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Principles of cancer treatment by chemotherapy

Jaishree Bhosle Geoff Hall

Indications for chemotherapy

Palliative most patients receiving chemotherapy have advanced metastatic disease. In these patients, chemotherapy cannot completely eradicate the cancer due to the presence or development of chemotherapy resistance (see below). Palliative chemotherapy can often signicantly improve symptoms and overall quality of life. Palliative chemotherapy improves survival in some cancer types. Clinical trials of palliative chemotherapy focus on improving response rates and overall survival without signicantly increasing toxicity. Curative a number of cancers are extremely sensitive to cytotoxic chemotherapy. Testicular tumours, the lymphomas, acute leukaemias and many paediatric malignancies respond so well that chemotherapy may be curative even in extensive disease. If chemotherapy is given with curative intent, short-term toxi-city is considered more acceptable and, therefore, many of these treatments are extremely toxic (e.g. high-dose chemotherapy (see below)). Current randomized clinical trials aim to reduce toxicity without compromising outcome. Adjuvant many patients may be cured of their disease after surgery or primary radiotherapy, but many others relapse and die due to micro-metastatic disease undetected at diagnosis. Chemotherapy may be an adjunct to primary therapy to kill micrometastases. Adjuvant chemotherapy is used routinely in the treatment of breast cancer. Neoadjuvant chemotherapy should be given before surgery or radiotherapy in some clinical scenarios. The aim of this neoadjuvant therapy is to treat micro-metastases not visible on conventional imaging. It may also reduce the size of the tumour, permitting surgery or allowing a less radical procedure to be done. Examples include neoadjuvant therapy in breast cancer, enabling women to undergo a wide local excision rather than a mastectomy; it is also used routinely in the management of oesophageal cancers and osteosarcomas.

Abstract
This contribution focuses on the indications for chemotherapy, mechanism of action and classication of chemotherapy, chemotherapy resistance, combination versus single-agent chemotherapy, administration of chemotherapy, clinical assessment before chemotherapy, chemotherapy toxicity, and chemotherapy in breast and colorectal cancer.

Keywords adjuvant; cancer treatment; chemotherapy resistance; metastatic disease; myelosuppression; neoadjuvant; performance status

The term chemotherapy refers to the use of drugs to kill or inhibit the growth of cancer cells. Most chemotherapy drugs cause damage to deoxyribonucleic acid (DNA) or prevent chromosomal replication, which leads to programmed cell death (apoptosis). More recently, drugs that inhibit pathways involved in cell growth have been developed. The systemic delivery of chemotherapy ensures that the anti-cancer treatment reaches all disease sites, including micrometastatic lesions, a clear advantage over surgery (see page 70) and radiotherapy (see page 62). The systemic delivery of chemotherapy is also associated with toxicity, which at best is unpleasant and at worst may threaten life. Chemotherapy for solid tumours began in the 1940s with the use of mustard gas for the management of lymphomas. Over the last 60 years, newer cytotoxic drugs that affect the natural progression of a tumour have been developed. Cure is a possibility in a small number of malignancies, such as lymphoma and germ cell tumours, even in advanced disease. Many chemotherapy agents are naturally occurring compounds extracted from bacteria or plants (e.g. the vinca alkaloids vinblastine and vincristine are derived from the periwinkle ower; paclitaxel is derived from the bark of the pacic yew tree). Other drugs are chemicals specically developed for their cytotoxic effects (e.g. cisplatin, developed after the observation that bacteria stopped dividing after exposure to an electric eld produced by platinum electrodes).

Mechanism of action and classication

Most chemotherapy drugs act by reducing the rate of cell growth. This is achieved through an interaction with DNA (leading to damage which cancer cells are relatively inefcient at repairing compared to normal cells) or by interfering with cell division; this prevents further cell division and often leads to the activation of apoptotic pathways. Chemotherapy drugs are grouped according to their mechanism of action (Table 1). Drugs that belong to the same class often have completely different side-effect proles and a different range of anti-tumour efcacy.

Chemotherapy resistance
Primary resistance to chemotherapy occurs if tumours fail to respond to chemotherapy from the start; this may be due to:  biological resistance (e.g. genetic changes within the tumour imparting a resistant phenotype)  physiological resistance (e.g. relative hypoxia found in a tumour deposit, reducing the efcacy of chemotherapy)  pharmacological resistance (e.g. poor penetration of drugs through the bloodbrain barrier or into the testes).
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Jaishree Bhosle MRCP is a Specialist Registrar in Medical Oncology at Cancer Research UK Clinical Centre, Leeds, UK. Conicts of interest: none declared. Geoff Hall FRCP is a Senior Lecturer and Consultant in Medical Oncology at Cancer Research UK Clinical Centre, Leeds, UK. Conicts of interest: none declared.

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Classication of chemotherapy drugs

Alkylating agents Platinums (cisplatin, carboplatin), nitrogen mustard derivatives (chlorambucil, melphalan), oxazophosphorines (cyclophosphamide, ifosfamide). Pyrimidine analogues (gemcitabine, 5-uorouracil, capecitabine), anti-folates (methotrexate, raltitrexed) Vinca alkaoids (vincristine, vinorelbine), taxanes (paclitaxel, docetaxel) Topoisomerase-I inhibitors (irinotecan, topotecan), topoisomerase-II inhibitors (etopside) Anthracyclines (doxorubicin, epirubicin), bleomycin, mitoxantrone

Combination chemotherapy is central to the management of tumours in which chemotherapy is given with curative intent such as lymphomas, germ cell tumours, and many paediatric cancers. In many other cancer types, combination chemotherapy is superior with regard to response rates when compared to single agents. This may not result in improvements in progressionfree or overall survival, suggesting the sequential use of single agents may be more appropriate.

Anti-metabolites

High-dose chemotherapy
The maximum dose of many chemotherapy drugs is limited by haematological toxicity. Higher doses of chemotherapy used without haematological support lead to prolonged periods of myelosuppression or total ablation of bone marrow, and are associated with high rates of neutropenic infection and death. Haematological support may be achieved using growth factors (e.g. granulocyte colony-stimulating factor) or transplant of bone marrow or stem cells. Growth factors such as granulocyte colony-stimulating factor allow only modest increases in dose. Bone marrow or stem cells obtained from the patient (autologous) or a matched donor (allogeneic) and given after chemotherapy can repopulate the marrow within three to four weeks. Reducing the duration of profound neutropenia in this way signicantly reduces (but does not eradicate) the risk of life-threatening infection and allows signicant escalation of dose. High-dose chemotherapy is used in the management of acute leukaemias, lymphomas and germ cell tumours that have failed to respond to conventional chemotherapy. High-dose regimens have also been assessed in a number of solid tumours (e.g. breast), but have not improved outcomes and are considered experimental.

Mitotic inhibitors

Topoisomerase inhibitors

Anti-tumour antibiotics

Table 1

Primary resistance may also reect inadequate dosing, an inappropriate route of administration or poor compliance. Secondary (acquired) resistance to chemotherapy follows exposure of cells to chemotherapy. The mechanisms by which tumour cells become resistant to chemotherapy reect physiological processes required by normal cells or tissues to handle toxic metabolites or substances. Tumour cells that develop this phenotype gain a survival advantage with chemotherapy over other clones within the tumour and become dominant. A variety of mechanisms of acquired resistance to drugs are recognized, including:  a reduction in drug uptake or activation  an increase in drug inactivation alterations in DNA repair mechanisms.  Increased extrusion of drug from cells due to expression of the membrane pump P-glycoprotein is associated with resistance to a wide range of naturally occurring cytotoxic agents (e.g. doxorubicin, vincristine, paclitaxel, etoposide). This is a relatively common cause of drug resistance and is known as the multi-drug resistance phenotype.

Administration of chemotherapy
Chemotherapy is often given on a cyclical basis (e.g. every two, three or four weeks) so that normal tissues can recover. The cells typically affected include the haematopoietic stem cells and gut lining, producing myelosuppression and mucositis, respectively. Most chemotherapy regimens involve 1824 weeks of treatment; extending treatment beyond this period is usually associated with increasing toxicity with no additional benet. Chemotherapy is usually given intravenously. There has, however, been considerable progress with the development of active oral chemotherapy drugs with stable and predictable pharmacokinetics. These are used in the management of several solid tumours eg. breast, colon and prostate. Most rst-line chemotherapy is given via a peripheral cannula, taking special care before injection to ensure correct placement of the cannula to avoid extravasation and tissue damage. Patients with poor venous access, those receiving prolonged infusions or weekly chemotherapy may have a central catheter placed into the jugular or subclavian veins (e.g. Hickman or Groshong catheters) or peripherally (e.g. peripherally inserted central catheter i.e. PICC Line).

Combination versus single-agent chemotherapy

Many tumours may respond to a single chemotherapy drug, but such therapy is rarely curative, even in highly sensitive cancers. The simultaneous use of two or more chemotherapy drugs aims to improve outcome by maximizing the tumour cell kill while minimizing the development of drug resistance. In general, the combinations are designed to satisfy several broad principles. Each of the drugs used within a regimen should have efcacy as a single agent and should ideally be used at its optimal dose and using a standard schedule. Drugs with different toxicities are often combined to prevent additive toxicity; the combination of drugs with similar toxicities leads to compromises in dose and hence efcacy.
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Clinical assessment before chemotherapy

Clinical review is necessary before each cycle of chemotherapy. This should assess the toxicity of the previous cycle, performance status (Table 2) and ensure that there is no clinical evidence of

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Eastern Cooperative Oncology Group Performance Status

0  Fully active, able to carry on all pre-disease performance without restriction 1 Restricted in physically strenuous activity, but ambulatory and able to carry out work of a light or sedentary nature (e.g. light housework, ofce work) 2 Ambulatory and capable of all self-care, but unable to carry out any work activities. Up and about >50% of waking hours 3  Capable of only limited self-care, conned to bed or chair >50% of waking hours 4  Completely disabled. Cannot carry on any self-care. Totally conned to bed or chair 5 Dead
Karnofsky and WHO performance scales can also be used.

Table 2

disease progression, which would make further chemotherapy inappropriate. Performance status is one of the key determinants of chemotherapy tolerability. Patients with a poor performance status usually receive chemotherapy only if they have a chance of cure (e.g. lymphomas, germ cell tumours) or a highly chemotherapysensitive tumour (e.g. small-cell lung cancer). The decision to continue with chemotherapy should be carefully reviewed if there is a progressive deterioration in performance status while receiving chemotherapy. Care must be taken to distinguish a fall in performance status due to disease progression from that due to chemotherapy toxicity, where dose reductions or other supportive measures may be appropriate. Assessment of response clinical examination should be done with each cycle and should include measurement of clinically evaluable disease using callipers or tape-measures where appropriate. Routine blood tests (including full blood count, tests of renal and hepatic function) may show changes that reect a response to chemotherapy. Measuring specic tumour markers (e.g. -fetoprotein, -human chorionic gonadotropin, cancer antigen125, carcinoembryonic protein, lactate dehydrogenase) with each cycle of chemotherapy often provides evidence of response or progression. A chest radiograph may also be done to monitor response to treatment. A combination of clinical assessment and measurement of tumour markers usually provides an accurate assessment of response. A more formal assessment of response, required in many clinical trials, and frequently done in routine clinical practice to accurately dene the degree of response, is cross-sectional imaging using CT or MRI. In clinical trials, internationally agreed standards (e.g. Response Evaluation Criteria in Solid Tumours, WHO) dene response and allow direct comparison of results from different centres.

Chemotherapy toxicity
Chemotherapy is associated with a wide variety of side effects. Each of these are graded as 1 (mild), 2 (moderate), 3 (severe),
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4 (life-threatening) or 5 (death) according to an internationally agreed standard (Common Terminology Criteria for Adverse Events, Table 3). The development of signicant toxicity usually results in a change in supportive care (better antiemetics), dose reduction or discontinuation of the chemotherapy regimen. Nausea and vomiting are probably the most feared side effects of chemotherapy by patients. Antiemetics (e.g. metoclopramide, dexamethasone) are given intravenously routinely before chemotherapy. Additional oral antiemetics are given to ease symptoms over the next 57 days. The 5-hydrotryptamine-3 antagonists (ondansetron, granisetron) are given to patients in whom standard antiemetics fail or those receiving highly emetogenic drugs (e.g. cisplatin, doxorubicin). Before their introduction, many of these patients experienced intolerable vomiting, requiring sedation, hence they are one of the most signicant advances in cancer care in the last 20 years. Myelosupression after chemotherapy, the blood count drops to its lowest point about 1014 days later (depending on the drugs and cycle length). Severe neutropenia (neutrophils <1.0 109/l) associated with an infection is a serious and potentially life-threatening risk. Patients must be carefully counselled of the need to contact the Cancer Unit immediately if they develop signs of an infection, particularly a temperature of >38 C, for immediate admission to hospital and adminstration of broad-spectrum antibiotics. Severe neutropenia is often an indication for dose modication with subsequent cycles of treatment; growth factors such as granulocyte colony-stimulating factor may be used to maintain dose intensity if treatment is given with curative intent (e.g. adjuvant chemotherapy for breast cancer). Signicant anaemia (Hb <10 g/dl) is managed with blood transfusions or recombinant erythropoietin. Severe thrombocytopenia (platelets <10 109/l) requires immediate platelet transfusion. Platelet counts less severely affected require transfusion in active bleeding or concurrent infection. Platelet counts of > 50 109/l are rarely associated with clinical problems. Gastrointestinal the epithelium covering the entire gastrointestinal tract is rapidly dividing, and thus is highly susceptible to chemotherapy. Patients may complain of soreness of the mouth due to ulceration or oral candida: this can be severe and affect oral intake. Diarrhoea or constipation is common. Alopecia many chemotherapy agents result in total alopecia, although hair usually starts to regrow within weeks of stopping chemotherapy. The provision of wigs may ease the distress felt by many patients. Scalp cooling may reduce the delivery of chemotherapy to the hair follicles and may signicantly reduce the severity of hair loss. Neurological many drugs can cause a peripheral neuropathy that may require dose reduction or a discontinuation of treatment. Vinca alkaloids can cause an autonomic neuropathy which can be present as a late effect of chemotherapy. Cisplatin results in high-tone hearing loss and tinnitus, which often improves after stopping the drug. Genitourinary platinum chemotherapy drugs are excreted by the kidneys, and require adequate renal function to be excreted efciently; many of these drugs can affect renal function. Renal function must be checked before each treatment. Cyclophosphamide can cause haemorrhagic cystitis, which can be quite severe.

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Criteria for adverse events

Grade 1 Fatigue Nausea Mild fatigue over baseline Loss of appetite without alteration in eating habits Grade 2 Moderate fatigue or causing difculty in doing ADL Oral intake decreased without signicant weight loss, dehydration or malnutrition: i.v. uids indicated for <24 hours 25 episodes in 24 hours: i.v. uids indicated for <24 hours Patchy ulcerations or pseudomembranes Grade 3 Severe fatigue interfering with ADL Inadequate oral caloric or uid intake; i.v. uids, tube feeding or TPN for 24 hours or more 6 or more episodes in 24 hours: i.v. uids or TPN indicated for 24 hours or more Conuent ulcerations or pseudomembranes; bleeding with minor trauma Present Grade 4 Disabling fatigue Life-threatening consequences

Vomiting

1 episode in 24 hours

Life-threatening consequences

Mucositis

Erythema of the mucosa

Febrile neutropenia

Haemoglobin Neutrophils Platelets

<LLN to 10 g/dl <LLN to 1.5109/l <LLN to 75.0109/l

<10 to 8.0 g/dl <1.5 to 1.0109/l <75.0 to 50.0109/l

<8.0 to 6.5 g/dl <1.0 to 0.5109/l <50.0 to 25.0109/l

Tissue necrosis; signicant spontaneous bleeding; lifethreatening consequences Life-threatening consequences (e.g. septic shock) <6.5 g/dl <0.5109/l <25.0109/l

LLN: Lower limit of normal; ADL: Activities of daily living; TPN: Total parenteral nutrition. Source: www.ctep.cancer.gov.

Table 3

Hepatic many drugs require adequate liver function to be metabolized. Some chemotherapy agents can transiently affect liver enzymes. Myopathy paclitaxel commonly causes myalgia and generalized arthralgia. Lethargy most chemotherapy drugs cause lethargy independently of any anaemia they may cause. Cardiac 5-uorouracil can cause coronary artery spasm, resulting in cardiac ischaemia. This drug is avoided in patients with uncontrolled angina. Anthracycline drugs (e.g. doxorubicin) can affect cardiac function. Left ventricular function must be measured before and during treatment in patients with a cardiac history. Infertility many chemotherapy agents can impair fertility to some extent. Infertility caused by chemotherapy is unusual and, in general, is associated with alkylating agents (particularly in high-dose regimens). Sperm donation is routinely offered to young men undergoing chemotherapy for haematological malignancies or germ-cell tumours. Secondary malignancies many chemotherapy agents can induce a second malignancy. Leukaemias tend to occur after a few years with solid tumours (e.g. sarcomas) occurring many years later.

and cyclophosphamide given as six cycles every three weeks achieves a 2038% reduction in the risk of death. Chemotherapy is used in addition to hormone therapy (see page 59) in patients with hormone receptor-positive tumours. The appropriate use of chemotherapy in combination with hormones and radiotherapy has approximately halved the risk of death from breast cancer. Neoadjuvant chemotherapy (e.g. epirubicin/cyclophosphamide) may be given to women with large tumours in whom a mastectomy would otherwise be required. About 25% of women who were initially thought require a mastectomy achieved sufcient response to chemotherapy to undergo breast-conservation surgery instead. Metastatic disease a number of chemotherapy drugs and hormonal agents can be used in patients with metastatic disease. The drug chosen depends upon:  the site of disease  the rate of progression  previous responses to chemotherapy or endocrine treatment  the function of the liver and bone marrow  patient preference. On average, patients with metastatic breast cancer live for 1824 months with treatment; those achieving very good, prolonged responses to treatment may improve their survival signicantly. Colorectal cancer Neoadjuvant chemotherapy is routinely used in patients with potentially operable liver metastases. A combination of oxaliplatin and 5-uorouracil produces response rates of about 40%, with about 20% of patients becoming operable.
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Chemotherapy in breast and colorectal cancer

Breast cancer Adjuvant chemotherapy for breast cancer is well established. Combination chemotherapy such as 5-uorouracil, epirubicin

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Adjuvant chemotherapy with six months of 5-uorouracil and folinic acid is the standard regimen in patients with stage III disease. Adjuvant chemotherapy provides a 2230% reduction in mortality at 5 years; the number needed to treat is 1:10 (i.e. for every ten patients treated, one patient is saved from developing recurrence within 5 years).

Metastatic disease the aim of chemotherapy in the metastatic setting is to palliate symptoms and prolong survival. Median survival with rst- and second-line chemotherapy is about 1820 months. Oxaliplatin or irinotecan in combination with 5-uorouracil are used in the rst- and second-line settings, depending on the chemotherapy the patient has already received.

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