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Long-Term Adverse Effects of Antineoplastic Agents

Essentials

  • Drugs are used to cure cancer, to slow down the spread of metastatic disease, to prolong survival and to alleviate symptoms.
  • If the disease is to be cured, also some adverse effects of treatment must be accepted.
    • If the aim of treatment is just to slow down the progression of cancer, significant adverse effects affecting quality of life should be avoided.
  • The treatment of chronic adverse effects is challenging.
    • There are few possibilities for treatment of adverse effects based on their underlying mechanisms.
    • Adverse effects cannot be prevented.
    • It is not possible to say in advance which patients will develop most adverse effects.
  • It is most important to concentrate on alleviating chronic symptoms of adverse effects.
  • The main groups of antineoplastic agents are:
    • agents affecting hormonal functions
    • cytostatic agents
    • biological agents
    • immunomodulators.
  • When follow-up is transferred to primary health care, the final assessment in specialized care should specify the need for monitoring or investigating any long-term adverse effects.

Hormonal treatments

  • Most breast and prostate cancers are hormone dependent.
    • The drugs used for their treatment prevent the synthesis of oestrogen or testosterone or their effects on the target tissue (picture F1).
    • Treatment typically continues for several years.
  • The long-term adverse effects of the drugs are the result of inhibition of hormonal activity.
    • Typical symptoms in women include secondary amenorrhoea, menopausal and joint symptoms and osteoporosis.
    • Men suffer from impotence, loss of muscle bulk and menopausal symptoms.

LHRH analogues

  • LHRH analogues are given as subcutaneous depot injections every 1, 3 or 6 months.
  • They act at the hypothalamic level, leading to decreased oestrogen and testosterone secretion and chemical castration.

Aromatase inhibitors

  • Aromatase inhibitors are used for postmenopausal women, only.
  • Their adverse effects are usually milder than those of LHRH analogues.
  • They cause osteoporosis .
  • Joint stiffness and pain may occur during the treatment.

CYP17A1 inhibitor

  • Abiraterone prevents cholesterol from being converted to testosterone in the adrenal gland.
  • Adverse effects of abiraterone include elevated liver values, oedema and cardiac dysfunction.

Receptor antagonists

  • Tamoxifen is an oestrogen receptor antagonist that:
    • may predispose the patient to venous thrombosis and cerebrovascular disorders
    • may cause endometrial hyperplasia
    • acts as a receptor agonist in bone; therefore, osteoporosis will not develop.
  • Antiandrogens
    • Bicalutamide causes gynaecomastia.
    • Enzalutamide causes adverse effects such as fatigue, exhaustion, hot flushes and sometimes confusion.

Cytostatic drugs

  • Cytostatic drugs have been used for decades and are still a central form of treatment.
  • As their therapeutic range is narrow, the risk of adverse effects is high.
  • If the aim is to cure cancer, high drug doses and intensive treatment are needed but the duration of treatment is relatively short (a few months, only).
  • If the aim is to delay cancer progression, lower doses are used but the duration of treatment is longer (as long as several years).
  • In both cases, there is a risk of long-term adverse effects.

Adverse CNS effects

  • The blood-brain barrier protects the central nervous system (CNS) from adverse effects of cytostatic drugs but prevents therapeutic effects of many such drugs on the CNS.
    • A small share of the drugs cross the blood-brain barrier and may cause adverse CNS effects.
  • The treatment is symptomatic. Depression, for example, is treated with antidepressants .
  • Cytostatic drugs may cause prolonged brain fog (fatigue, memory problems).
    • The exact cause of this is not clear.
    • Brain fog usually clears spontaneously after the end of treatment.

Neuropathy

Peripheral neuropathy caused by cytostatic drugs

  • Peripheral neuropathy Polyneuropathies is a significantly more common adverse effect of cytostatic drugs than CNS toxicity.
    • Cytostatic drugs easily cross the blood-nerve barrier, accumulating in nerve endings.
  • The risk increases with prolonged treatment.
  • In most cases, neuropathy is reversible if the treatment is withdrawn in time.
    • Nerve recovery may continue for about 2 years from the end of treatment.
    • Advanced neuropathy is rarely reversible.
  • Various cytostatic drugs cause similar symptoms.
  • Peripheral stocking-glove type sensorimotor polyneuropathy is typical (picture F2).
    • Sensory symptoms, such as pins and needles, numbness, loss of sensation and also pain, are predominant.
    • Motor symptoms, such as muscle weakness, clumsy fingers or balance problems, develop more slowly.

Antineoplastic agents causing neuropathy

  • Taxanes
    • Paclitaxel causes neuropathy more often than docetaxel.
    • Hypaesthesia and pain in hands and feet are common but motor weakness is rare.
  • Platinum compounds
    • Cisplatin, carboplatin and oxaliplatin commonly cause chronic neuropathy.
    • Clumsiness of hands and fingers and numbness of the soles of the feet and fingers are typical.
  • Vinca alkaloids
    • Vincristine is the most commonly used vinca alkaloid.
    • The first symptoms include numbness and pain of hands and feet.
    • Muscle weakness in wrists and toes and disorders of the autonomic nervous system, such as bladder atony, paralytic ileus, impotence, orthostatic hypotension and cardiac problems develop later.
  • Proteasome inhibitors
    • Bortezomib is the most commonly used proteasome inhibitor.
    • It causes neuropathy in about half of patients.
    • The risk of adverse effects increases with increasing total dose.
    • Neurogenic pain and orthostatic hypotension are common.
  • Immunomodulators
    • Thalidomide is the most widely used immunomodulator.
    • It causes mainly hypaesthesia.

Prevention and treatment of neuropathy

  • Numerous treatments, such as calcium and magnesium infusions and vitamins, have been used to prevent neuropathy but without significant benefit.
  • Neuropathic pain has the most prominent effect on quality of life. It is difficult to treat, and no studies have been performed in cancer patients.
  • For the treatment of neuropathic pain, see articles Chronic pain Chronic Pain, Diabetic neuropathy Diabetic Neuropathy and Polyneuropathies Polyneuropathies.

Kidney damage

  • Cytostaticc drugs disturb the function of the renal tubules or small capillaries, thus damaging the kidneys.
    • Advanced age, a history of renal disease, and other underlying diseases, such as hypertension or diabetes, predispose the patient to kidney damage.
  • Cisplatin is the best known cytostatic drug causing kidney damage.
    • Plasma creatinine levels increase, and magnesium and potassium are excreted in urine.
    • The changes are reversible at first but as treatment continues they become permanent.
  • Ifosfamide may cause tubular damage as its main metabolic product, chloroacetaldehyde, causes renal toxicity.
  • Pemetrexed is accumulated in cells, gradually leading to tubular fibrosis and atrophy.
  • Gemcitabine damages renal circulation and causes thrombotic microangiopathy.

Adverse cardiovascular effects

  • Cardiotoxicity of cytostatic drugs may be due to:
    • a direct destructive effect on cardiomyocytes
    • increased blood pressure or
    • thromboembolic complications.
  • Cytostatic drugs may cause left ventricular failure Chronic Heart Failure, myocarditis Myocarditis, pericarditis Pericarditis or arrhythmias Symptoms of Arrhythmia and Examination of an Arrhythmia Patient.
    • These may appear immediately during treatment or only several years after the end of treatment.
  • Anthracyclines (such as epirubicin, doxorubicin or daunorubicin)
    • Left ventricular failure is the most feared adverse cardiac effect.
    • Anthracyclines cause irreversible, progressive cardiomyocyte damage.
    • The risk depends on the cumulative dose.
    • Advanced age, female sex, a history of heart disease, radiotherapy of the heart region and other antineoplastic agents affecting the heart predispose the patient to myocardial damage.
    • Carvedilol and ACE inhibitors can be used to prevent and to treat myocardial damage.
    • There is no uniform recommendation for late monitoring of the heart after anthracycline treatment but individual tumour-group-specific guidelines may address monitoring.
  • Trastuzumab (humanized antibody)
    • Prevents cardiomyocytes from repairing damage and causes left ventricular failure.
    • The effect is not dose-dependent. When trastuzumab is withdrawn, failure symptoms usually resolve.

Increased blood pressure

  • Antineoplastic agents may increase blood pressure by preventing the activity of the vascular endothelial growth factor (VEGF).

Adverse lung effects

  • Adverse lung effects may be due to cytostatic drugs, to the cancer itself or to infections.
  • Bleomycin
    • The best known cytostatic drug causing lung damage
    • 2-46% of patients develop lung damage.
    • Predisposing factors include age over 70 years, a cumulative dose exceeding 450 mg, lung radiotherapy, renal failure and smoking.
    • On biopsy, diffuse alveolar damage, interstitial pneumonia and fibrosis can be seen.
    • Spirometry and diffusion capacity values become worse.
    • There is no specific treatment available. It is most important to withdraw the drug sufficiently early, no later than when the first signs of damage appear.
  • Taxanes
    • Both paclitaxel and docetaxel may cause lung reactions. It is not clear whether the problems are caused by the cytostatic agents as such or the solvents used, and the injury mechanism is unknown.
    • Adverse lung effects of paclitaxel may appear as soon as within 2 days from exposure. They can be treated with a glucocorticoid and will resolve within a few days.
    • Pneumonitis caused by docetaxel will develop and resolve more slowly.
    • Docetaxel also causes fluid accumulation in the pleura.

Adverse liver effects

  • Most cytostatic drugs are metabolized by the liver.
  • However, little is known about liver damage, and investigation is complicated because patients use several other drugs placing a burden on the liver, and progression of cancer may also cause liver failure.

Adverse effects on sex hormone producing organs

Ovaries

  • The effects of cytostatic drugs on ovarian function and ovarian damage depend on the patient's age, the dose and the duration of the treatment.
  • Menstrual disturbances, secondary amenorrhoea and menopausal symptoms are the first signs of ovarian toxicity.
  • Cytostatic drugs may cause infertility.
  • The cancer status permitting, women of fertile age should be referred for fertility counselling before starting the treatment.
  • In patients without a hormone-dependent cancer (such as breast, uterine or ovarian cancer), symptoms can be alleviated by oestrogen replacement therapy Menopausal Symptoms and Hormone Therapy.

Testes

  • As gametes are most sensitive to the effects of cytostatic drugs, the first clinical sign of testicular toxicity is azoospermia.
  • Semen banking should be used to ensure fertility.
  • As Leydig cells are better able to tolerate cytostatic drugs, testosterone levels stay normal or around the lower limit of normal for a long time.
  • Testosterone deficiency shows as fatigue, loss of muscle bulk and lack of sexual desire.
  • If the cancer is not a hormone-dependent one (such as prostate or testis cancer), the symptoms can be alleviated by testosterone replacement therapy Male Hypogonadism and Hormone Replacement.

Long-term adverse metabolic effects

  • Adverse metabolic effects have mostly been studied in patients treated for cancer in childhood. See articleProblems of Childhood or Adolescence Cancer Survivors in Adulthood.
    • An increase in the prevalence of overweight and of insulin resistance appears as early as within a few years from treatment.
    • Blood pressure increases and the blood lipid balance gets worse.
    • Radiotherapy of the CNS area and liberal use of supportive glucocorticoids increase the risk of metabolic syndrome (picture F3).
  • Long-term adverse metabolic effects are treated as in other patients by medication and by encouraging physical activity and a healthy lifestyle.

Biological agents and immunomodulators

  • Relatively new antineoplastic agents
  • Used primarily to slow down the progression of cancer; hence, the periods of treatment are quite short.
  • Limited data are so far available on their long-term adverse effects.

    References

    • Perachino M, Massarotti C, Razeti MG, et al. Gender-specific aspects related to type of fertility preservation strategies and access to fertility care. ESMO Open 2020;5(Suppl 4):e000771 [PubMed]
    • Harris C, Sander CR. Late respiratory effects of cancer treatment. Curr Opin Support Palliat Care 2017;11(3):197-204 [PubMed]
    • Addington J, Freimer M. Chemotherapy-induced peripheral neuropathy: an update on the current understanding. F1000Res 2016;5(): [PubMed]
    • Curigliano G, Cardinale D, Suter T, et al. Cardiovascular toxicity induced by chemotherapy, targeted agents and radiotherapy: ESMO Clinical Practice Guidelines. Ann Oncol 2012;23 Suppl 7():vii155-66 [PubMed]

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