Complications of cytotoxic therapy -part 1

Chemotherapy can cure some cancers, but it has many adverse effects which can affect any system of the body. Some may not appear until after treatment is completed. As more people are being treated as outpatients, general practitioners need to be aware of the toxicities. While some adverse effects can be treated symptomatically, others may be lifethreatening. Any patient presenting with a fever after chemotherapy may have febrile neutropenia. This is a medical emergency and requires urgent referral to hospital.

Currently available cytotoxic drugs do not discriminate between cancer cells and normal cells undergoing rapid division. The toxicity of anticancer treatment will continue to be a significant problem until therapies are developed which are highly selective for malignant cells.

Nausea and vomiting are the most common distressing early toxic features of cytotoxics. Dehydration, electrolyte imbalance, weakness, weight loss, oesophageal tears, fractures, wound dehiscence and anorexia may result. Many factors influence emesis, particularly the type of cytotoxic used, and the risk of a particular individual vomiting cannot be predicted.

Delayed emesis and anticipatory emesis are common (up to 25%). Anticipatory emesis is a conditioned response which is more likely to occur when previous emesis has been poorly controlled. Not all nausea and vomiting is related to chemotherapy; therefore, other causes such as biochemical abnormalities, gut obstruction, brain secondaries and anxiety should be excluded.

Chemotherapy induced nausea and vomiting is mediated by the vomiting centre in the medulla. The vomiting centre is close to the chemoreceptor trigger zone (CTZ) in the area postrema of the 4th ventricle. Vomiting occurs when the vomiting centre is stimulated from the CTZ or nerve fibres from the cerebral cortex, gastrointestinal tract (especially duodenum), heart and vestibular system. Several neurotransmitters act at the CTZ. They include dopamine, histamine, acetylcholine, serotonin and endorphins. Antiemetics work by blocking these neurotransmitter

receptors. For example, metoclopramide, chlorpromazine and haloperidol antagonise dopamine receptors and ondansetron and tropistetron antagonise serotonin (5HT3) receptors (Table1). Dexamethasone is useful for acute and delayed emesis, especially when combined with other antiemetics. Its mode of action is unclear, but may be related to reduction of prostaglandin synthesis.

The major principles of antiemetic treatment are:

• high doses
• intravenous administration for moderately and highly emetogenic cytotoxics
• combination of antiemetics with different modes of action and different adverse effects
• the prophylactic administration of antiemetic drugs
• patient support, behavioural and psychological intervention.

Other gastrointestinal adverse effects may occur. Structural changes in the small intestine may be related to malabsorption. The dose limiting toxicity of fluorouracil given as a weekly bolus is myelosuppression. Mucositis and diarrhoea occur more often when it is given as a continuous infusion or as daily boluses. The modulation of fluorouracil activity with leucovorin (folinic acid) increases effectiveness, but also increases gastrointestinal toxicity.

Vincristine may cause autonomic dysfunction (colicky abdominal pain, constipation, adynamicileus), especially in elderly patients. This occurs within 3 days of treatment. Actinomycin D, doxorubicin, methotrexate, fluorouracil, bleomycin, hydroxylurea, mercaptopurine, BCNU, procarbazine and vinblastine may increase the severity of acute and delayed radiation damage to the gut, mucous membranes and skin. Gastrointestinal bleeding (unless associated with severe thrombocytopenia) is rarely a complication of chemotherapy.

The degree of suppression of the major cell lines (erythrocytes, white blood cells and platelets) depends on the different effects of the anticancer drugs on the precursor cells (stem cells) and the kinetics of the cell line in the peripheral blood compartment.

A few drugs primarily affect the primitive pluripotential stem cell and cause suppression of all cell lines. These cycle nonspecific drugs, such as nitrosoureas and some alkylating agents (e.g. chlorambucil), prolong the duration of bone marrow suppression more than phase-specific drugs, such as vinca alkaloids and antimetabolites.

Some drugs, such as corticosteroids, bleomycin, colaspase and vincristine, cause little or no myelosuppression. Steroid hormones, e.g. medroxyprogesterone acetate, have some myeloprotective effects. Coagulation abnormalities may follow chemotherapy and the haemolytic uraemic syndrome has been associated with mitomycin, bleomycin, cisplatin, methotrexate and carboplatin.

Neutropenia

The earliest and most common adverse effect is neutropenia as the half life of a granulocyte is only 4-6 hours.

Thrombocytopenia

Certain drugs predominantly produce thrombocytopenia. The timing of this effect is intermediate as platelets have a half life of 5-7 days. However, the nitrosoureas produce a late and severe thrombocytopenia with a nadir 4-6 weeks after treatment. The risk of haemorrhage is significantly increased when platelet counts are below 20 x 10⁹/L and platelet concentrates may be required (in the presence of bleeding, associated sepsis or the use of antiplatelet drugs). Platelets should be given prophylactically if the count is below 10 x 10⁹/L.

Anaemia

Anaemia is a late effect because the half life of erythrocytes is 120 days. This toxicity is usually not dose limiting and often the anaemia is due to the underlying cancer. The peripheral blood smear shows anisocytosis and, occasionally, macrocytosis. The bone marrow may show severe megaloblastic changes, especially after treatment with folic acid antagonists, pyrimidine and purine antagonists and hydroxyurea.

Management of bone marrow toxicity

Supportive care is critical. Infection secondary to neutropenia is a major life threatening complication and should be treated as a medical emergency. The risk is usually proportional to the neutrophil count, the duration of neutropenia and the presence of breaks in the skin or mucosa.

Neutropenic patients frequently present with nonspecific signs and symptoms: unexplained malaise, anorexia, headache, dizziness, vomiting, dyspnoea, diarrhoea, fever, sweating, rigors, cough, sputum, localised discomfort/pain (perirectal skin, recent injection sites and operation sites should be inspected), cyanosis, tachypnoea, tachycardia and hypotension.

Specific signs of a localised infection can be subtle in the absence of neutrophils, especially when analgesics and steroids may mask fever. Infections are usually Gramnegative bacteria, staphylococci or fungi, and can kill rapidly. An immuno compromised patient with a white blood cell count <1.5 x 10⁹/L or neutrophil count <0.5 x 10⁹/L and a fever of 38.2oC or other reasonable suspicion of infection should be investigated. Tests include a chest Xray and cultures of peripheral blood (and from central lines if present), urine and any suspected site of infection. The source of infection cannot be found in at least one third of patients. Empiric treatment with broad spectrum systemic antibiotics should be started within 2 hours. The patient should be in a single room and staff should wash their hands before and after touching the patient. Laminar flow beds and granulocyte transfusions are usually unnecessary.

The haemoglobin should be maintained above 9 g/dL unless symptoms dictate a higher Hb level. Other causes of anaemia such as haemolysis, bleeding and bone marrow replacement by tumour should be excluded.

The use of growth factors such as erythropoietin can ameliorate the anaemia associated with cancer and chemotherapy, and reduces the need for transfusions. Interleukin 1 (IL1) and IL2, and colony stimulating factors (GCSF, GMCSF, MCSF) have been used to stimulate myelopoiesis and granulocyte-macrophage function after chemotherapy. Colony stimulating factors produce a higher absolute granulocyte nadir and may shorten the duration of neutropenia, hospital stay and parenteral antibiotic therapy. However, no change in survival has been shown.

Chemotherapy can exert both direct and indirect effects on the oral mucosa, dental pulp, periapical tissues and periodontium. Dental implications includes a list of toxicities and suggested treatments.

Adverse effects on the skin due to chemotherapy include alopecia, hyper pigmentation, nail disorders, interactions with radiation and ultraviolet light, and extravasation injury.

Most cytotoxic drugs cause alopecia. It usually begins 7-10 days after chemotherapy and may be prominent within 1-2 months of treatment. Regrowth occurs after treatment, but the hair may be a different texture or colour.

Hyper pigmentation is mainly of cosmetic concern and may be from stimulation of melanocytes. It is most commonly due to alkylating agents and antitumour antibiotics. Usually, hyper pigmentation resolves with time, but, in some cases, it may be permanent.

Radiation recall reactions occur when a drug causes an inflammatory reaction in tissue that was previously (usually within weeks, but occasionally up to years) exposed to radiotherapy. These reactions can occur in the skin, lung, gut or heart and are especially associated with dactinomycin and doxorubicin. Reactions to ultraviolet light resemble a severe sunburn and occur especially with fluorouracil and methotrexate.

Acral erythema is sharply-demarcated, tender erythematous plaques on the palms of the hands and the soles of the feet. It can occur with fluorouracil, cytarabine and doxorubicin.

Extravasation

Accidental extravasation occurs in 0.1-6.0% of patients. The consequences vary from mild erythema and discomfort to severe pain, tissue necrosis, skin ulceration and invasion of deep structures such as tendons or joints. The most toxic agents include anthracyclines, nitrogen mustard and the vinca alkaloids. If the patient complains of pain during an infusion, suspect extravasation even if there is no visual evidence. It is unwise for practitioners inexperienced in the use of these drugs to administer intravenous cytotoxics capable of causing tissue necrosis.

Prevention is the optimum management. Chemotherapy should be given by experienced staff through a cannula in the proximal forearm. If venous access is difficult, a central line should be inserted (Portacath or Hickmans). Infusions should not be given distal to the site of a recent vein puncture. The patient should be watched carefully during the infusion, which should be stopped if there is any question of extravasation. If extravasation occurs, attempt to withdraw 3-5 mL of blood, and instil dexamethasone 4 mg before removing the cannula. Then infiltrate hydrocortisone 100 mg subcutaneously, apply a cold compress for an hour, and apply hydrocortisone 1% ointment twice daily until any erythema subsides.

As many young patients are cured of their malignancies, gonadal failure is becoming an important sequel to chemotherapy. It has far reaching effects on interpersonal relationships, self esteem and overall quality of life. However, there is no evidence of increased risk of abortion, genetic diseases, congenital anomalies or malignancy attributable to chemotherapy in children of successfully treated patients.

In Hodgkin's disease, MOPP (mustine, vincristine [Oncovin], prednisolone, procarbazine) damages germinal epithelium. It results in infertility in 85% of males and 25% of females and has a dismal outlook for recovery. In testicular cancer, BEP (bleomycin, etoposide, cisplatin) results in 96% infertility. After 2-3 years, 40% of patients regain fertility.

Although the prepubertal gonad is relatively resistant to cytotoxics, the fertility is still diminished (relative fertility in males 0.69 and females 0.86). Women are more affected by radiotherapy, males by alkylating drugs.

Adjuvant chemotherapy in premenopausal patients with breast cancer (CMF: cyclophosphamide, methotrexate, fluorouracil; and AC: adriamycin, cyclophosphamide) causes early menopause in many patients.

Preventive measures include sperm banking in males, and oocyte and embryo cryopreservation for future in vitro fertilisation in females. If possible, drugs with less gonadal toxicity can be used.

(See also Dental implications)

The following statements are either true or false.

1. Ondansetron prevents vomiting by stimulating serotonin receptors in the gut and in the chemoreceptor trigger zone.

2. In neutropenic septic patients, the source of the infection cannot be found in at least one third of patients.