General aspects of chemotherapy

Background

Neoplastic disease is a result of proliferation of abnormal cells. It can affect every system in the body and is a major cause of mortality and morbidity around the world.

Chemotherapy is used to kill neoplastic cells - however, there are usually a number of healthy cells which are also killed. The abnormal malignant cells take longer than the normal cells to grow. Therefore, chemotherapy is given in cycles to allow the 'normal' cells to recover.

Chemotherapy can be used for curative intent or palliation. It can be used alone or as an adjunct to other treatments - eg, surgery, hormonal therapy or radiotherapy. Often chemotherapeutic agents are used in combination but, occasionally, they are used alone.

The main groups of chemotherapeutic agents are:¹

• Alkylating agents, eg, cyclophosphamide, busulfan, chlorambucil, melphalan, lomustine, carmustine, dacarbazine.

• Anthracyclines: daunorubicin, doxorubicin hydrochloride, epirubicin hydrochloride and idarubicin hydrochloride are anthracycline antibiotics. Mitoxantrone is an anthracycline derivative.

• Taxanes, eg, docetaxel, paclitaxel.

• Histone deacetylase inhibitors, eg, entinostat.

• Topoisomerase inhibitors. eg, eg, topotecan, etoposide.

• Kinase inhibitors, eg, bortezomib, erlotinib, vismodegib.

• Nucleotide analogues and precursor analogues, eg, azathioprine, cytarabine, hydroxyurea, mercaptopurine, methotrexate.

• Antimicrobial peptides, eg, actinomycin, bleomycin

• Platinum-based agents, eg, cisplatin.

• Retinoids, eg, tretinoin

• Vinca alkaloids and derivatives, eg, vinblastine, vincristine.

Methods of administration of chemotherapy

• Oral.

• Intramuscular.

• Intravenous.

• Intrathecal.

• Topical.

• Others - eg, intravesical, subcutaneous.

Side-effects

See individual drug monographs for details.

Some people only have minimal side effects, but for many, a course of chemotherapy can be very unpleasant. Feeling tired and weak all the time is common. Side effects may also include:

• Myelosuppression with possible anaemia, or increased susceptibility to infection or bleeding diathesis.

• Alopecia.

• Infertility.

• Impaired wound healing.

• Nausea and vomiting.

• Mouth ulcers.

• Teratogenicity.

• Some agents may lead to menopausal symptoms in female patients - eg, alkylating agents in Hodgkin's lymphoma.²

Safe use of cytotoxics¹

• Chemotherapy initiation is a decision made by oncology consultants.

• Prior to administering cytotoxics, basic blood counts and appropriate other tests are checked - eg, LFTs.

• Patients may need antiemetics prior to drug delivery.

• Trained personnel should reconstitute cytotoxics.

• Reconstitution should be carried out in designated pharmacy areas.

• Protective clothing (including gloves, gowns, and masks) should be worn.

• The eyes should be protected and means of first aid should be specified.

• Pregnant staff should avoid exposure to cytotoxic drugs (all females of child-bearing age should be informed of the reproductive hazard).

• Use local procedure guidelines for dealing with spillages and safe disposal of waste material, including syringes, containers, and absorbent material.

• Staff exposure to cytotoxic drugs should be monitored.

• Patients need to be aware that, for some agents, high concentrations are found in urine, sweat and vomit. They should be advised on appropriate clothing and how to dispose of soiled linen.

Specific problems¹

Extravasation

A number of cytotoxic drugs will cause severe local tissue necrosis if leakage into the extravascular compartment occurs. To reduce the risk of extravasation injury it is recommended that cytotoxic drugs are administered by appropriately trained staff.¹

• Associated with pain, redness and inflammation. Very serious, as may lead to skin necrosis which could require limb amputation.

• There may be blotching of the skin or blistering and necrosis in severe cases.

• Treatment involves a high index of suspicion and careful monitoring if symptoms develop.

• The actual management of extravasation, once it has occurred, varies. Topical agents can be applied to act as antidotes - eg, dimethyl sulfoxide topically. In more severe cases, debridement and grafting may be necessary. However, the evidence base in this area is lacking and the best method is prevention. ³

Nausea and vomiting

• Symptoms may be acute (occurring within 24 hours of treatment), delayed (first occurring more than 24 hours after treatment), or anticipatory (occurring prior to subsequent doses).

• Mildly emetogenic: fluorouracil, etoposide, methotrexate (lower dosages), the vinca alkaloids, and abdominal radiotherapy.⁴

• Moderately emetogenic treatment—the taxanes, doxorubicin hydrochloride, intermediate and low doses of cyclophosphamide, mitoxantrone, and high doses of methotrexate.

• Highly emetogenic treatment: cisplatin, dacarbazine, and high doses of cyclophosphamide.

• Prevention of acute symptoms:

  • Patients at low risk of emesis: pretreatment with dexamethasone or lorazepam.

  • Patients at high risk of emesis: a 5HT3-receptor antagonist, usually given in combination with dexamethasone and the neurokinin receptor antagonist aprepitant is effective.

• Prevention of delayed symptoms:

  • Associated with moderately emetogenic chemotherapy: combination of dexamethasone and 5HT3-receptor antagonist.

  • Highly emetogenic chemotherapy: combination of dexamethasone and aprepitant is effective. Rolapitant and metoclopramide hydrochloride are also licensed for delayed chemotherapy-induced nausea and vomiting.

• Prevention of anticipatory symptoms: good symptom control is the best way to prevent anticipatory symptoms. Lorazepam can be helpful for its amnesic, sedative, and anxiolytic effects.

A Cochrane review concluded that the most effective antiemetics to prevent chemotherapy-induced nausea and vomiting in childhood remains uncertain. The review suggested that 5-HT3 antagonists are effective, with granisetron or palonosetron possibly better than ondansetron. Adding dexamethasone improved control of vomiting, although the risk-benefit profile of adjunctive steroid remains uncertain.⁵

Oral mucositis

• A sore mouth is a common complication. Mucositis is self-limiting but with poor oral hygiene it can lead to blood-borne infection.

• It is most often associated with fluorouracil, methotrexate, and the anthracyclines.

• Good oral hygiene (rinsing the mouth frequently and effective brushing of the teeth with a soft brush 2–3 times daily) is beneficial.

• For fluorouracil, sucking ice chips during short infusions of the drug is also helpful.

• Once a sore mouth has developed, treatment is much less effective. Saline mouthwashes should be used. There is no good evidence to support the use of antiseptic or anti-inflammatory mouthwashes.

Tumour lysis syndrome

• Tumour lysis syndrome occurs secondary to spontaneous or treatment-related rapid destruction of malignant cells.

• Patients at risk include those with non-Hodgkin’s lymphoma (especially if high grade and bulky disease), Burkitt’s lymphoma, acute lymphoblastic leukaemia and acute myeloid leukaemia (particularly if high white blood cell counts or bulky disease), and occasionally those with solid tumours.

• Pre-existing hyperuricaemia, dehydration, and renal impairment are also predisposing factors.

• Features include hyperkalaemia, hyperuricaemia, and hyperphosphataemia with hypocalcaemia.

• Renal damage and arrhythmias may occur. Early identification of patients at risk, and initiation of prophylaxis or therapy for tumour lysis syndrome, is essential.

Hyperuricaemia

• Hyperuricaemia may occur with high-grade lymphoma and leukaemia. It can be markedly aggravated by chemotherapy and is associated with acute kidney injury.

• Allopurinol should be started 24 hours before treating these malignancies and patients should be adequately hydrated.

• The dose of mercaptopurine or azathioprine should be reduced if allopurinol needs to be given concomitantly. Febuxostat may also be used and should be started 2 days before cytotoxic therapy is initiated.

• Rasburicase, a recombinant urate oxidase, rapidly reduces plasma-uric acid concentration and may be of particular value in preventing complications following treatment of leukaemias or bulky lymphomas.

Bone-marrow suppression

• All cytotoxic drugs except vincristine sulfate and bleomycin cause bone-marrow suppression. This often occurs 7 to 10 days after administration, but is delayed for certain drugs, such as carmustine, lomustine, and melphalan.

• Peripheral blood counts must be checked before each treatment, and doses should be reduced or therapy delayed if bone-marrow has not recovered.

• Cytotoxic drugs may be contra-indicated in patients with acute infection. Any infection should be treated before, or when starting, cytotoxic drugs.

• Fever in a neutropenic patient (neutrophil count less than 1.06×109/litre) requires immediate broad-spectrum antibacterial therapy. Appropriate bacteriological investigations should be conducted as soon as possible.

• Patients taking cytotoxic drugs who have signs or symptoms of infection should be advised to seek prompt medical attention. All patients should initially be investigated and treated under the supervision of the appropriate oncology or haematology specialist.

• In selected patients, the duration and the severity of neutropenia can be reduced by the use of recombinant human granulocyte-colony stimulating factors.

• Symptomatic anaemia is usually treated with red blood cell transfusions.

Alopecia

• Reversible hair loss is a common complication, but varies in degree between drugs and individual patients. No pharmacological methods of preventing this are available.

• Alopecia can have psychosocial consequences on patients in an already difficult situation.⁶

• There is no clear evidence, but use of scalp hypothermic regimens may be helpful - eg, cold caps. ^{7 8}

Thromboembolism

Deep vein thrombosis or pulmonary embolism can complicate cancer itself, but chemotherapy increases the risk.

Pregnancy and fertility¹

• Most cytotoxic drugs are teratogenic and should not be administered during pregnancy, especially during the first trimester.

• Exclude pregnancy before treatment with cytotoxic drugs. Contraceptive advice should be given before cytotoxic therapy begins. Women of childbearing age should use effective contraception during and after treatment.

• Regimens that do not contain an alkylating drug or procarbazine may have less effect on fertility, but those with an alkylating drug or procarbazine carry the risk of causing permanent male sterility. Pretreatment counselling and consideration of sperm storage may be appropriate.

• Women are less severely affected, though there is a risk of premature menopause.

• No increase in fetal abnormalities or abortion rate has been recorded in patients who remain fertile after cytotoxic chemotherapy.