Summary

With advances in chemotherapy agents and bone marrow support, more cancer patients are indicated for curative or palliative chemotherapy. Family physicians should know about the indications and side effects, so that early referral for treatment can be made and side effects can be managed while the patient is in the community. The benefits of chemotherapy in palliative medicine and the management of common side effects are discussed.

摘要

隨著化療藥物的進步和骨髓支持治療的發展，更 多癌症病人通過治療性或姑息性化療，可以痊癒或減輕症狀。家庭醫生應當了解化療的適應症及副作用，以便及早轉介，並且治療非住院病人，與化療相關的副作用。本文討論姑息性化療的好處以及常見副作用的處理。

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Introduction

Chemotherapy was once regarded as an often futile and always dangerous type of therapy by both the public and professionals. The cost is also considered together with the benefit versus risk ratio. However, it has been shown that the comfort of many patients can be enhanced following chemotherapy, provided that the toxic side-effects do not significantly impair health-related quality of life.

Apart from the haematological malignancies such as leukaemia, lymphoma and myeloma, as well as the malignancies which have been long known to be chemosensitive such as small cell lung cancer, more and more malignant conditions are now indicated for chemotherapy because of the availability of many new agents in recent years. With the advances in bone marrow support, chemotherapeutic agents are used in higher dosage and for longer time. This results in a higher incidence of side effects.

Family doctors need to know about its palliative indications so that patients can be referred appropriately. More and more patients are staying in the community while undergoing chemotherapy, whether for curative treatment or for palliation, family physicians need to know about its side effects and their proper treatment.

Benefits

Patients with poor performance status fare badly in chemotherapy trials; response rates are reduced, the usefulness of a response is usually minimal in comparison to toxicity, and the length of response is reduced.¹ They cannot tolerate high doses of chemotherapy. Therefore, patients considered for chemotherapy with any tumour type should receive treatment before they are severely limited by disease.

Symptom relief

It has been shown that chemotherapy can increase survival in only a few tumours like small cell lung cancer and ovarian cancer. In palliative care, improvement in symptoms and quality of life are usually the principal aims of therapy. However, patients and family may over-estimate the life-prolonging benefits of chemotherapy and relate its use to hopes for cure or prolonged survival.

Patients may express more concern about chemotherapy-induced symptoms than about the ultimate effect of the cancer.² However, it has been shown that chemotherapy-induced symptoms were less disruptive to quality of life than were the effects of the cancer itself.³

It reduces pain by a rapid release of pressure and its effect on the inflammatory and immune mediators as well as the central and peripheral neurotransmitter system. It is particularly effective for bone metastases of breast and small cell lung cancer. Pain relief is usually obvious within several days of initiation of therapy, well before tumour regression has occurred.^4,5 It is possible that the chemotherapy interferes with chemical mediators of pain.⁶

Women with advanced breast cancer are candidates for systemic therapy. Patients who have had prior chemotherapy may still benefit from another course of alternate treatment.⁷ Continue chemotherapy if symptom relief is noted and side-effects are tolerable, even if the disease is stable or progressive.⁸ Therapy should start when symptoms occur and while the patient has a good performance status.

It can improve symptoms and quality of life in superior vena cava obstruction, spinal cord compression, bronchial obstruction and hypercalcaemia. It also reduces tenesmus in rectal cancer and reduces lymphoedema in some patients.

Bleeding and fungation

It can help in controlling bleeding and fungation of breast cancer. It can also control haemoptysis, haematuria and rectal bleeding.

Psychological benefits

At the desperate stage, the use of chemotherapy may also improve the patient and his family's psychological well being because something is being done. Positive placebo effect is worthwhile only if the cost is reasonable and side effects minimal. However, it should not be the main indication for using chemotherapy.

Side effects and their management

Chemotherapy has well-known, acute, but often self-limited, adverse effects. Chemotherapy with a high symptom-inducing capacity, given frequently, may do more harm than good.⁹ It has been recommended that chemotherapy for non-small cell lung cancer in general be discontinued after four to eight cycles of treatment.¹⁰ The symptom response may be maintained long after chemotherapy has been discontinued.⁸ However, the major source of deterioration in quality of life in symptomatic cancer is likely to be the cancer itself rather than the chemotherapy for the cancer.

Some side-effects are common to all chemo-therapeutic agents. Each agent has its own specific side-effects which are not to be discussed one by one here.

Bone marrow failure

It is the most well known side-effect. It disturbs the rapid turnover of haematopoiesis temporarily. However, repeated cycles may produce a cumulative effect in some patients. Some agents have profound, long-standing marrow depression.¹¹ Full blood count (FBC) should be measured before each chemotherapy treatment. If white blood cell (WBC) or platelet count is low, treatment should be delayed for a week or two.

Neutropenia

Because of its short half life, WBC lowers most rapidly. Maximum depression (nadir) occurs at about 2 weeks from day 1 of therapy. The patient becomes at risk of bacterial infection. Bacterial septicaemia especially may occur if the neutrophil count is <1.0. The patient may die within hours of onset of fever. Anyone undergoing or soon after chemotherapy, who develops fever or other signs of infection should be assessed in hospital with FBC for WBC count, mid-stream urine culture, chest x-ray, sputum culture and blood culture. Intravenous antibiotics (Timentin with gentamycin or ceftazidine alone) should be given while waiting for the culture results. Appropriate antibiotics should be given for at least 5 days followed by 2 weeks of broad spectrum oral antibiotics such as Augmentin or ciprofloxacin.

Anaemia

Anaemia can be caused by cancer, bleeding and chemotherapy. Transfusion is indicated only if the haemoglobin is less than 10gm/litre and the patient has symptoms such as dyspnoea, dizziness or syncopy.

Thrombocytopaenia

Most patients are asymptomatic if the platelet count is greater than 40 10⁹/litre. Whether platelet transfusion is indicated depends on the patients condition.

Hair loss

It may be the most concerning side effect for all patients, not only for women. Use of head scarves and wigs is highly recommended. The patient can be reassured that hair will regrow with time. However, very often, if the chemotherapy has been used for palliation, the patient normally dies before the hair regrows.

Gastrointestinal (GI) complications

Desquamation of GI mucosa causes extremely painful oropharyngeal-oesophageal ulceration, abdominal pain and diarrhoea. These can prevent any oral intake. This is one of the very few indications for total parenteral nutrition in palliative care.

Mucositis

Mucositis is caused by the cytotoxic effect of the chemotherapeutic agents in blood and saliva on the rapidly multiplying oral epithelium, and/or by secondary infection. The patient commonly presents with sore mouth and halitosis. There may be painful ulcers on the mucosa, tongue and gum. The gum and tongue may be swollen and bleed easily. Oral candidiasis is common as the primary or secondary infection. Concurrent liberal use of antifungal is helpful. Herpes simplex infection or reactivation is commonly seen in severely immunocompromised patients, e.g. leukaemia, AIDs, following chemotherapy and bone-marrow transplantation. It usually appears more than two weeks after the start of chemotherapy. It can occur on all mucosal surfaces, but more commonly on the hard palate and gingiva. It appears as vesicles which rupture to form small and large ulcers with haemorrhage or pseudomembranes.

Management

Good oral hygiene is essential. Give soft and liquid diet. Chlorhexidine mouthwash can be given after food and mouth cleansing.¹² It has both antibacterial and antifungal effects.

If oral candidiasis is present, give an oral antifungal suspension such as nystatin oral suspension 1ml or miconazole oral gel one teaspoonful four times a day after food. Amphotericin lozenges can be sucked in mouth four times a day. However, it is not suitable if the patient has dry mouth. Systematic treatment such as oral ketoconazole and fluconazole may be indicated in severe cases and those with oesophageal candidiasis.¹³

Coating agents such as sucralfate suspension or 2 tablets crushed with 10ml water forming a liquid paste can be taken without water 15 minutes before food. It protects the painful ulcers.

With severe pain, one teaspoon Xylocaine viscous 2% gel can be retained in mouth for 30 seconds 3-4 hourly. It can be swallowed if painful oesophagitis is also present. Do not give any food within 60 minutes because of risk of aspiration. If the patient cannot tolerate oral medication, parenteral opioid may be necessary. Non-steroidal anti-inflammatory drugs can be given as suppository to reduce inflammation and pain. However, avoid if the patient also has a low platelet count from chemotherapy. Combination of coating agent and xylocaine can be used if necessary.

Mucositis tends to improve when the white cell count improves in 1-2 weeks. Oral systemic analgesics such as opioids and NSAIDs can then be used. The local anaesthetics can then be tapered off.

Systemic antibiotic can be given for infection. Anti-viral agents such as acyclovir can be given orally or parenterally for viral infection.

Nausea and vomiting

An intravenous or oral 5HT₃ antagonist is commonly given before the administration of chemotherapeutic agent, followed by oral agents or subcutaneous infusion. However, nausea and vomiting may still occur at home more than 24 hours after therapy. It significantly decreases the quality of life of the patient.¹⁴

If oral medication cannot be tolerated, it can be controlled with intravenous anti-emetics, in combination or alone. Metoclopramide (Maxolon), a dopamine antagonist acting on the chemoreceptor trigger zone, can be given four hourly in a high dosage (10-20mg).¹⁵ Alternatively, prochlorperazine (Stemetil) 12.5-25mg can be given intramuscularly or rectally four hourly.¹⁶ However, it is weaker than metoclopramide and has more extra-pyramidal side-effects. Rectal absorption is unreliable. Dexamethasone, in a high dosage of 8-20mg, also has an effect on the nausea and vomiting caused by chemotherapy. Lorazepam (Ativan) 1-2mg can be given orally, sublingually or intravenously once or twice a day.

If the symptom is severe, use 5HT₃ antagonists which have specific effect for nausea and vomiting caused by chemotherapy and radiotherapy. Ondansetron, tropisetron or dolasetron mesylate can be given either as slow intravenous bolus or as continuous subcutaneous infusion via syringe driver. Ondansetron is also available in the form of wafer tablets which melt on the tongue. However, these 5HT₃ antagonists are quite expensive.

Dexamethasone is very effective to help controlling vomiting in the week following chemotherapy. A combination of 5HT₃ antagonist and dexamethasone can completely abrogate chemotherapy-induced emesis in nearly half of patients, even after highly emetogenic chemotherapy such as high dose cisplatin.¹⁷

Control of nausea and vomiting can be maintained by oral administration of metoclopramide 10-20mg six hourly or prochlorperazine 10mg (two tablets) six hourly. Oral tablets of ondansetron, tropisetron and dolasetron can also be used for maintenance.

Abdominal pain

The spastic abdominal pain may be quite severe. It usually responds to anticholinergics like hyoscine butylbromide (Buscopan) 20mg tds orally or intramuscularly.

Diarrhoea

Diarrhoea can range from mild to extremely severe. Fluid and electrolyte replacement is mandatory. Oral replacement is preferrable if tolerated. If necessary, try regular loperamide. Diphenoxylate with atropine (Lomotil) can worsen dry mouth.¹⁸ Opioid that the patient is already on may help in controlling diarrhoea.

In very severe cases, give octreotide (Sandostatin) 0.1-0.3mg/24 hour as eight hourly bolus subcutaneous injections at a maximum dose of 1.5mg/24 hour. The patient may need blood transfusion for blood loss. Diarrhoea tends to resolve in 1-2 weeks as the white cell count improves.

Urinary complications

Renal toxicity especially occurs in cisplatinum based chemotherapy. The patient must take a large amount of water to reduce the concentration of the agent in the renal tubules. They are more toxic in elderly patients.

Haemorrhagic cystitis is more common with cyclophosphamide treatment. Patients should take more water to prevent obstruction of the urethra. They may need transfusion if blood loss is severe.

Neurotoxicity

There has been an increase in symptomatic neuromyopathy in recent years because higher doses of nerve damaging drugs are made possible by advances in bone marrow support. They especially occur with cisplatin, vincristine, paclitaxel and cytokines. However, the symptoms can be part of the paraneoplastic syndrome caused by cancer itself¹⁹ or the comorbid neuropathies in elderly diabetic or alcoholic patients.

They can cause peripheral neuropathy, myalgia and arthralgia such as jaw pain. Peripheral neuropathy can present as painful paraesthesias and hyporeflexia and less commonly motor and sensory loss or autonomic dysfunction. Pain occurs in the hands and feet, with a burning sensation and is exacerbated with cutaneous stimulation. In some patients, hyperesthesia and autonomic change may be severe.

Some neuropathies have slow and incomplete recovery, while in others, these usually reverse when the therapy is stopped. No definitive treatment is necessary except for neuropathic pain. Sympathetic blocks may be indicated.

Cardiomyopathy

Congestive heart failure is associated with anthrocycline and high dose cyclophosphamide therapy. It is usually reversed after discontinuation of therapy. The treatment is similar to that for heart failure from other causes.

Conclusion

Chemotherapy has an important place in the palliative care of terminal cancer patients. Early recognition and treatment of its side-effects can greatly improve the quality of life of the patients.

Key messages

1. Chemotherapy is a treatment module possible for palliative care patients. Its main aim is to improve the quality of life.
2. The improvement of quality of life is greatest in those who have good performance status when they start chemotherapy. Hence, early referral is important.
3. The main source of deterioration in quality of life in symptomatic cancer is likely to be the cancer itself rather than the chemotherapy for the cancer.
4. Most of the side-effects of chemotherapy can be relieved with appropriate management and many of them are reversible after discontinuation of therapy.

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References