Adverse effects of antineoplastic agents

Essentials

  • Antineoplastic agents can be divided roughly into classic cytostatic/cytotoxic agents, hormonal agents, antibodies, drugs affecting signalling and other drugs. All have adverse effects. In most cases the therapeutic window is narrow.
  • Antineoplastic agents may cause immediate, delayed or late adverse effects. Late effects may only appear until several years after the end of treatment.
  • Antineoplastic agents cause adverse effects such as nausea, blood count changes, hair loss, neuropathy, damage to the myocardium, lungs, liver and kidneys, skin reactions, gastrointestinal effects and endocrinopathies.
  • Before beginning antineoplastic treatment, blood tests, at least, should be performed. Depending on the drug combination, laboratory tests should be repeated regularly, usually at least before beginning each new cycle of treatment.
  • The adverse effects of antineoplastic drugs may to some extent be controlled by adjusting the dose, by pausing treatment, and by giving supportive medication.
  • Most antineoplastic drugs may cause miscarriages or fetal abnormalities, so birth control counselling and contraception must be taken care of. The most aggressive treatments may cause permanent or transient infertility and premature menopause.
  • If antineoplastic medication is suspected of having adverse effects, it is important to check the patient’s medication list and to make sure that the causative drug is not given again until the matter has been investigated.
  • It may be difficult to differentiate between an adverse drug effect, progression of the cancer being treated and other diseases.
  • Due to the extensive range of pharmaceutical treatments and adverse effects, it is important to investigate the case carefully and to consult experts: to interview the patient and his/her relatives (patients often have with them material concerning their medication), to consult an appropriate drug database, the oncology unit in charge of the patient's cancer treatment or, during on-call hours, doctors on call at secondary or tertiary care hospitals.

Nausea and other gastrointestinal symptoms

  • Different antineoplastic drugs and their combinations cause very different degrees of nausea. Some drugs do not cause more nausea than placebo, while the most problematic drugs cause nausea in almost all patients.
  • Susceptibility to nausea also depends on the patient’s age, gender, earlier susceptibility to nausea and alcohol history.
  • Acute nausea begins within 24 h from treatment. In the case of mildly emetogenic courses of antineoplastic drugs, antiemetic therapy may be carried out with metoclopramide, dexamethasone or a 5-HT3 receptor blocker, and in the case of more emetogenic antineoplastic drugs, by combinations of these, together with an NK1 receptor blocker and/or olanzapine, as necessary; the antiemetic medication is administered before the antineoplastic drug.
  • Metoclopramide, concomitantly with dexamethasone, as necessary, is effective for delayed nausea (beginning 24 h or more after drug administration). A 5-HT3 receptor blocker, NK1 receptor blocker, olanzapine and/or benzodiazepine, such as lorazepam, can be added to the regimen, as necessary.
  • Anticipatory nausea (the mere fear of nausea, smells or the sight of the hospital may be enough to initiate nausea) can be prevented by benzodiazepines, such as lorazepam. These should be started the night before or a few hours before the treatment.
  • Breakthrough nausea can be treated with the above drugs other than NK1 receptor blockers. Other options include haloperidol, prochlorperazine and scopolamine.
  • Other gastrointestinal symptoms include stomatitis, constipation and decreased appetite, for example.
  • Many antineoplastic drugs may increase liver values.

Evidence Summaries

Blood cytopenias

  • Antineoplastic treatments are often associated with leucopenia, thrombocytopenia and sometimes even anaemia. Leukopenia and thrombocytopenia typically appear within 1–3 weeks, anaemia within a few months.
  • Neutropenia (see also below ) (Leucopenia) is associated with an increased risk of infections, which may be decreased by giving a white cell growth factor. The effect is best if the treatment is initiated within 24–48 hours after administration of the antineoplastic treatment, when the blood count is still normal. In prolonged neutropenia, a white cell growth factor may also be given later on.
  • Thrombocytopenia (Thrombocytopenia) can be treated with thrombocyte transfusion if there is an evident risk of haemorrhaging or if the patient has a simultaneous neutropenic infection. In most cases, it will be sufficient to wait for spontaneous remission.
  • Anaemia can be treated with red cell transfusions. If the response is insufficient and the anaemia affects the patient’s condition, intravenous iron infusion and sometimes also erythropoietin products may be used in a patient with iron deficiency.

Evidence Summaries

Neutropenic infection

  • Patients on antineoplastic treatment, whose general condition is deteriorating, with blood values falling, the CRP level increasing and/or fever, can be considered to have a neutropenic infection until otherwise proven.
  • Rapid initiation of treatment may be necessary.
  • The cornerstones of management are rapid history taking, clinical examination (such as general condition, fever, confusion vs. orientation, skin, mucosa, portals of entry, urine production, blood pressure, peripheral temperature), rapid blood tests with blood cultures, urine testing, administration of copious supportive fluids, and rapid initiation of intravenous broad-spectrum antimicrobial treatment.
  • A patient with a severe neutropenic infection may be confused, understate his/her symptoms and appear in better condition than he/she actually is (apyrexia, flushed cheeks).

Hair loss

  • Hair loss is a common adverse effect of many cytotoxic drugs. Choosing another cytotoxic drug can sometimes prevent it. Intense cooling of the scalp using a special cooling cap during the administration of cytotoxic agents and for some time thereafter may decrease or slow down alopecia.
  • Hair is usually lost about 2–5 weeks after the first antineoplastic administration and it usually grows back after termination of the treatment. Usually the hair will have grown back to such an extent after 3–4 months that the patient no longer needs to wear a wig.
  • The oncology unit may provide the patient with an undertaking to pay for the wig. Find out about local policies and practices concerning wigs.

Adverse tissue and skin effects

  • Many cytotoxic drugs cause tissue damage if they escape from the vein. Severe damage may require surgical revision. Pain during infusion (if not caused by drug extravasation) can be alleviated by slowing the infusion rate or with an irrigating solution. Fluorouracil can cause innocent dark discoloration of the vein and the adjacent skin.
  • Some antineoplastic agents cause palmoplantar erythrodysaesthesia, i.e. erythema, pain and hypersensibility in the palmar and plantar skin. At its most extreme, this may lead to painful ulcerations and exfoliation.
  • Some antineoplastic agents cause various kinds of rash, dry skin, paronychia and nail symptoms.

Adverse cardiovascular effects

  • Anthracyclines (such as doxorubicin or epirubicin) cause myocardial damage and may lead to cardiac failure. Such damage is rare if the cumulative dose is kept sufficiently low. Sometimes the damage does not become apparent until after several months or years.
  • Fluorouracil and capecitabine may cause angina pectoris symptoms.
  • Some antineoplastic agents may cause a prolonged QT interval, arrhythmias or hypertension. In some patients, antihypertensive medication needs to be started.

Evidence Summaries

Adverse lung effects

  • Drugs such as methotrexate, bleomycin, mitomycin and busulphan may damage gas exchange in the lungs. Differentiating this condition from changes caused by the cancer, such as lymphangitis carcinomatosa, and from infections may be difficult. After courses of bleomycin, particular care must be taken during anaesthesia, for example.
  • Some antineoplastic agents may cause pneumonitis.

Adverse renal and urinary effects

  • Particularly cisplatin or high doses of iphosphamide or methotrexate may damage the kidneys.
  • Cyclophosphamide and iphosphamide in high doses cause irritation in the urinary bladder. This may be prevented with mesna (Uromitexan®).

Adverse neurological and CNS effects

  • Some cytotoxic drugs, such as vincristine, oxaliplatin, cisplatin and taxanes, cause peripheral neuropathy. Typical symptoms are paraesthesias, muscle pain and weakness, pain, tenderness to touch or sensitivity to cold. Usually the symptoms start in the fingers.
  • Some cytotoxic drugs may be associated with acute adverse CNS effects, such as drowsiness, confusion or even convulsions (ifosfamide, cytarabine and busulfan, for example).
  • Glucocorticoids which are part of many regimens may affect alertness and mood.
  • Antineoplastic treatment is often also associated with fatigue and exhaustion.
  • In addition, some patients experience adverse cognitive effects.

Adverse effects on the fetus, pregnancy, fertility and hormone activity

  • Antineoplastic medication during pregnancy may lead to miscarriage or fetal abnormality.
  • Depending on a female patient’s age and treatment, her periods may stop transiently or permanently.
  • In some female patients, antineoplastic medication will lead to premature menopause.
  • In male patients, antineoplastic medication may lead to transient or permanent cessation of sperm production.
  • In female patients, hormonal agents may cause menopausal symptoms.
  • Hormonal treatment of prostate cancer typically causes vasomotor symptoms and decreased libido.

Other adverse effects

  • Many antineoplastic drugs cause electrolyte disturbances and allergic reactions.
  • Immuno-oncological treatments may typically cause various endocrinopathies (such as hypo-/hyperthyroidism, hypophysitis, adrenalitis or diabetes).
  • Hormonal agents may cause decreased bone density.
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