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Systemic anti-cancer therapy 

Systemic anti-cancer therapy
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Systemic anti-cancer therapy
DOI:
10.1093/med/9780198701101.003.0017
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date: 20 September 2019

Introduction to systemic anti-cancer therapy

The term systemic anti-cancer therapy (SACT) is now currently employed widely within the UK and elsewhere to describe medication which is administered systemically via a range of routes (oral, SC, IV), in order to treat cancers.

The term has developed to replace the generic description ‘chemotherapy’ over the last 5 years, in response to the rapidly increasing number of agents which could be described as biological, immuno-, or targeted therapies.

The term SACT is also the chosen description employed by UK health services (e.g. NHS England) when referring to cytotoxic, biological, and hormonal therapies as a group of treatments.

With this in mind, the overarching SACT chapter contains three large sections on cytotoxic chemotherapy, biological and targeted therapies, and hormonal therapies.

Cytotoxic chemotherapy: principles and uses

The term ‘cytotoxic chemotherapy’ is used here to differentiate between broad-spectrum cytotoxic agents affecting the cell cycle and targeted and immunotherapy and hormone therapies. Cytotoxic chemotherapy can be used with curative or palliative intent, either alone or in conjunction with other treatment modalities. Cytotoxic drugs disrupt cell division and replication, with rapidly proliferating cells being most susceptible to their action. As cytotoxic drugs are unable to distinguish between cancer cells and normal cells, rapidly proliferating cells of the bone marrow, GI tract, reproductive system, and hair follicles are particularly vulnerable to their effects, resulting in many of the common side effects of chemotherapy. Normal cells have a greater capacity for repair and renewal than cancer cells. Despite the more recently developed biological therapies having a more sophisticated selective approach, with the capability to target specific tissues and processes within tumour cells, it seems likely that cytotoxic chemotherapy will remain part of the armoury used to treat cancer for some years to come.

Cancer cell growth

Chemotherapy aims to reduce the number of actively dividing cells in a tumour, thereby reducing the growth potential. Smaller tumours tend to have a faster growth rate, are likely to have more actively dividing cells, and are therefore more sensitive to chemotherapy. Examples would be germ cell tumours and small cell cancer.

Effects of cytotoxic drugs on the cell cycle

Cytotoxic drugs have the greatest effect on actively dividing cells. Many cytotoxic drugs act on specific phases of the cell cycle, e.g. S phase (cell cycle-specific drugs), whilst others act on cells in any phase of the cell cycle (cell cycle-non-specific drugs). Drugs acting on a specific phase of the cycle will only affect cells that are in that phase at the time of administration. Cell cycle-non-specific drugs affect both cells that are actively cycling and quiescent cells. Multiple courses of chemotherapy are required to affect cells entering different phases of the cell cycle at different times. Examples of cell cycle-specific and cell cycle-non-specific drugs are shown in Table 17.1.

Table 17.1 Examples of cell cycle-specific and cell cycle-non-specific drugs

Cell cycle-specific drugs

Cell cycle-non-specific drugs

Cytosine arabinoside, fluorouracil (5FU), gemcitabine, methotrexate (S phase)

Bleomycin, etoposide, irinotecan, topotecan (G2 phase)

Vincristine, vinorelbine, docetaxel, paclitaxel (M phase)

L-asparaginase (G1 phase)

Chlorambucil, doxorubicin, procarbazine, cisplatin, cyclophosphamide, ifosfamide, melphalan

Classification of drugs

Cytotoxic drugs have differing modes of action, which are not yet fully understood. Most disrupt cell reproduction either by damaging DNA or by affecting mitosis and are categorized according to their mode of action (see Table 17.2).

Table 17.2 Classification of cytotoxic drugs

Classification

Mode of action

Examples

Antimetabolites

Replace or compete with naturally occurring purines, pyridamines, or folates necessary for synthesis of nucleic acids

Methotrexate, cytosine arabinoside, 5FU, gemcitabine, 6-thioguanine, capecitabine, fludarabine

Anthracyclines (cytotoxic antibiotics)

Inhibit synthesis of ribonucleic acid (RNA) and DNA by different mechanisms, e.g. breaks and cross-links in strands of DNA, intercalation of base pairs

Doxorubicin, epirubicin, idarubicin, mitoxanthrone

Alkylating agents (plus platinum agents)

Cause breaks and cross- links in strands of DNA

Chlorambucil, cyclophosphamide, ifosfamide, melphalan, dacarbazine, busulfan, cisplatin, carboplatin, carmustine, lomustine, procarbazine

Mitotic inhibitors: vinca alkaloids

Inhibit mitosis by binding to tubulin, an essential component of the mitotic spindle

Vincristine, vinblastine, vindesine, vinorelbine

Taxanes

Cause mitotic arrest by binding to microtubules

Paclitaxel, docetaxel

Topoisomerase inhibitors

Inhibit topoisomerase enzymes necessary for DNA replication. Cause single-strand breaks in DNA strands

Etoposide, topotecan, irinotecan (drugs from other categories, e.g. doxorubicin, mitoxantrone, are also topoisomerase inhibitors)

Chemotherapy regimens

Different cytotoxic drugs with proven efficacy against a particular cancer are combined in different chemotherapy regimens. Other agents with anti-cancer activity, e.g. hormonal and biological therapies, may also be included in these regimens. The dose and combination of drugs aim to achieve the maximum therapeutic effect with acceptable toxicity levels. A fine balance exists between the therapeutic dose of a cytotoxic drug and a lethal dose.

Combination chemotherapy

Combinations of drugs are used to overcome problems associated with single-agent drug resistance. Most chemotherapy regimens include a combination of cell cycle-specific and non-specific drugs to increase malignant cell destruction. Drugs with different, but complementary, actions and efficacy are combined. Drug toxicities should differ or occur at different times, so that maximum tolerated doses of drugs can be administered without severe toxicity.

Scheduling and sequencing of drugs

The order in which drugs are given can either affect their efficacy or cause Systemic anti-cancer therapy toxicity, e.g. clearance of paclitaxel is significantly Systemic anti-cancer therapy if it is administered after cisplatin, leading to Systemic anti-cancer therapy myelosuppression.1 Other drugs are synergistic, enhancing each other’s effect, e.g. cisplatin and etoposide.

Intervals between pulses of chemotherapy

The time interval between pulses of chemotherapy is important; too short and normal cells will not have recovered, resulting in Systemic anti-cancer therapy toxicity; too long and cancer cells may regrow between treatments. The interval between pulses is the period of time required for the most sensitive normal cells (usually the bone marrow) to recover. Most chemotherapy regimens are therefore repeated every 3–4 weeks. However, this is dependent on the toxicity of the drugs used.

Modes of use

Chemotherapy can be used in different ways and with different intent.

  • Curative: chemotherapy is used as first-line treatment to cure a number of cancers, particularly haematological and lymphatic cancers.

  • Adjuvant: following surgery, to remove the primary tumour, adjuvant chemotherapy is used as a means of destroying micrometastases.

  • Neo-adjuvant: neo-adjuvant chemotherapy is used before surgery to:

    • Reduce the size of the primary tumour (possibly making it more amenable to surgery)

    • Reduce metastatic potential

    • Measure tumour response to chemotherapy.

It is used to treat various cancers, including H&N, bladder, cervical, non-small cell lung (NSCLC), and early breast cancers. Clinical trials continue to investigate the effectiveness of neo-adjuvant chemotherapy for different cancers.

Concurrent chemo-irradiation

Chemotherapy is administered concurrently with radiotherapy to increase the effectiveness of radiotherapy, whilst reducing the potential for metastatic disease. Certain cytotoxic drugs, e.g. cisplatin, 5FU, and gemcitabine, are known to have radio-sensitizing properties, increasing the sensitivity of cancer cells to radiotherapy and increasing therapeutic potential. The use of concurrent radiotherapy has been investigated for various cancers, including colorectal, cervical, oesophageal, laryngeal, pancreatic, cervical, NSCLC, and stomach.

The optimal dose, schedule, and combination of drugs to use concurrently with radiotherapy have yet to be established. Ongoing clinical trials are investigating the effects on both survival and toxicity profiles. Concurrent therapy may increase treatment toxicities, e.g. haematological and GI in cervical cancer, neutropenia and acute oesophagitis in NSCLC, and severe mucositis in H&N cancer.

High-dose therapy

High-dose therapy involves increasing the dose of cytotoxic drugs to a point where they are lethal to the normal bone marrow. Bone marrow then has to be replaced by haematopoietic stem cell transplant (HSCT). High-dose therapy and HSCT are used mainly for haematological and lymphoid cancers (Systemic anti-cancer therapy see Chapter 18, High-dose therapy (autologous transplant)).

Palliative

Palliative chemotherapy is used to control symptoms, improve quality of life, and treat oncological emergencies, e.g. superior vena cava syndrome. There may be no survival benefit associated with palliative chemotherapy, and treatment toxicities may impact on QoL. Therefore, the costs of chemotherapy need to be balanced against the survival benefit and compared to the cost of best supportive care.

References

1 Wilkes G, Barton-Burke M. The 2015 Oncology Nursing Drug Handbook. Sudbury, MA: Jones and Bartlett Publishing; 2015.Find this resource:

Chemotherapy: safe handling

Cytotoxic drugs are known to be teratogenic, mutagenic, and carcinogenic and therefore are potentially hazardous to patients, staff, and the environment. Exposure can occur through ingestion, inhalation, and absorption through the skin. Exposure can occur at all stages of preparation, administration, and disposal of drugs, most notably when reconstituting or mixing drugs, connecting and disconnecting IV tubing, and disposing of used equipment and patient excreta.2

It is vital that health-care professionals involved in the preparation, administration, and disposal of cytotoxic drugs and waste adopt safe handling procedures to protect themselves and others from the potential health risks associated with exposure.

Measures to reduce exposure to cytotoxic drugs

The evidence supporting safe handling practices is incomplete. However, various guidelines exist, based on the available evidence and expert opinion.

Preparation

Cytotoxic drugs should be reconstituted by appropriately trained personnel, wearing personal protective equipment, under aseptic conditions in a biological safety cabinet or an isolator within a pharmacy department. Cytotoxic drugs should only be reconstituted outside pharmacy departments in exceptional circumstances.

Transport and storage

Cytotoxic drugs should be transported and received in patient areas by staff trained in safe handling and safe storage procedures. Cytotoxic drugs should be securely stored in appropriate conditions in a clearly marked location, separate to other medicines.

Personal protective equipment

Gloves should be worn at all times when handling cytotoxic drugs and excreta. No gloves are completely impermeable to cytotoxic drugs. Permeability of gloves increases with time, and gloves should be changed on a regular basis to reduce the potential for exposure.

Eye and respiratory protection is advised when there is a risk of splashing or if the risk of generating an aerosol exists.3,4 Aprons and gowns can protect clothing and subsequent skin exposure. A COSHH risk assessment should be undertaken for each handling activity to assess whether a gown or plastic apron offers the most protection.

Administration

Drugs should be supplied ready for administration and not require any further mixing or reconstitution. Oral preparations should not be handled. Tablets should not be crushed, and capsules should not be opened. A recent Cochrane Review (2018) illustrated that there was not enough good quality evidence to support the use of ‘closed systems’ in reducing exposure to staff administering chemotherapy.

Disposal of waste

Gloves and aprons should be worn when disposing of used IV equipment, excreta, blood, and body fluids. Contaminated needles, syringes, and IV giving sets should be disposed of intact. All waste should be placed in clinical waste bags and clearly marked cytotoxic. Patient excreta may contain traces of cytotoxic drugs for up to 72 hours following administration.

Spillage

Procedures should be in place for preventing and dealing with spillage. Spillage kits should be available in all areas where cytotoxic drugs are administered. Any spillage should be dealt with promptly. A warning sign should be in place to indicate the spill and prevent exposure and contamination, measures taken to contain the spill, and protective clothing worn. Contaminated materials should be clearly labelled and packaged for disposal. Porters and laundry staff should be aware of procedures for handling and disposing of contaminated materials.

Copious amounts of soap and water should be used for skin contact. Eyes should be flooded with water or an isotonic eye wash solution for at least 5 minutes, and medical advice obtained.3 Spillage of a large amount of cytotoxic drug incurring exposure to people should be reported to RIDDOR5 (Reporting Injuries, Diseases, and Dangerous Occurrences Regulations 2013).

Cleaning

Drug residue may be left on work surfaces in drug administration areas. All staff involved in cleaning areas where cytotoxic chemotherapy is administered should have training in minimizing exposure. Procedures for minimizing exposure should also be in place.4

References

2 Health and Safety Executive (2003). Safe Handling of Cytotoxic Drugs. HSE Information Sheet. Available at: Systemic anti-cancer therapy http://www.hse.gov.uk/healthservices/safe-use-cytotoxic-drugs.htm

3 Royal College of Nursing. Clinical Practice Guidelines: The Administration of Cytotoxic Chemotherapy. Recommendations. London: Royal College of Nursing; 1998.Find this resource:

4 Scottish Executive Health Department (2005). Guidance for the Safe Use of Cytotoxic Chemotherapy. Available at: Systemic anti-cancer therapy https://www.sehd.scot.nhs.uk/mels/HDL2005_29.pdf

5 Health and Safety Executive (2013). Reporting Accidents and Incidents at Work: A Brief Guide to the Reporting of Injuries, Diseases and Dangerous Occurrences Regulations 2013 (RIDDOR). Available at: Systemic anti-cancer therapy http://www.hse.gov.uk/pubns/indg453.pdf

6 Close-system drug-transfer devices plus safe handling of hazardous drugs versus safe handling alone for reducing exposure to infusional hazardous drugs in health-care staff, Cochrane Worg Group, 27th March 2018.

Chemotherapy: safe administration

Cytotoxic drugs can have severe and potentially fatal consequences if administered incorrectly. Prevention of errors and patient safety are of paramount importance, and policies and procedures relating to cytotoxic drug administration should be adhered to at all times. All practitioners involved in chemotherapy administration must have undertaken specific education and training, be knowledgeable about the drugs they are administering and their side effects, and have demonstrated competence in their role.

  • Patient consent should always be obtained and documented before the administration of chemotherapy.

  • Cytotoxic chemotherapy should be administered during normal working hours, in a specifically designated area.

  • Administration should not be rushed, and care should be taken to avoid distraction during administration.

  • Practitioners should be aware of emergency situations which may occur during and following administration of cytotoxic drugs, e.g. allergic reactions, anaphylaxis, and extravasation, and be competent in managing them.

  • Resuscitation equipment, emergency drugs, and extravasation kits should be available in all areas where cytotoxic drugs are administered.

Before administering drugs, practitioners should be familiar with the individual patient’s:

  • Blood count and general physical condition. Neutropenia or thrombocytopenia may mean that chemotherapy is delayed. Abnormal liver or renal function may require dose modification

  • Allergy history

  • Any contraindications to chemotherapy administration

  • Any drugs they are taking (including non-prescription drugs) and any possible interactions

  • Recommended dose range and maximum dose of drugs

  • Route of administration

  • Potential adverse reactions

  • Short- and long-term side effects

  • Route of excretion

  • Compatibility of any drugs or IV fluids to be administered in conjunction with cytotoxic drugs.

Note: the British National Formulary and specific drug information sheets should always be consulted before drugs are administered.

Chemotherapy guidelines for safe practice

The Manual of Cancer Standards (England and Wales)6 and Guidance for the Safe Use of Cytotoxic Chemotherapy (Scotland)7 set clear guidelines for the administration and handling of chemotherapy. Local trusts are able to adapt these to their own local circumstances where appropriate.

All staff must follow their local Trust guidelines on administration and handling of cytotoxic chemotherapy at all times. These guidelines must be available in any area where cytotoxic drugs are administered.

References

6 Department of Health. Manual of Cancer Standards. London: Department of Health; 2004.Find this resource:

7 Scottish Executive Health Department (2005). Guidance for the Safe Use of Cytotoxic Chemotherapy. Available at: Systemic anti-cancer therapy https://www.sehd.scot.nhs.uk/mels/HDL2005_29.pdf

Chemotherapy: routes of administration

Cytotoxic drugs can be administered by a number of different routes. The route of administration is chosen to achieve maximum cancer cell death by optimizing the bioavailability and exposure of cancer cells to drugs, thereby improving efficacy.

Main routes of chemotherapy administration

  • Intravenous (IV)

  • Intrathecal (IT)

  • Intracavity, e.g. intravesical, intraperitoneal

  • Subcutaneous (SC)

  • Intramuscular (IM)

  • Intra-arterial

  • Topical

  • Oral

Intravenous

The IV route remains the most commonly used route for the administration of cytotoxic drugs.8 It is the most reliable route, as the drug is delivered systemically. Drugs can be delivered through a variety of venous access devices (VADs).

Venous access devices

The choice of device depends upon the condition of the patient’s veins, the drugs to be administered, and the length of treatment. For those having lengthy courses of treatment, a central VAD (CVAD) should be considered. Choosing the right VAD for the treatment to be administered is important in reducing potential complications. Prevention of infection is vital, and strict asepsis is required, irrespective of the choice of VAD. Extravasation and subsequent tissue damage are major potential problems with the IV route (see Table 17.3).

Table 17.3 Venous access devices

Type of cannula

Use

Peripheral cannula

Short-term use

Mid-line cannula

Medium term use (2–4 weeks)

Peripheral IV central catheter

Can be used for several months

CVAD (e.g. Groshong and Hickman catheters)

Long-term use

Implantable port (e.g. Port-a-cath)

Long-term use

Peripheral cannulation

Careful placement of any peripheral VAD is required, and nurses administering chemotherapy need to be skilled in cannulation. Individuals with cancer may have veins difficult to cannulate.

  • Patients may have experienced previous problems with venous access and should always be asked if they have a preferred choice of arm for cannulation.

  • Limbs affected by lymphoedema, dermatitis, cellulitis, skin grafts, previous fractures, stroke, arteriovenous fistulae, or wounds should be avoided. The forearm is the cannulation site of first choice. Joints such as the antecubital fossa and wrist should be avoided, as there is a greater chance of dislodging the cannula.

  • If the first cannulation attempt is unsuccessful, a subsequent one should be proximal to the first.

  • The smallest gauge of cannulae should be used and be firmly secured.

  • Pre-existing IV lines should be avoided for chemotherapy administration, wherever possible.

Administration

Drugs may be administered by direct bolus injection, by bolus injection into the side arm of a fast-running infusion of 0.9% normal saline, or by infusion. The choice of method depends upon the pharmacological properties of the drug (e.g. whether it is a vesicant or requires dilution, stability, osmolarity, and pH of the drug) and the type of VAD used. Any prescribed pre-hydration fluids or anti-emetics should be given before chemotherapy is commenced.

Before any drug is administered, the patency of the VAD should be assessed by withdrawing blood and then flushing with 0.9% sodium chloride. If a peripheral cannula is being used, the site should be closely observed throughout the infusion for signs of tissue infiltration or extravasation, e.g. resistance, swelling, pain or discomfort, redness, or signs of leakage. Cannula dressings should allow clear visibility of the insertion site and surrounding area. Cannulae should be flushed between drugs and after completion of drug administration with a compatible fluid.

Note: sodium chloride is not compatible with all drugs.

Intrathecal

Many cytotoxic drugs are unable to cross the blood–brain barrier, and the IT route is used in the treatment of acute lymphocytic leukaemia and some lymphomas. Cytotoxic drugs are injected into the cerebrospinal fluid, usually into the subarachnoid space, via a lumbar puncture, but drugs can also be injected into a ventricular space. Only certain drugs can be safely administered IT: methotrexate, cytosine arabinoside, and thiotepa.

Box 17.1 highlights the key recommendations for prescribing, issuing, dispensing, transport, storage, and administration of IT chemotherapy.9

Fatal vinca alkaloid administration

Around 55 patients worldwide, some in the UK, have died or been paralysed due to erroneous IT injection of vinca alkaloids (usually vincristine) causing severe or fatal neurotoxicity. Strict guidelines for everyone involved in IT administration of cytotoxic drugs have now been implemented.

Full details of guidance for IT administration can be found at Systemic anti-cancer therapy http://webarchive.nationalar http://www.dh.gov.uk/prod_consum_dh/groups/dh_digitalassets/documents/digitalasset/dh_086844.pdf

The implications of these guidelines for Scotland8 are outlined at Systemic anti-cancer therapy https://www.scot.nhs.uk/publications/

From Department of Health. HSC 2008/001. (2008). Updated National Guidance on the Safe Administration of intrathecal chemotherapy. London: DH © Crown Copyright, reproduced under the Open Government License v.4.0.

Intra-cavity

Cytotoxic drugs are instilled into body cavities such as the bladder (intravesical) and peritoneum. Malignant cells are therefore exposed directly to the drug, maximizing effectiveness.

Intravesical

Intravesical chemotherapy is used, following surgery to treat bladder cancer (Systemic anti-cancer therapy see Cancer of the bladder and ureter, pp. [link][link]). Patients are catheterized, residual urine in the bladder drained, and the cytotoxic drug instilled slowly. The drug is retained for 2 hours either by clamping the catheter or by removing it and asking the patient not to pass urine for 2 hours. Patients should be encouraged to change position every 15 minutes from back to front and from side to side, so that all of the bladder mucosa is exposed to the cytotoxic drug. Drugs most commonly used are mitomycin and doxorubicin.

Most drugs can irritate the bladder, inducing chemical cystitis, and a high fluid intake is recommended after the drug has been voided. Urinary frequency, urgency, and burning when passing urine are common following intravesical chemotherapy. Contact dermatitis may be experienced, particularly with mitomycin, and this can be avoided by thorough washing of the hands and genitals immediately after instillation and subsequent voiding of urine. Sexually active patients should protect their partners from exposure to cytotoxic drugs by wearing a condom.

Few systemic side effects are experienced with mitomycin and doxorubicin, although allergic reactions have been reported with doxorubicin.

Intraperitoneal

The peritoneal cavity can act as a sanctuary site for tumour cells, and cytotoxic drugs may be instilled to treat malignant ascites and control tumour growth. Intraperitoneal chemotherapy has been used primarily for treating ovarian cancer. Cytotoxic drugs can be delivered by a temporary suprapubic catheter, a Tenckhoff external catheter, or an implantable port. Drugs are usually diluted in 2L of fluid, warmed, and instilled by gravity.

Complications include catheter-related complications, abdominal pain, fatigue, haematological effects, metabolic abnormalities, and neuropathy. Respiratory distress, abdominal discomfort, and diarrhoea may also be experienced due to Systemic anti-cancer therapy abdominal pressure. Infection is a further common problem, and temperature should be monitored.

Subcutaneous and intramuscular routes

Few cytotoxic drugs are administered by these routes because of the potential for tissue damage, bleeding, discomfort, and fibrosis. Drug absorption is also slow via these routes. However, more of the biological therapies are now administered SC.

Cytotoxic drugs administered by these routes include methotrexate (for some indications), asparaginase, and cytosine arabinoside.

The smallest needle size should be used and sites rotated to prevent side effects. For IM administration, a large muscle and the Z track technique should be used to avoid leakage of the drug into the skin. Platelet counts should always be checked before administration to reduce the possibility of bruising and bleeding.

Intra-arterial

A high concentration of cytotoxic drug is delivered directly to the tumour by the artery that provides tumour blood supply. The concentration of the drug to the tumour is Systemic anti-cancer therapy, whilst systemic circulation is Systemic anti-cancer therapy, thus reducing the occurrence of side effects. An example of this technique in action would be ‘TACE’ (trans-arterial chemo-embolization). This is a minimally invasive technique used in specialist centres to treat primary liver cancers whereby chemotherapy is introduced into the liver via the hepatic artery; other smaller vessels within the liver are deliberately occluded. Using this methodology, high doses of chemotherapy can be delivered directly into primary liver cancers.

Topical

Topical cytotoxic drugs may be used for skin lesions such as SCC and T-cell lymphoma; 5% 5FU cream is most commonly used. With repeated applications, tissue necrosis and sloughing of dead tissue occur. Normal tissue surrounding the lesion should be protected. Systemic effects are uncommon, although slight nausea may occur.

References

8 Scottish Executive Health Department (2004). Safe Administration of Intrathecal Cytotoxic Chemotherapy [issued under NHS HDL (2004) 30, 2 June 2004]. Available at: Systemic anti-cancer therapy http://www.sehd.scot.nhs.uk/mels/HDL2004_30.pdf

9 Department of Health. HSC 2008/001. Updated National Guidance on the Safe Administration of Intrathecal Chemotherapy. London: Department of London; 2008.Find this resource:

Oral chemotherapy

The role of oral chemotherapy has markedly Systemic anti-cancer therapy with the introduction of capecitabine in metastatic colorectal and breast cancers, and oral vinorelbine in lung and breast cancers. Other examples of drugs given orally include etoposide, chlorambucil, and procarbazine. Many chemotherapy and biological agents in development are also oral, so this trend towards oral therapy is likely to continue.

Advantages of oral chemotherapy

There are many potential advantages:

  • Most patients prefer it

  • Reduction of complications due to IV lines and pumps, e.g. spillage, infection, extravasation

  • Shorter treatment time/reduction in patient–staff contact can free up nursing time for other service activities

  • Improved QoL

  • Improved side effect profile

  • Cost-effectiveness

  • Allows for easier modernization of chemotherapy pathways, e.g. nurse-led clinics, nurse prescribing of chemotherapy, and telephone assessment.

Potential risks

However, there are a number of important issues when managing individuals receiving oral chemotherapy:

  • Patients and health-care professionals may think that oral chemotherapy is less serious or less dangerous than IV therapy.

  • Patients have Systemic anti-cancer therapy responsibility for administering their chemotherapy, as well as monitoring and responding appropriately to adverse events.

  • Patient compliance is difficult to assess. Patients need information about the importance of strict adherence to the prescribed drug regimen, the correct dosage, what to do if they miss a dose, and what to do if they have any side effects.

As a general rule, the benefits from oral chemotherapy outweigh the risks. This is reflected in the recommendation from NHS England, which promotes ‘maximizing the use of oral medications’ as a way of reducing inpatient visits in chemotherapy.10

In 2008, in the UK, the National Patient Safety Agency (NPSA) published an alert outlining the large number of dosing errors associated with oral cytotoxic agents resulting in three deaths and several hundreds of incidents. The NPSA recommended that chemotherapy should be ‘initiated by a cancer specialist and non-specialists who prescribe, dispense, or administer ongoing oral anti-cancer medication should have ready access to written protocols and treatment plans, including guidance on monitoring and treatment of toxicity’.

Note: it is essential to assess whether patients are able to safely manage an oral chemotherapy regime. Issues to consider include reading ability, manipulative abilities of elderly/frail patients, memory/concentration, and support at home from family or other professionals.

  • Patients have less contact time with staff. Patient education time may therefore be quite short, e.g. all initial vital information may need to be given at a one-off visit prior to treatment. Educational strategies and patient information material need to be well designed and evaluated.

  • Oral drugs can have varied metabolism between patients; therefore, dose modification and interruptions are a normal and essential part of therapy in response to any adverse events, i.e. hand and foot syndrome (HFS), diarrhoea, nausea and vomiting, and mucositis. Absorption of oral drugs may also be affected by food, GI problems, e.g. nausea and vomiting or diarrhoea, and concurrent medications. In the presence of any of these factors, patients may experience Systemic anti-cancer therapy toxicity or a lower dose of the drug than prescribed. These issues all serve to highlight the need for good patient education in order to maintain patient safety and compliance.11

Patient compliance and education

To ensure that patients are safe in self-administering oral chemotherapy at home, effective patient education is essential. Pre-chemotherapy assessment clinics, dedicated oral chemotherapy clinics, and nurse-led follow-up (outpatient or telephone contact) are examples of developments that can support this process. Clear communication channels between primary and secondary care need to be developed. Well-designed information packs, treatment guides, and patient diaries will all help.

Patients may not wish to report adverse events if they think that dose reduction or interruption will reduce the efficacy of the drug. It is essential to inform patients that dose reductions of up to 50% and short interruptions in treatment will not reduce the efficacy of their treatment.

Essential aspects of patient information and education include:

  • Correct dosage and administration schedule

  • Accurate and clear information about how to recognize, grade, and manage common side effects

  • Who to report to if any concerns

  • The role of dose reduction and interruptions.

Further reading

(Whole journal issue dedicated to issues of oral chemotherapy) Eur J Oncol Nurs 2004;8(Suppl 1).Find this resource:

References

10 2013/14 NHS standard contract for cancer: chemotherapy (adult) – NHS England NHS England /B15/S/a. Available at: Systemic anti-cancer therapy https://www.england.nhs.uk/wp-content/uploads/2013/06/b15-cancr-chemoth.pdf

11 Wood L. A review on adherence management in patients on oral cancer therapies. Eur J Oncol Nurs 2012;16:432–8.Find this resource:

Chemotherapy: administering vesicants and extravasation

Vesicant drugs have the potential to cause tissue damage and necrosis if extravasated. Extravasation is defined as infiltration of a drug into the subcutaneous tissues. The amount of damage usually correlates directly with the amount of drug infused. Damage may not be apparent immediately, and it may be 1 or 2 days before evidence of progressive tissue damage occurs.12 Damage can continue for several weeks after extravasation (see Table 17.4). In severe cases, extravasation can result in loss of function or amputation. Surgical debridement or skin grafting may also be required. Prevention of extravasation is paramount when administering vesicant drugs. Extravasation is most frequently associated with peripheral cannulae but can also occur with the use of CVADs.

Table 17.4 Extravasation risk factors and prevention

Risk factors

Prevention

Previous chemotherapy as veins are often fragile and difficult to cannulate

Avoid small veins

Avoid veins adjacent to tendons, nerves, or arteries

Avoid sites distal to recent venepuncture or cannulation attempts

Winged steel devices, such as ‘butterfly’ needles, should not be used, as they can easily dislodge and puncture vein walls

Flexible cannula should be used

Previous radiotherapy

Avoid previously irradiated areas

Circulatory impairment, e.g. lymphoedema, peripheral vascular disease, Raynaud’s disease, and comorbidity, e.g. diabetes, superior vena cava syndrome

Administer vesicants first when vein integrity is greatest, to reduce the risk of extravasation13

Administer bolus slowly into a fast-running infusion

Check infusion flow quality and cannula site regularly throughout infusion

Never rush drug administration

Never use infusion devices and pumps for vesicant drugs

Use a peripherally inserted central catheter (PICC) or central catheter for slow infusion of high-risk drugs

No return blood flow from CVAD

Do not administer vesicant drugs before the patency of CVAD is evaluated

Needle dislodgement with implanted ports

Monitor needle placement with continuous infusion of vesicants, particularly during movement, which increases the risk of dislodgement

In 2012, the European Society of Medical Oncology (ESMO), together with the European Oncology Nursing Society (EONS), classified drugs into three groups to help develop a grading system for extravasation risk (see Table 17.5).

Table 17.5 Classification of chemotherapy drugs according to their ability to cause local damage after extravasation (ESMO-EONS guidelines)

Vesicants

Irritants

Non-vesicants

DNA-binding compounds

Alkylating agents:

Carmustine

Ifosfamide

Streptozocin

Dacarbazine

Melphalan

Anthracyclines (others):

Liposomal doxorubicin

Liposomal daunorubicin

Mitoxantrone

Topoisomerase II inhibitors:

Etoposide

Teniposide

Antimetabolites:

Fluorouracil

Platin salts

Carboplatin

Cisplatin

Oxaliplatin*

Topoisomerase I inhibitors:

Irinotecan

Topotecan

Others:

Ixabepilone

Arsenic trioxide

Asparaginase

Bleomycin

Bortezomib

Cladribine

Cytarabine

Etoposide phosphate

Gemcitabine

Fludarabine

Interferons

Interleukin-2

Methotrexate

Monoclonal antibodies

Pemetrexed

Raltitrexed

Temsirolimus

Thiotepa

Cyclophosphamide

Alkylating agents:

Mechloretamine

Bendamustine*

Anthracyclines

Doxorubicin

Daunorubicin

Epirubicin

Idarubicin

Others (antibiotics):

Dactinomycin

Mitomycin

Mitoxantrone*

Non-DNA-binding compounds

Vinka alkaloids:

Vincristine

Vinblastine

Vindesine

Vinorelbine

Taxanes:

Docetaxel*

Paclitaxel

Others:

Trabectedin

* Single case reports describe both irritant and vesicant properties.

Reprinted from Perez-Fidalgo J et al (2012) – Management of chemotherapy extravasation: ESMO-EONS Clinical Practice Guidelines. Annals of Oncology 23 (Supplement 7): vii167–vii173 with permission from Oxford University Press.

Nurses administering chemotherapy should be knowledgeable about the vesicant properties of the drugs they are administering, observe the vein regularly during the administration procedure, recognize the signs and symptoms of extravasation, and be competent in managing such an emergency, should it occur. Prompt recognition and management are imperative.

References

12 Bertelli G. Prevention and management of extravasation of cytotoxic drugs. Drug Saf 1995;12:245–55.Find this resource:

13 Perez-Fidalgo J, Garcia Fabregat L, Cervantes A, Margulies A, Vidall C, Roila C; ESMO Guidelines Working Group. Management of chemotherapy extravasation: ESMO-EONS clinical practice guidelines. Ann Oncol 2012;23(Suppl 7):vii167–73.Find this resource:

Chemotherapy: recognizing extravasation

Signs of extravasation may initially be slight, and neither nurses nor patients may notice them (see Table 17.6). Patients should be asked to report any feelings of pain, burning, or discomfort, as they may quickly recognize if an injection feels different to previous experiences. Initially, it may be difficult to differentiate between an extravasation and other reactions.

Table 17.6 Signs and symptoms of extravasation

Signs and symptoms

Other reaction complicating diagnosis

Erythema, discoloration, swelling, leakage, or a change in skin temperature

Flare reactions, common with drugs such as doxorubicin and epirubicin, often present as a red streak along the vein, blotchy skin, urticarial reactions, and pruritus. Flare reactions are temporary and subside within 30–90 minutes

Burning, stinging, and pain

Venospasm may also result in pain on administration. Usually described as dull ache. Stinging and pain may occur with flare reaction

Systemic anti-cancer therapy resistance to syringe or slowing of infusion rate

Patient position and kinking of administration set may also cause Systemic anti-cancer therapy resistance

Lack of blood return

Can be misleading. The act of withdrawing blood can pull the cannula back into the vein, and blood can be withdrawn. On recommencing administration, extravasation occurs through the hole in the vessel wall, exacerbating the injury

Vessel wall puncture can occur during venepuncture; the cannula remains in the vein, and blood is returned, but drugs can leak through the puncture hole into surrounding tissues

Patient reports of pain, burning, or discomfort are particularly important for CVADs. Extravasation may not be immediately apparent. Signs and symptoms include:

  • Difficulty withdrawing blood from CVADs

  • Shoulder pain—may be described as dull, aching, burning, or stinging sensation

  • Supraclavicular, chest wall, or lower back pain can occur with extravasation from an implantable port

  • Pyrexia

  • Erythema, warmth, and tenderness of chest wall or around port site

  • Pain and swelling along catheter tunnel or around port site.

Managing extravasation

Management of extravasation is controversial. Local protocols and procedures should be followed. Table 17.7 outlines generally accepted principles in the management of extravasation.

Table 17.7 Management of extravasation

Management

Rationale

Stop infusion immediately

Prevent further extravasation

Leave the cannula in place

Allows aspiration of the drug and administration of antidote

Inform a doctor experienced in the management of extravasation injuries

Management of extravasation is controversial; an experienced person should always advise on management

Mark the affected area with a pen

Extravasated area is clearly marked

Aspirate as much of the drug as possible from the cannula. SC injection of 0.9% sodium chloride may help to dilute the drug

Remove the drug from tissues, although it is recognized that little may be obtained

Remove the cannula

For all drugs other than vinca alkaloids, the principle of ‘localize and neutralize’ is used. Ice packs should be applied regularly for 24–48 hours

Causes vasoconstriction and reduced local uptake of the drug

Topical dimethylsulfoxide (DMSO) may be applied

For anthracycline extravasation, then administration of dexrazoxane should be considered

Has been found to be particularly successful in the treatment of anthracyline extravasation

Has been found to be effective in reducing tissue damage if regime commences no later than 6 hours after extravasation occurred

For vinca alkaloid extravasation, administer SC hyaluronidase 1500U as an antidote. Apply warm

The principle of ‘spread and dilute’ is used for vinca alkaloid extravasation

Elevate the limb following application of warm or cold packs

To remove extravasated material whilst preserving the overlying skin

Some authorities advocate flushing the infiltrated area with 0.9% sodium chloride, using multiple stab incisions in the subcutaneous tissue around the extravasated area

Accurately document the extravasation incident

Chemotherapy: side effects and complications

See Table 17.8 for common side effects and complications of chemotherapy. Management of side effects and patient care are discussed in subsequent chapters.

Table 17.8 Short- to medium-term side effects and complications

Short- to medium-term side effects

GI

  • Nausea and vomiting (can be delayed with some drugs, e.g. cisplatin)

  • Mucositis

  • Constipation

  • Diarrhoea

  • Anorexia

  • Taste changes

  • Metallic taste (e.g. cyclophosphamide)

Skin and nails

  • Alopecia

  • Plantar–palmar erythrodysesthesia (HFS)

  • Rash

  • Erythema

  • Hyperpigmentation

  • Radiation recall

  • Ridging of nails and Bowman’s lines

  • Nail loss

Bone marrow

Myelosuppression, neutropenia, thrombocytopenia, anaemia

May be prolonged or delayed with some drugs, e.g. carmustine, lomustine, melphalan, mitomycin

General side effects

Fatigue

Flu-like symptoms

Fluid retention and oedema (docetaxel, paclitaxel)

Reproductive system

Amenorrhoea/early menopause

Infertility (particularly alkylating agents)

Cardiac

Tachycardia and other rhythm disturbances

Hypertension (mainly anthracyclines)

Neurological

Peripheral neuropathy

Autonomic neuropathy

Cranial nerve neuropathy

Ocular nerve toxicities

Renal and bladder

Hyperuricaemia

Coloured urine (doxorubicin, epirubicin, mitoxantrone)

Haemorrhagic cystitis (cyclophosphamide, ifosfamide)

Complications

  • Hypersensitivity reactions and anaphylaxis

  • Tumour lysis syndrome

  • Sepsis

  • Pulmonary toxicity (e.g. pulmonary fibrosis with bleomycin, busulfan, chlorambucil, carmustine)

  • Cardiomyopathy (anthracyclines)

  • Neurotoxicity

  • Ototoxicity (tinnitus and hearing loss with cisplatin)

  • Nephrotoxicity

  • Hepatotoxicity (asparaginase, amsacrine, carmustine, cisplatin, chlorambucil, dacarbazine, methotrexate); hepatic veno-occlusive disease (busulfan)

  • Secondary cancers

  • Cognitive dysfunction

Chemotherapy closer to home

Use of chemotherapy in the home and non-traditional environments such as mobile chemotherapy units or local clinics is likely to expand in the future. This is linked to changes in the way health care is delivered, with an increasing move to care closer to patients’ homes and an increasing number of oral and SC anti-cancer therapies available (Systemic anti-cancer therapy see Oral chemotherapy, pp. [link][link]). Nurses caring for patients in these environments need to be knowledgeable about the drugs the patient is receiving, potential side effects, safe handling, and who to contact if they need advice or support.

Before administration is commenced, it is vital that policies and procedures are developed for all aspects of cytotoxic drug administration, including management of side effects and emergency situations, e.g. spillage, extravasation, and hypersensitivity reactions. Safe handling guidelines and regulations should be adhered to at all times.

Considerations when administering chemotherapy in non-traditional environments

  • Drugs should be transported in a robust and tamper- and leak-proof container, clearly marked cytotoxic.

  • Drugs should be stored in correct conditions and kept out of the reach of children and pets.

  • Clear information on safely handling oral chemotherapy, e.g. handwashing, not crushing tablets.

  • Disposal methods for cytotoxic drugs and waste should be clearly established.

  • All necessary equipment should be available before drug administration, including spillage and extravasation kits for IV chemotherapy.

  • Administration and checking procedures should be adhered to.

  • Clear communication pathways should be established between primary and secondary care and the teams delivering the chemotherapy.

Further reading

Department of Health. National Guidelines on the Safe Administration of Intrathecal Chemotherapy. London: Department of Health; 2001.Find this resource:

Health and Safety Executive (2013). Reporting Accidents and Incidents at Work: A Brief Guide to the Reporting of Injuries, Diseases and Dangerous Occurrences Regulations 2013 (RIDDOR). Available at: Systemic anti-cancer therapy http://www.hse.gov.uk/pubns/indg453.pdf.Find this resource:

Skeel RT, Khleif S. Handbook of Cancer Chemotherapy, 8th ed. Philadelphia, PA: Lippincott, Williams, and Wilkins; 2011.Find this resource:

Introduction to targeted and biological therapies

In recent years, we have developed a greater understanding of the tumour microenvironment and the role of the immune system in the development of cancer. Our increasing knowledge of the mechanisms of cell division, and more recently the complexity of cell signalling pathways, has led to an explosion in the number of new targeted and biological therapies moving into clinical trial and standard use.

The number of potential targets for anti-cancer treatments continues to grow, and the hope is that this will continue to enable future development of anti-cancer therapies.

This chapter will cover the main principles of commonly used targeted and biological therapies and highlight some of the more commonly used agents. However, due to the regular changes in treatment guidelines, it is essential that the reader consults current NICE guidelines to ensure that they are properly up-to-date with current practice (Systemic anti-cancer therapy http://www.nice.org.uk/Guidance).

Further reading

Keeping tabs on MABs. The latest on monoclonal antibodies. Br J Nurs 2015;24(16), Suppl 1.Find this resource:

Semin Oncol 2012;39:243–366 (Note: whole journal volume focusing on cancer vaccine development).Find this resource:

Zeron-Medina J, Ochoa de Olza M, Brana I, et al. The personalization of therapy: molecular profiling technologies and their application. Semin Oncol 2015;42:775–87.Find this resource:

Small molecule inhibitors

An Systemic anti-cancer therapy knowledge of the mechanism of cell growth, in particular signal transduction pathways and signal amplification, has led to a number of new protein targets for new small molecules. These inhibit the functions of proteins in growth signalling pathways.

Tyrosine kinase inhibitors

Tyrosine kinase (TK) is an enzyme that has a key function as an on/off switch in growth factor signalling pathways. The two main classes are:

  • Cell surface receptors with TK activity, e.g. epidermal growth factor (EGF) receptor, human epidermal growth factor receptor 2 (HER-2)

  • Intracellular growth factor signalling proteins, active in the receptor signalling pathway, e.g. c-Abl.

There are a number of anti-cancer drugs that inhibit TK activity in growth signalling pathways, including:

  • EGFR signalling pathway, e.g. erlotinib

  • HER-2/Neu signalling pathway, e.g. lapatinib

  • VEGF pathway, e.g. sorafenib.

Some other drugs have a broad-spectrum inhibition of >1 pathway, e.g. sunitinib.

Commonly used drugs

Imatinib

Oral medication used for both chronic myeloid leukaemia (CML) and GI stromal tumours (GISTs); targets the mutant form of the Abl protein encoded by the Bcr–Abl fusion gene.

In metastatic GISTs, it has provided an effective treatment where previously there were no therapeutic options. It produces response rates of around 50%, with 2-year survival of >70%.

Common side effects include:

  • Oedema/effusions

  • Nausea

  • Diarrhoea

  • Rash

  • Myelosuppression.

Gefitinib

Oral medication which targets the EGFR pathway. Used as first-line treatment in patients with locally advanced or metastatic NSCLC, with a positive EGFR mutation.

Common side effects include:

  • Diffuse acneiform rash

  • Diarrhoea

  • Fatigue.

Erlotinib

Also targets the EGFR pathway. Encouraging results in:

  • NSCLC: in patients with locally advanced or metastatic NSCLC, with a positive EGFR mutation

  • Pancreatic cancer: used in clinical trials in combination with gemcitabine.

Common side effects include:

  • Diffuse, often distressing acneiform rash

  • Diarrhoea

  • Fatigue.

Sunitinib

Inhibits the VEGF receptor but also affects closely related pathways. Reduces cell proliferation and also has an anti-angiogenesis effect. Main use is in advanced renal cell carcinoma (RCC). Also used in pancreatic neuroendocrine tumours (NETs) and GIST tumours resistant to imatinib.

Common side effects include:

  • Fatigue

  • Diarrhoea

  • Skin toxicity—dry, cracked, yellowing

  • Hypertension.

Everolimus

Oral medication which targets the mammalian target of rapamycin (mTOR) pathway. Inhibits cell division. Main use in metastatic RCC. Also used in pancreatic NETs.

Common side effects include:

  • Skin rash

  • Stomatitis

  • Fatigue

  • Risk of infection.

Side effect management

The Systemic anti-cancer therapy use of tyrosine kinase inhibitors (TKIs) has seen a related increase in the number of patients presenting with rash, HFS, and diarrhoea. Diarrhoea should be managed as with other causes (Systemic anti-cancer therapy see Diarrhoea, pp. [link][link]). Appropriate dose reduction and/or interruption is an important aspect of toxicity management, with oral medications. It is important that nurses make themselves aware of the individual drug protocols and grading of treatment toxicities, as they may be a first contact point for these patients, who will often be managing their medication from home.

Dose modification

Despite side effects, many patients will struggle with advice to reduce or stop medication, when they see it as their main chance to treat their cancer effectively. Assessing and supporting compliance with correct dosing is an essential part of the cancer nurse’s role for these patients.

Tyrosine kinase inhibitors: skin toxicity

  • Ensure that patients are reviewed regularly and have any skin toxicities graded. Many problems may be reduced by avoiding hot showers, reducing sun exposure, and wearing loose-fitting clothing.

  • In mild rash, ensure topical treatments are available—urea-containing lotions, fragrance-free moisturizers. Can use topical steroid cream, e.g. hydrocortisone 1%.

  • For HFS, give patients advice regarding the need to moisturize the hands and feet (including the use of urea-based creams) and to avoid rubbing (e.g. ill-fitting shoes). Patients need monitoring for superimposed infections and may need antibiotic support and possible dermatological referral.

  • If toxicities reach grade 3, then the anti-cancer drug should be interrupted till improvement to grade 1 and can be restarted at a reduced level.

Note: other side effects, e.g. fatigue, risk of infection, are covered in the appropriate chapters under those headings.

Immunotherapy

The principle of immunotherapy is the administration of antibodies to the patient with cancer, enabling their immune response to attack cancer cells within their body.

Immune checkpoint inhibitors

This cell surface receptor has a key role in downregulating the immune system, suppressing T-cell activity. It keeps T-cells from attacking other cells by attaching to programmed death-ligand 1 (PD-L1). This is a protein which is found on some normal cells but is often found in large numbers on cancer cells, helping them to evade immune attack. Monoclonal antibodies that target either programmed cell death protein 1 (PD-1) or PD-L1 can block this binding and boost the immune response against cancer cells. These drugs have shown a great deal of promise in treating a number of cancers.

PD-1 inhibitors

For example:

  • Pembrolizumab (Keytruda®)

  • Nivolumab (Opdivo®).

These have shown efficacy in treating several types of cancer, including melanoma of the skin and NSCLC. Trials are also being undertaken in a number of other cancers.

PD-L1 inhibitors

For example:

  • Atezolizumab (Tecentriq®).

Used to treat bladder cancer and NSCLC.

CTLA-4 inhibitors

CTLA-4 is another protein on some T-cells that acts as a type of ‘off switch’ to keep the immune system in check. CTLA-4 inhibitors target this protein to prevent it from working, therefore boosting the immune response against cancer cells.

  • Ipilimumab (Yervoy®) has shown excellent efficacy in treating metastatic melanoma.

Side effects

A key issue is the Systemic anti-cancer therapy risks of severe immune-mediated inflammation of the lungs, colon, liver, or kidneys and the endocrine system, which can be fatal. Detailed and regular assessment of respiratory function, diarrhoea, and liver function tests (LFTs) is essential, as well as assessment of possible endocrine disorders. Patients will need intensive courses of corticosteroids if symptoms occur.

Cytokines

Cytokines are soluble proteins, which have biological activity on several tissues, mainly on those originating from the haematopoietic and immune systems. Cytokines can both inhibit and promote tumour growth. The main cytokines that have therapeutic activity in cancer are:

  • Interferons

  • Haematopoietic growth factors.

Interleukins and TNF have also been used experimentally in some advanced cancers.

Interferons

Several types of interferon are produced by the immune system in response to viral infections. Interferon alfa is the interferon used to treat a range of cancers (see Box 17.2), though, in most cases, its first-line use has been replaced by the development of newer targeted therapies.

Interferons have the following anti-tumour activity:

  • They interfere with, or directly stop, tumour cell growth.

  • They affect the expression of oncogenes.

  • They enhance the cytotoxic activity of natural killer cells, macrophages, and T-cells. They reduce the amount of blood vessels around the tumour.

  • They promote tumour cells to change to less aggressive cells.

The main side effects of interferons are: flu-like symptoms (>90%), anorexia, fatigue, Systemic anti-cancer therapy LFTs, rashes, GI complaints, lethargy, depression, and thrombocytopenia. Flu-like symptoms can be treated with prophylactic paracetamol. Patients usually begin to tolerate the side effects of interferons after prolonged administration. The side effects are reversible once treatment stops. Slow-release (pegylated) versions of interferons are now commercially available, allowing less frequent administration than normal interferons.

Interleukins

Interleukins are cytokines produced by several immune system cells. They have an important role in mediating many immune responses. Interleukin-2 has been clinically evaluated in several advanced cancers (see Box 17.2).

It is limited in clinical practice by its toxicity profile. The main side effects are: flu-like symptoms, capillary leak syndrome, severe hypotension, angina, arrhythmias, respiratory distress, somnolence, anaemia, thrombocytopenia, and multi-organ failure.

Tumour necrosis factor

TNF is a mediator of the inflammatory response. It is still an experimental treatment. The clinical use of TNF is limited by severe side effects, including acute fever, anaemia, thrombocytopenia, liver, renal, and CNS toxicity. Prospective randomized controlled trials in melanoma and sarcoma have had disappointing results.

Haematopoietic growth factors

Haematopoietic growth factors are cytokines that have a role in controlling the formation and development of blood cells. Recombinant DNA technology has enabled the synthetic production of naturally occurring growth factors for use in clinical practice. They are primarily used to reduce the impact of bone marrow suppression caused by anti-cancer therapy. There are three main growth factors used in cancer care:

  • Erythropoietin (EPO)

  • Granulocyte colony-stimulating factor (G-CSF)

  • Granulocyte-macrophage colony-stimulating factor (GM-CSF).

Erythropoietin

EPO has a role in stimulating red blood cell production. In the cancer setting, it is used to manage anaemia caused by chemotherapy (Systemic anti-cancer therapy see Erythropoietin, p. [link]).

Granulocyte colony-stimulating factor

G-CSF is a cytokine that regulates proliferation and differentiation of a range of haematopoietic cells. G-CSF:

  • Can reduce the risk of neutropenia, febrile neutropenia, and infection in patients receiving myelosuppressive anti-cancer drugs

  • Is used with treatment where there is a high risk of febrile neutropenia, e.g. high-dose chemotherapy, blood and stem cell transplant settings. It is also used to maintain the dose and schedule of drugs in standard chemotherapy regimes, e.g. testicular cancer, breast cancer

  • Is recommended by current European guidance as primary prophylaxis if the risk of febrile neutropenia is ≥20%

  • As secondary prophylaxis, following an episode of febrile neutropenia, is an alternative option to dose reduction in the adjuvant setting

  • Is also used in mobilizing stem cells for stem cell harvest

  • Has a short half-life and requires regular SC injections for each treatment. Pegylated G-CSF (pegfilgrastim) has an Systemic anti-cancer therapy half-life, and only one injection is required in each course of chemotherapy.

Granulocyte-macrophage colony-stimulating factor

GM-CSF increases the number of neutrophils and monocytes. It also stimulates dendritic cells to divide, which help the immune system to recognize and attack cancer cells.

It is currently being used in trials to boost the numbers of dendritic cells and also in cancer vaccine trials.

Bacille Calmette–Guérin (BCG)

Activates macrophages, T- and B-lymphocytes, and natural killer cells. Also induces local response via interleukins.

Its main use in cancer treatment is in treatment of superficial bladder cancer (Systemic anti-cancer therapy see Cancer of the bladder and ureter, pp. [link][link]).

Intravesical instillation for superficial bladder cancer

  • 38% reduction of recurrence in Ta and T1 bladder cancer. Main treatment for bladder carcinoma in situ. Complete response rate of >70%.

  • Side effects: dysuria, haematuria, mild fever, urinary frequency. Rarely sepsis.

Monoclonal antibodies

Monoclonal antibody therapy is a therapeutic modality that has become mainstream in the treatment of a number of cancers, e.g. breast, melanoma, lung, gastric, ovarian, colorectal, haematological, often combined with more conventional chemotherapy agents.

All cells have protein markers on their surface, known as antigens. Monoclonal antibodies are designed in the laboratory to recognize particular protein markers on the surface of some cancer cells or other cells such as T-cells (e.g. PD-1 or CTLA-4). The monoclonal antibody then ‘locks’ on to this protein.

Monoclonal antibodies have several mechanisms of action by which they destroy or prevent the replication of malignant cells, such as:

  • Triggering the immune system to attack cancer cells, e.g. rituximab, ofatumumab

  • Blocking molecules that stop the immune system from working (checkpoint inhibitors), e.g. ipilimumab, nivolumab, pembrolizumab

  • Blocking signals from telling cancer cells to divide, e.g. cetuximab, bevacizumab

  • Carrying toxic therapy to specific cell targets by combining radionuclides, cytotoxic drugs, or cell toxins with the antibody, known as ‘conjugated’ monoclonal antibodies, e.g. brentuximab, ibritumomab.

Staff safety issues

Monoclonal antibodies are not infective, but as they are proteins, there is a theoretical risk of operator sensitization to non-human monoclonal antibodies on repeated exposure. However, there is little evidence to suggest this is a problem in practice. Ideally, the manipulation of monoclonal antibody preparations should be undertaken in pharmacy aseptic facilities, to ensure operator protection from contamination and patient protection from cross-contamination.

  • Vials should not be shaken to avoid prolonged foaming.

  • It is important not to create aerosols when removing content from the vial.

  • On addition of the vial’s contents to an infusion bag, gently invert the bag to mix. Do not shake.

Hypersensitivity reactions

The most common side effects of monoclonal antibodies are infusion-related, including flu-like symptoms and a cytokine release syndrome. This is generally observed with the first or second dose, and the probability of it occurring increases in patients with a large tumour burden or pulmonary insufficiency. The symptoms of this sort of reaction normally appear 1 or 2 hours after the infusion and range from very mild to a severe and/or fatal anaphylactic reaction (Systemic anti-cancer therapy see Anaphylaxis, pp. [link][link]). It can also be associated with features of tumour lysis syndrome (TLS) (Systemic anti-cancer therapy see Tumour lysis syndrome, pp. [link][link]). The risk of such reactions means that these drugs should be administered in areas where resuscitation equipment is available.

Rapid infusion protocols

Protocols exist in many areas for rapid infusion of a number of monoclonal antibodies, when patients have tolerated licensed rates without any signs of reaction.

There are several examples of monoclonal antibodies, which have become standard treatments for some cancers.

Trastuzumab

Trastuzumab is a humanized monoclonal antibody used to treat breast cancer patients whose tumours overexpress the HER-2 protein. The HER-2 protein is overexpressed in 20–30% of breast cancers and is a poor prognostic factor. Trastuzumab targets the HER-2 protein. Immunohistochemistry assays are required to assess whether patients are overexpressing the HER-2 protein. There is a standard scoring system (0, +1, +2, or +3). Patients with a HER-2 score of +3 are eligible for treatment with trastuzumab.

Established treatment:

Trastuzumab works by:

  • Downregulating HER-2 receptors

  • Inhibiting growth signalling pathways

  • Engaging natural killer cells of the immune system to attack the tumour

  • Inducing cell lysis

  • Enhancing chemotherapy cytotoxicity.

Side effects:

  • Cardiotoxicity—patients’ cardiac function must be monitored [echocardiography or MUGA (multigated acquisition) scanning at baseline and then at 3-monthly intervals during treatment]

  • Fever or chills—can be prevented with prophylactic paracetamol

  • Hypersensitivity reactions; can be delayed onset (Systemic anti-cancer therapy see Allergic reactions in oncology, p. [link]).

Rituximab (Mabthera®)

Rituximab is used for CD20-positive B-cell NHL, in combination with chemotherapy (usually CHOP). Rituximab binds the antigen CD20 on the cell surface, which is found in high levels on B-cell malignancies, e.g. NHL. This causes cell lysis.

Main therapeutic use:

Side effects:

  • Infusion-related side effects of rituximab usually occur during the first infusion and include fever, chills, and hypersensitivity reactions (Systemic anti-cancer therapy see Hypersensitivity reactions, p. [link]).

  • Patients should be pre-medicated with paracetamol and chlorphenamine to minimize these side effects.

  • Patients at higher risk of this side effect include those with a high tumour burden, pulmonary insufficiency, or tumour infiltration. These patients will also need to be treated with allopurinol or rasburicase to reduce their risk of TLS (Systemic anti-cancer therapy see Tumour lysis syndrome, pp. [link][link]).

  • Rituximab should be used with caution in patients receiving cardiotoxic chemotherapy or in those with cardiovascular disease.

Bevacizumab (Avastin®)

Bevacizumab is a recombinant human monoclonal antibody against the extracellular VEGF. VEGF is produced and secreted by most malignant cells, as it is required for the formation of blood vessels. Its established uses include:

Serious side effects:

  • GI perforation, delayed wound healing

  • Infections

  • Thrombosis and haemorrhage.

Cetuximab (Erbitux®)

Cetuximab is a monoclonal antibody against the epidermal growth factor receptor (EGFR), causing inhibition of the EGFR signalling pathway. Its main clinical roles are in:

Main side effects:

  • Hypersensitivity reactions (~3%)

  • Acneiform rash

  • Sore mouth

  • Diarrhoea

  • Common side effects of TKIs.

Management of common side effects of monoclonal antibodies

Chills and rigors

These begin after around 30 minutes and can last for up to 90 minutes. Pre-medication with paracetamol and chlorphenamine. Provide warmth (hot water bottles, blankets) and reassurance (can be very frightening for both the patient and carers).

Fever and sweating

Occur after chills, often with headache, tachycardia, and hypotension. Pre-medication with paracetamol. Encourage Systemic anti-cancer therapy fluid and food intake.

Diarrhoea

The increasing use of checkpoint inhibitors has Systemic anti-cancer therapy the incidence of potentially life-threatening colitis-induced diarrhoea in patients receiving them (Systemic anti-cancer therapy see Chapter 40, Altered bowel function). If colitis is suspected, then immediate treatment should be established with high-dose steroids.

Note: other side effects are covered in the appropriate chapters under those headings.

Biosimilars

In 2017, the first biosimilar monoclonal antibodies was introduced into the UK: biosimilar rituximab for haematological malignancies and biosimilar trastuzumab for breast cancers. It is expected that many more biosimilar MABs will be introduced into clinical practice in the next decade. Nurses will have a key role in informing and reassuring patients about possible changes to their treatment.

Tumour vaccines

Tumour vaccines are a form of biological therapy used to prevent the development of virus-induced cancers and treat non-virus induced cancers.

Virally induced tumours

  • A HPV vaccination programme is now in place in the UK to target HPV strains 16 and 18, which are responsible for over 70% of cervical cancer.

  • Hepatitis B vaccine is a widely used vaccine against hepatocellular carcinoma (HCC).

  • Tumour vaccines are also in development for EBV, which is closely linked to the development of Burkitt’s lymphoma and NHL.

Non-virally induced tumours

  • Vaccines are also in development for cancers that are not caused by a virus. Tumour cells or extracts of tumour cells can be used as cancer vaccines to enhance an immune response to the relevant tumours.

  • Tumour vaccines using tumour-associated antigens are also being developed. These vaccines work by stimulating the immune system to recognize and destroy specific cancer cells.

Talimogene laherparepvec

This is a genetically modified herpesvirus, indicated for the local treatment of unresectable skin and nodal lesions in patients with recurrent melanoma. It is given as a direct intralesional injection. It directly replicates in the lesion and may also stimulate an immune response.

  • Main side effects: fatigue, chills, fever, and nausea.

Vaccines are undoubtedly one of the most interesting and exciting areas in the genesis of new cancer therapies. Treatments are in development, targeting breast, colon, bladder, and lung cancers and melanoma.

Future advances

There will be a continuing increase in the knowledge of cancer and related biology, plus technological advances, which allow more accurate and quicker mapping of genes and more accurate diagnosis and delivery of drugs. These may lead to treatments tailored and stratified by individual tumour biology.

Further vaccines to prevent cancer or reduce risk may be just over the horizon. However, it is always difficult to predict the future. Gene therapy was hailed as the new breakthrough over 20 years ago and has yet to make a major impact. Yet few people foresaw the introduction of a tablet—imatinib—with few side effects that would fundamentally change the outlook for individuals with CML.

Nursing issues

Information support

The rapid development of new cancer drugs has a number of implications for cancer nurses at all levels. Nurses working in chemotherapy units have a range of new drugs to get to understand and inform patients about. Many new medications are tablets. These give patients Systemic anti-cancer therapy autonomy when managing their medication. However, they also require highly skilled information giving and support for patients regarding the safety aspects of each particular medication and their safe dosing and storage. Many centres have set up oral chemotherapy clinics to support patients in managing their medication at home, including accurate reporting of side effects and assistance with dose modification or interruption.

Hormonal therapy: background

Some tumour growth is stimulated by one of the body’s hormones. These cancers can respond to hormonal therapy; they include breast, prostate, endometrium, renal cell, ovary, testis, and thyroid cancers. The best evidence of this relates to the sex steroid hormones progesterone and oestrogen in breast and endometrial cancers and androgens in prostate cancer.

Breast and prostate cancer treatment accounts for the vast majority of hormonal therapy that is administered, and these are the main focus of this section. More detail of specific disease treatments are found within the relevant chapters (Systemic anti-cancer therapy see Chapter 22, Breast cancer; Systemic anti-cancer therapy Gynaecological cancers, pp. [link][link]; Systemic anti-cancer therapy Prostate cancer, pp. [link][link]).

The aim of hormonal therapy is to inhibit the production of the hormone influencing cancer growth or to block the effect of the hormone on the target organ. By inhibiting the action of the hormone, tumour cell growth can be slowed down or the tumour volume can be shrunk. These treatments can often prolong survival for many years. However, hormone-sensitive tumours can become resistant to hormonal therapy if the treatment fails to reduce the levels of hormones below the level needed for tumour cell growth.

Knowledge of how hormones or hormone antagonists act on cancer cells is the basis of hormone manipulation in cancer treatment. When a hormone enters a cell, it binds to a receptor. This receptor–hormone complex, in turn, stimulates the action of the hormone in the cell nucleus.

The strategies for hormonal therapy modifying tumour growth are:

  • To reduce the overall amount of the stimulating hormone in the body

  • To prevent the hormone from binding to a cell receptor by:

    • Competitive inhibition of the receptor site

    • Reduction in receptor numbers

  • To block the hormone–receptor complex from activating the cell nucleus.

Key hormone targets in cancer therapy

Tumour type

Hormone to be blocked by treatment

Breast

Oestrogen

Endometrium

Oestrogen

Prostate

Testosterone

Oestrogen production

In pre-menopausal women, the ovaries are the source of 90% of oestrogen production. This is regulated by the hypothalamus and the pituitary gland. If oestrogen levels are low, the hypothalamus releases luteinizing hormone-releasing hormone (LHRH), also known as gonadotrophin hormone-releasing hormone (GHRH). This stimulates the release of the gonadotrophic hormones luteinizing hormone (LH) and follicle-stimulating hormone (FSH) by the pituitary. These stimulate the ovaries to produce oestrogen. Many tissues, including breast tissue, have specific receptors, which will be stimulated by oestrogen.

Around 10% of oestrogen is produced in subcutaneous fatty tissue under the control of the adrenal glands. This continues after the menopause. The androgens that the adrenal gland produces are converted to oestrogen by the enzyme aromatase.

Testosterone production

Testosterone, an androgen hormone, is produced by the testes. A small amount is also produced by steroids released from the adrenal glands. Like ovarian production of oestrogen, it is under pituitary control, via LHRH and LH. Prostate tissue is dependent on androgens, mainly testosterone, for growth and function. Androgen receptors are found in the nucleus of prostate cells.

Hormonal therapy in prostate cancer aims to reduce testosterone production (LHRH analogues) or block the androgen receptors (anti-androgens). In recent years, two powerful anti-androgens have been developed for administration where other hormonal therapies and cytotoxic chemotherapy have proven ineffective. Enzalutamide and abiraterone acetate are currently used in metastatic, castrate-resistant (does not respond, or stops responding, to standard hormonal therapies) disease, but research is ongoing into their use in earlier-stage prostate cancer.

Treatment decision-making

There are now several different options involving hormonal therapy for the treatment of breast and prostate cancers. However, hormonal therapy does have both short- and long-term effects, which can have far reaching implications for the QoL, particularly in terms of sexual functioning, for both men and women, and in menopausal symptoms in pre-menopausal women. Patients need accurate and timely information and support to aid them in making decisions about the appropriate treatment approach, as in some cases, patients are asked to make a choice between extended longevity and QoL13 (Systemic anti-cancer therapy see Aromatase inhibitors and breast cancer, p. [link], Systemic anti-cancer therapy Prostate cancer, Hormonal therapy alone, p. [link]).

Main hormone drugs

The mechanism of action, efficacy, and side effect profile for each medication is taken into account when deciding on the best hormonal therapy for a patient. In some cancers, notably breast cancer, it is possible to assess which hormone receptors are present in tumours. This ensures that the patient receives the most appropriate hormonal treatment for the characteristics of their cancer.

The main classes of hormonal treatments used in cancer include oestrogens, progestogens, and hormone antagonists. (See Table 17.9 which shows examples of drugs in each of these classes and their use in treating different tumour types.)

Table 17.9 Commonly used hormonal therapies

Drug class

Mode of action

Tumour type

Drug

ER antagonist

Block ERs

Breast: used as adjuvant in early breast cancer to reduce recurrence post-surgery. Can also be used as a neo-adjuvant, pre-surgery to shrink a tumour

  • Tamoxifen

Aromatase inhibitors

Inhibit the conversion of androgens to oestrogens peripherally. This stops the stimulation of oestrogen-dependent tumours

Breast: used first, second, or third line in post-menopausal breast cancer (Systemic anti-cancer therapy see Chapter 22, Breast cancer)

  • Anastrozole

  • Exemestane

  • Letrozole

  • Fulvestrant

  • Toremifene

Progestogens

Directly reduce adrenal and ovarian sex hormones and indirectly reduce pituitary gonadotrophin levels. Anti-oestrogen

Endometrium, breast, prostate

  • Medroxyprogesterone acetate

  • Megestrol acetate

LHRH agonists

Treatment causes downregulation of the pituitary, preventing LH release and causing a fall in serum testosterone levels in men and serum oestradiol levels in women

Prostate: used in a range of situations (Systemic anti-cancer therapy see Prostate cancer, pp. [link][link])

Breast: adjuvant treatment for pre-menopausal women with early disease. Also used in metastatic disease in pre-menopausal women. Initial treatment can cause a flare in symptoms by temporarily increasing hormone levels. Men can be treated with anti-androgens given immediately prior to, and for the first few weeks of, treatment. In women, these effects are managed symptomatically

  • Buserelin

  • Goserelin

  • Leuprorelin

  • Triptorelin

Anti-androgens

Block testicular and adrenal androgens

Prostate: used alone or in combination with LHRH agonists

  • Bicalutamide

  • Cyproterone acetate

  • Flutamide

  • Enzalutamide

  • Abiraterone acetate

Oestrogens

Oppose the action of androgens. This suppresses the growth of androgen-dependent prostate cancer

Prostate

  • Diethylstilbestrol

  • Ethinylestradiol

* More specific treatment information can be seen in Systemic anti-cancer therapy Breast cancer and Systemic anti-cancer therapy Prostate cancer.

Hormone testing in breast cancers

As part of the normal pathology assay of breast tumours, all are tested for sensitivity to hormones. This is normally expressed as the degree of oestrogen receptor (ER) or progesterone receptor (PR) positivity. The Allred scale is used, giving a score out of a maximum of 8 (e.g. ER 7/8 and PR 7/8 for a tumour with a high number of both ERs and PRs). These scores are used to guide the provision of hormonal therapies.

References

13 Baumgart J, Nilsson K, Stavreus-Evers A, Kallak T, Sundström Poromaa I. Sexual dysfunction in women on adjuvant endocrine therapy after breast cancer. Menopause 2013;20:162–8.Find this resource:

Hormonal therapy: assessment and management of side effects

As with any drug therapy, hormonal therapy can have side effects. Patients need to be assessed regularly for their response to treatment and any side effects they may be experiencing. The main side effects of the drugs are shown in Table 17.10.

Table 17.10 Common side effects of hormonal therapy

Drug

Common side effects

Tamoxifen

Systemic anti-cancer therapy risk of endometrial cancer, DVT and stroke, mood swings, cataracts, hot flushes, fatigue, irregular menstrual cycles, vaginal discharge or bleeding, vaginal skin irritation, rashes, GI disturbances, headache, visual disturbances

Anti-androgens

Loss of libido, impotence, damaged liver function, steroidal effects, hypertension, fluid retention, seizures

Aromatase inhibitors

Hot flushes, osteoporosis, joint pains, drowsiness, fatigue, lethargy, rash, vaginal dryness, pain on intercourse

Progestogens

Nausea, fluid retention, weight gain, tremors, sweating, muscular cramps, Cushingoid features

LHRH analogues

Women: tumour flare, joint pains, loss of libido, fatigue

Men: loss of libido, impotence, tumour flare, gynaecomastia

Oestrogens

Sodium retention with oedema, thromboembolism, jaundice, nausea, impotence, gynaecomastia (men)

The risks and benefits of treatment must be assessed if patients experience severe side effects. It is sometimes beneficial for patients to be prescribed another drug in the same class if they are experiencing severe side effects.

Management of menopausal symptoms

These can be severe and are generally worst in women who are initially pre-menopausal. Women with breast cancer are also currently advised not to take HRT, so they are more likely to suffer from these symptoms.

Problems include:

  • Disruptions to the menstrual cycle, amenorrhoea

  • Hot flushes, night sweats (can be severe)

  • Difficulty sleeping, fatigue, depression

  • Joint pain, headaches

  • Vaginal dryness, painful intercourse

  • Psychological impact: ageing, body image, loss of fertility.

Patients need detailed and honest information about the whole potential impact of the menopause. An in-depth assessment is useful to plan with each individual what aspects of the menopause, if any, are major issues for her. A management package of pharmacological and non-pharmacological measures can then be planned.

Hot flushes (also occur with men having LHRH treatment)

Can range from frequent and severe to mild. They can be very disruptive, may be accompanied by drenching sweats, and can occur many times a day. They are generally more severe in those having cancer treatments, rather than natural menopause.

Pharmacological approaches

  • Use of HRT is generally considered unsafe, due to oestrogen and the risk of breast cancer. However, there is controversy about whether HRT increases cancer recurrence.

  • Gabapentin, selective serotonin reuptake inhibitors (SSRIs), e.g. venlafaxine or paroxetine, clonidine. Many women find the side effect profile problematic (see British National Formulary for further information).

Self-help/behavioural measures

Many women will employ a range of self-help measures:14

  • Behavioural modification, e.g. loose-fitting layers of thin, absorbent clothes (cotton)

  • Keeping diaries to identify patterns of flushing and exacerbating factors

  • Complementary therapies, e.g. evening primrose oil, black cohosh (limited evidence of effectiveness)

  • Cognitive strategies that have been effective include relaxation techniques. These may also improve other side effects and feelings of control in general15 (Systemic anti-cancer therapy see Progressive muscle relaxation, p. [link]).

Osteoporosis

  • Dietary advice regarding Systemic anti-cancer therapy calcium, exercise; improved fitness and muscle strength, monitoring for bone density. Dietary and exercise advice should also consider issues of weight gain

Body image

(Systemic anti-cancer therapy See Body image, p. [link].)

Sexual health issues

(Systemic anti-cancer therapy See Sexuality and cancer, p. [link].)

Further reading

Tobias J, Hochhauser D. Cancer and its Management, 7th ed. Oxford: Blackwell; 2014.Find this resource:

National Institute for Health and Care Excellence (2018). Early and Locally Advanced Breast Cancer Overview (section on adjuvant endocrine treatments). Available at: Systemic anti-cancer therapy https://pathways.nice.org.uk/pathways/early-and-locally-advanced-breast-cancer

References

14 Fenlon D. Endocrine therapies. In: Corner J, Bailey C (eds). Cancer Nursing: Care in Context, 2nd ed. Oxford: Blackwell Press; 2008. pp. 262–79.Find this resource:

15 Fenlon D. A randomized controlled trial of relaxation training to reduce hot flashes in women with primary breast cancer. J Pain Symptom Manage 2008;35:397.Find this resource: