fluorouracil (5-FU) Vinca alkaloids Capecitabine
Antimetabolites	Vincristine
Alkylating agents	Cyclophosphamide
Taxanes	Taxotere Taxol

Most cytotoxic drugs are given in combination – usually two or three drugs are used within a regimen. This enhances the effect of the drugs by killing more cells and minimising the range of side effects as well as lessening the risk of cancer cells becoming resistant. For instance, one cell cycle non-specific drug, one cell cycle non-phase-specific and one cell cycle phase-specific drug may be used. Each of the three drugs has different side effects which means the patient is able to tolerate a high dose and a greater tumour kill may be achieved if the drugs all have different modes of action. As an example, the most commonly used chemotherapy regimen for breast cancer after surgery is 5-fluorouracil (5-FU), epirubicin and cyclophosphamide (FEC) (see Fig. 10.1). Sometimes a single drug is used to manage or reduce a patient’s symptoms.

Fig 10.1 Action of FEC cytotoxic drugs on the cell cycle

Cytotoxic drugs and radiotherapy are sometimes given at the same time. This allows for both the primary disease and the secondary spread to be treated. Some cytotoxic drugs act as radiosensitisers, such as paclitaxel, 5-FU and capecitabine. This makes the radiotherapy more effective, however the combination of treatment increases the severity of side effects.

The timing of administration is important. Cytotoxic regimens are given in cycles – most are scheduled and repeated every 21 days over a number of months. This schedule allows normal cells a recovery period before the next cycle is started.

The FEC regimen mentioned earlier involves 6 cycles, each given 21 days apart. Sometimes, a patient’s white blood cell count is reduced and does not return to the normal range at the end of the 21 days – then the next treatment may be delayed or deferred.

Cytotoxic drugs kill a percentage of cells rather than a fixed number, so the first few treatments kill more cells than the last treatment given. This is important if a patient requests to delay treatment. It is important that the early treatments are given to schedule, but there may be leeway with latter treatments (although this may depend on what the aim of treatment is).

Instead of being given in cycles, some cell cycle phase-specific drugs are given continuously. This is achieved by giving the drug orally or intravenously via a central venous access device (CVAD). The advantage of this is that the drug is constantly present in the blood and tissues. When each cell moves into the specific part of the cell cycle, the drug causes damage. Therefore, only a small number of cells are affected at any one time. For example, giving both 5-FU (intravenous) and capecitabine (oral) only damages cells that are in the S phase. A patient receives a continuous dose of 5-FU from a pump via a CVAD. The pump contains 7 days worth of cytotoxic drug and the patient will attend chemotherapy clinic weekly to have the pump changed for up to 6 months. The 5-FU is constant in the blood and tissues and will damage/destroy any cell that enters the S phase. Because only a few cells are being killed, there are fewer side effects.

Reflection point

What might be the implications of being attached to a pump for 6 months? Think about the physical risks and the impact this might have on an individual’s social/work life and body image.

NMC Domain 1: 1.4

NMC Domain 2: 2.6

NMC Domain 3: 3.1; 3.2; 3.3; 3.4; 3.6

Preparing the patient for cytotoxic treatment

Like for any treatment, patients must sign a consent form before they receive cytotoxic treatment. It is essential that they understand the reason why the treatment is needed; what is hoped to be achieved; what the potential effects of receiving the specific drugs are; and who they should inform if they experience any adverse side effects.

Before each treatment, the patient’s individual dose is calculated using their body mass index (BMI). Height is measured on the first treatment, but the patient must be weighed at every treatment as they may lose weight, and some may gain weight.

A number of medical tests will also be carried out before treatment is administered. The types of tests undertaken are dependent on the types of drugs used and their toxicities. Blood tests, such as a full blood count, and biochemistry are checked to ensure the patient has normal parameters. Tumour markers (e.g. prostate-specific antigen (PSA) for prostate cancer; Ca125 for ovarian cancer; carcinoembryonic antigen (CEA) for breast, colorectal and lung cancer) are taken as these may be used as a guide to monitor the response to treatment. Depending on the type of toxicity, the following investigations might be performed:

• Creatinine clearance (renal).

• Audiogram (hearing).

• Electrocardiogram/echocardiogram (heart).

• X-ray and/or lung function (lungs).

Scans (magnetic resonance imaging (MRI), computed tomography (CT)) may also be done at the beginning, midpoint and at the end of treatment, to judge the response to treatment.

At each cycle of treatment, the patient is reviewed by a healthcare professional to ensure that they are tolerating treatment and the side effects are not too severe.

Activity

Find out how and where the cytotoxic drugs are prepared and how they are stored.

NMC Domain 3: 3.4; 3.6

Routes of administration

Intravenous (IV) is the most common method of giving cytotoxic drugs as it is the most direct way of getting the drug into the bloodstream. However, there is the risk of infection and the procedure is uncomfortable. A variety of intravenous devices are used to access a vein: a peripheral cannula or CVAD such as a skin tunnelled (Hickman) line or Portacath or peripherally inserted central catheter (PICC) line. The choice of intravenous device is dependent on the quality of the patient’s venous access; the length and frequency of treatment; the potential risk of complications from a central venous catheter; the type of drug; and the expected need for additional interventions such as blood transfusions.

Activity

Watch the peripheral cannulation video at:

http://cancernursing.org/forums/topic.asp?TopicID=74 (accessed November 2011).

Find out which veins are used to site a peripheral cannula. What are the factors taken into consideration when choosing a site?

NMC Domain 3: 3.2; 3.4; 3.6

Another common method of giving cytotoxic drugs is orally. The number of drugs given this way is increasing due to pharmaceutical developments. It is clearly an attractive method as the patient may receive treatment at home. However, it does result in less contact time from healthcare professionals which may lead to undiagnosed side effects and less psychological support (Irshad & Maisey 2010). There is the issue of concordance (compliance) – patients may not take the tablets as instructed, either forgetting a dose or taking too many. There is also the safety issue of storing medication in the home environment.

Cytotoxics can also be given intrathecally, injected into the spinal canal (via a lumbar puncture) so the drugs reach beyond the blood–brain barrier. This is used to treat patients with leukaemia. This is a potentially hazardous procedure as the risk of infection is high and there is a risk of spinal cord damage. Only three drugs are licensed to be given intrathecally and there have been several fatal cases when the incorrect drug has been given intrathecally instead of intravenously.

Cytotoxic drugs can be inserted directly into a bodily cavity, such as the bladder, pleural and peritoneal cavities. Cytotoxic bladder instillation uses a urinary catheter to insert mitomycin C into the bladder immediately after the surgical removal of bladder cancer. The bladder instillation is repeated intermittently for a number of weeks afterwards. Topical cytotoxic cream can reduce the size of some cancers affecting the skin.

Subcutaneous/intramuscular injections are very occasionally used. However, as most cytotoxic drugs are vesicants or irritants, causing severe tissue damage, and the absorption rate is unpredictable, these routes are not routinely used.

Side effects

Not all patients will experience untoward side effects following cytotoxic treatment. It will depend on the type, dose, scheduling/frequency of the drugs given as well as individual patient idiosyncrasies (some patients react in unexpected ways).

Many (but not all) side effects are either preventable or treatable so it is very important that we know which drugs cause which side effects so that appropriate measures can be put into place. Prevention of side effects is key and it is very important that patients know what they can do to stay well, such as: complying with taking medications (such as antiemetics); maintaining good oral and personal hygiene; well-balanced nutrition and hydration; and avoiding people with coughs and colds. Early detection is also vital to ensure a positive outcome. Patients must know what side effects to look out for and who they should inform if they suspect they have adverse side effects.

Patients often see side effects as an inevitable part of receiving cytotoxic drugs and think that they must endure and tolerate them. As a result, some patients are reluctant to report side effects as they fear that treatment may be withdrawn, thus reducing the success. It is often difficult for patients to interpret the significance/severity of side effects and know when to seek advice. For instance, they might think that pins and needles might be due to a trapped nerve rather than a neurological toxicity of a cytotoxic (Table 10.2).

Table 10.2 Common toxicities of cytotoxic drugs

Seconds/minutes	Allergic reactions, flushing, nausea, taste alteration
Days/weeks	Mucositis, nausea and vomiting (acute, delayed, anticipatory), alopecia, diarrhoea, neutropenia, thrombocytopenia
Months/years	Anaemia, neurological, organ toxicity (heart, lung, liver, kidney), secondary tumours

Activity

Identify a patient undergoing cytotoxic therapy. Ask what side effects they have experienced. Then look up the relevant cytotoxic drugs – what are the common side effects caused by these drugs specifically? Does the patient’s experience reflect the expected side effects?

Keep a note of the name of the drug(s), mode of action and side effects in your notebook for future reference.

NMC Domain 1: 1.4

NMC Domain 2: 2.3

NMC Domain 3: 3.1; 3.3; 3.6; 3.7

Cytotoxic-induced nausea and vomiting

Cytotoxic drugs damage the rapidly dividing cells that line the gastrointestinal tract resulting in nausea and vomiting. In addition, the chemoreceptor trigger zone (CTZ) in the brain is stimulated, registering that there are toxic substances in the body. Cytotoxic-induced nausea and vomiting (CINV) is reported as one of the most distressing side effects of treatment (Bergkvist & Wengstrom 2006), with approximately 50% of patients experiencing nausea and/or vomiting, resulting in significant distress (Molassiotis et al 2008).

CINV can easily be prevented using appropriate antiemetics (anti-sickness) drugs which are usually given at the same time as the cytotoxic treatment and for a number of days afterwards. Each cytotoxic drug has been graded in terms of its emetogenic property, some causing severe CINV, others very little. Each regimen has a standard antiemetic protocol, usually a combination of antiemetics, although this may differ slightly in each hospital. If a patient experiences CINV despite receiving the antiemetic protocol, then additional or alternative antiemetics are used. Some individuals are more susceptible to CINV, such as women, those who experience travel sickness, those who have a low consumption of alcohol and those who experience antenatal nausea and vomiting.

Anticipatory nausea and vomiting is a distressing condition resulting from a psychological reaction to cytotoxic treatment. It usually develops over time and the patient associates a traumatic feeling with the hospital environment, a specific nurse or a cannula. This becomes overwhelming and is expressed as nausea and vomiting. Because this is caused by an emotional rather than a physiological reaction, it is not responsive to antiemetics. Instead, non-pharmacological therapy, such as hypnotherapy and visualisation techniques, may be helpful. Nausea and vomiting is explored further in Chapter 15.

Activity

Find out about the most common antiemetic drugs used to prevent and manage cytotoxic-induced nausea and vomiting. Which part(s) of the body do these drugs act upon?

NMC Domain 1: 1.7; 1.9

NMC Domain 3: 3.1; 3.2

Alopecia

Eighty-five per cent of hair follicles are actively in the cell cycle (this is why hair continually grows). Therefore, hair loss is a common side effect of cytotoxic treatment, especially when the drugs are cell cycle non-specific (killing more cells off in one go). It normally takes a month or two before the hair begins to come out in a noticeable amount, but after a couple of weeks the patient will find more hair in the plug hole after washing their hair and in the hairbrush. The more a patient styles or handles their hair, the quicker it will come out. Washing with a ‘frequent wash’ shampoo will help prolong the process, however eventually there will be complete loss. This is often extremely distressing for patients, affecting their body image and sexuality (Power & Condon 2008).

Scalp cooling is a way of trying to minimise hair loss by reducing the temperature of the scalp and restricting the blood flow to the hair follicles, thus reducing the amount of cytotoxic drug reaching the follicle and damaging the cell. There are several ways of cooling the scalp – the most common is using a cold cap that is filled with gel and then chilled. The cap fits closely to the scalp and is worn for half the time it takes for the body to get rid of the drug. In addition, the cap requires changing as it warms up. This means that scalp cooling can only be used for a small number of patients who are receiving cytotoxic therapy administered over a short period of time, with a short half-life. For example, with the FEC regimen (mentioned above), a normal treatment time is approximately 45 minutes in total. When using scalp cooling, the cannula is placed first and a cold cap is worn for 15 minutes. This is then replaced by another cap and treatment is commenced. After 45 minutes, the cap is replaced and worn for a further 45 minutes, a total of 1 hour and 45 minutes, more than doubling treatment time. Scalp cooling does not prevent hair loss – it is just a way of retaining some hair and often it is not successful. After treatment, hair will return but this may take a number of months. Also, the hair may return a different colour or texture (Van den Hurk et al 2010).

Activity

Find out which method of scalp cooling is used in your practice area. Observe it in action and consider the effects and benefits experienced by the patient. If this treatment is not available on your placement, find out where it is available and plan an ‘insight visit’ or spoke placement visit to that area.

NMC Domain 3: 3.4; 3.6

Neutropenia

Neutropenia, sometimes known as immunosupression, is the most life-threatening side effect of receiving cytotoxic treatment. As well as causing direct mortality, neutropenia may delay treatment, reducing the overall efficacy of cytotoxics (Methven 2010). Neutropenia-related infections result in additional hospital admissions and impact on patients’ quality of life.

Neutropenia occurs when the number of neutrophils in the blood drops below 1 × 10⁹/L. A normal range of neutrophils is 2.5–7.5 × 10⁹/L. We concentrate on neutrophils rather than white blood cells overall, as they are the type of white blood cells we have the most of (70% of white blood cells are neutrophils). They are also our first line of defence – being phagocytes, they ingest microorganisms or pathogens (bacteria, fungi or viruses).

Stem cells take 3 days to produce a neutrophil, before releasing it into the peripheral blood where it lives for 7 hours. Because of this long process of making a neutrophil and its short life span, the bone marrow is continually making neutrophils. Cytotoxic drugs kill/damage the neutrophils in the peripheral blood and the stem cells in the bone marrow. It takes an average of 7–10 days for a patient to become neutropenic and to reach the nadir (the lowest point). This is the time when the patient is most at risk from infection.

Individuals with a cancer diagnosis are at high risk of infection not only due to the effects of cytotoxic drugs, but also to the number of invasive procedures they undergo. Many medications they receive, such as steroids, increase the risk. As discussed in Section 1, cancer generally occurs in older individuals. As we get older, our immune system is less effective and there is increased likelihood of other co-morbidity, such as diabetes. This will increase the risk of infection.

Activity

Re-read your lecture notes or an anatomy and physiology textbook (such as to refresh your knowledge of the body’s immune response to infection. Read Coughlan and Healey (2008) (see References for details) for more information about caring for patients with neutropenia.

Make a list of factors that may influence the risk of infection in cancer patients.

NMC Domain 3: 3.1; 3.2; 3.3; 3.4; 3.7; 3.8; 3.10

When a patient is neutropenic, many endogenous pathogens living in the patient’s body (normally not doing any harm) are able to use the opportunity of the reduced immune system to cause damage (Vento & Cainelli 2003). A good example of this is the herpes simplex virus, otherwise known as a cold sore. We may never know how or when we became infected by the virus, but as soon as we are feeling run down or are getting over an illness, the virus can activate and develop in a lesion, usually on the lip. Another example is the varicella zoster virus, otherwise known as chickenpox. A patient may have had chickenpox as a small child – although they recover from the spots and fever, the virus remains in the body in a dormant state in the nerve tissues. It reactivates when the immune system is low or working especially hard; this is known as shingles. Shingles can be extremely painful and cause respiratory damage. In an immunosuppressed patient, it may be fatal.

Infections from external or exogenous sources can also cause harm. Effective hand washing is essential for the patient, family and healthcare professionals. Patients should also avoid contact with anyone with infections, like a cough or cold.

All patients undergoing cytotoxic therapy should take their temperature daily (at a similar time of day) and should be kept at home to avoid hospital-acquired infections. However, if they become pyrexial (temperature aboe 37.5°C on more than two occasions or 38°C on one occasion), they should telephone the chemotherapy unit urgently. Not all patients with an infection have a temperature, so if they feel unwell they should also phone the chemotherapy unit for advice.

Patients undergoing cytotoxic treatment should avoid taking paracetamol (Coughlan & Healey 2008). This is because having a temperature or pyrexia helps the body to mount an immune response to fight the pathogen in the body. A temperature acts as a signal to the immune system/white blood cells to go to the site of infection and kill the invader. Paracetamol artificially reduces body temperature by ‘resetting’ the hypothalamus (like a thermostat). This indicates to the immune system there isn’t a problem. When the temperature is within the normal range, the patient or healthcare professional may think that there is no longer a problem and not respond. If the cause of the infection is not treated then the patient may become septic and go into shock and may suffer a cardiac arrest. Therefore, it is vital that the early signs and symptoms of infection are detected and prompt action is taken.

Activity