CANcER TREAtMENt

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 significantly 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 significantly 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 classification 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 flower; paclitaxel is derived from the bark of the pacific yew tree). Other drugs are chemicals specifically developed for their cytotoxic effects (e.g. cisplatin, developed after the observation that bacteria stopped dividing after exposure to an electric field produced by platinum electrodes).

Mechanism of action and classification
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 inefficient 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 profiles and a different range of anti-tumour efficacy.

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 efficacy of chemotherapy) •  pharmacological resistance (e.g. poor penetration of drugs through the blood–brain barrier or into the testes).
173

Jaishree Bhosle MRCP is a Specialist Registrar in Medical Oncology at Cancer Research UK Clinical Centre, Leeds, UK. Conflicts of interest: none declared. Geoff Hall FRCP is a Senior Lecturer and Consultant in Medical Oncology at Cancer Research UK Clinical Centre, Leeds, UK. Conflicts of interest: none declared.

SURGERY 27:4

© 2009 Published by Elsevier Ltd.

The mechanisms by which tumour cells become resistant to chemotherapy reflect physiological processes required by normal cells or tissues to handle toxic metabolites or substances. oxazophosphorines (cyclophosphamide. PICC Line). 174 Clinical assessment before chemotherapy Clinical review is necessary before each cycle of chemotherapy. anti-folates (methotrexate. Mitotic inhibitors Topoisomerase inhibitors Anti-tumour antibiotics Table 1 Primary resistance may also reflect inadequate dosing. etoposide). Hickman or Groshong catheters) or peripherally (e. respectively. doxorubicin. In general. Anti-metabolites High-dose chemotherapy The maximum dose of many chemotherapy drugs is limited by haematological toxicity. raltitrexed) Vinca alkaoids (vincristine. breast). 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.g. This may not result in improvements in progressionfree or overall survival. Combination versus single-agent chemotherapy Many tumours may respond to a single chemotherapy drug. . breast. an inappropriate route of administration or poor compliance. Chemotherapy is usually given intravenously. High-dose regimens have also been assessed in a number of solid tumours (e. but such therapy is rarely curative. These are used in the management of several solid tumours eg. three or four weeks) so that normal tissues can recover. 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. carboplatin). combination chemotherapy is superior with regard to response rates when compared to single agents. suggesting the sequential use of single agents may be more appropriate. Pyrimidine analogues (gemcitabine. lymphomas and germ cell tumours that have failed to respond to conventional chemotherapy.g. epirubicin). germ cell tumours. Secondary (acquired) resistance to chemotherapy follows exposure of cells to chemotherapy.CANcER TREAtMENt Classification of chemotherapy drugs Alkylating agents Platinums (cisplatin. • Each of the drugs used within a regimen should have efficacy as a single agent and should ideally be used at its optimal dose and using a standard schedule. granulocyte colony-stimulating factor) or transplant of bone marrow or stem cells. The cells typically affected include the haematopoietic stem cells and gut lining.g. peripherally inserted central catheter i. including: •  a reduction in drug uptake or activation •  an increase in drug inactivation alterations in DNA repair mechanisms. however. mitoxantrone Combination chemotherapy is central to the management of tumours in which chemotherapy is given with curative intent such as lymphomas. colon and prostate. melphalan). Reducing the duration of profound neutropenia in this way significantly reduces (but does not eradicate) the risk of life-threatening infection and allows significant escalation of dose. bleomycin. A variety of mechanisms of acquired resistance to drugs are recognized. Patients with poor venous access. Haematological support may be achieved using growth factors (e.g. Tumour cells that develop this phenotype gain a survival advantage with chemotherapy over other clones within the tumour and become dominant. topotecan). been considerable progress with the development of active oral chemotherapy drugs with stable and predictable pharmacokinetics. every two. capecitabine). the combination of drugs with similar toxicities leads to compromises in dose and hence efficacy. and are associated with high rates of neutropenic infection and death. but have not improved outcomes and are considered experimental. producing myelosuppression and mucositis. even in highly sensitive cancers.g. nitrogen mustard derivatives (chlorambucil. taxanes (paclitaxel. performance status (Table 2) and ensure that there is no clinical evidence of SURGERY 27:4 © 2009 Published by Elsevier Ltd. docetaxel) Topoisomerase-I inhibitors (irinotecan. This should assess the toxicity of the previous cycle. Growth factors such as granulocyte colony-stimulating factor allow only modest increases in dose. • Drugs with different toxicities are often combined to prevent additive toxicity. those receiving prolonged infusions or weekly chemotherapy may have a central catheter placed into the jugular or subclavian veins (e. extending treatment beyond this period is usually associated with increasing toxicity with no additional benefit.g. •  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. vinorelbine). This is a relatively common cause of drug resistance and is known as the ‘multi-drug resistance phenotype’. In many other cancer types. paclitaxel. topoisomerase-II inhibitors (etopside) Anthracyclines (doxorubicin.e. Most first-line chemotherapy is given via a peripheral cannula. the combinations are designed to satisfy several broad principles. There has. Higher doses of chemotherapy used without haematological support lead to prolonged periods of myelosuppression or total ablation of bone marrow. vincristine. Most chemotherapy regimens involve 18–24 weeks of treatment. Administration of chemotherapy Chemotherapy is often given on a cyclical basis (e. ifosfamide). High-dose chemotherapy is used in the management of acute leukaemias. taking special care before injection to ensure correct placement of the cannula to avoid extravasation and tissue damage. 5-fluorouracil. and many paediatric cancers.

Each of these are graded as 1 (mild).g. β-human chorionic gonadotropin. which can be quite severe. 2 (moderate). small-cell lung cancer). SURGERY 27:4 © 2009 Published by Elsevier Ltd. The development of significant toxicity usually results in a change in supportive care (better antiemetics). is cross-sectional imaging using CT or MRI. Cannot carry on any self-care. Nausea and vomiting are probably the most feared side effects of chemotherapy by patients. requiring sedation. Renal function must be checked before each treatment. but ambulatory and able to carry out work of a light or sedentary nature (e. adjuvant chemotherapy for breast cancer). where dose reductions or other supportive measures may be appropriate. lactate dehydrogenase) with each cycle of chemotherapy often provides evidence of response or progression. Table 3).g. Response Evaluation Criteria in Solid Tumours. Antiemetics (e. Severe thrombocytopenia (platelets <10 × 109/l) requires immediate platelet transfusion. confined to bed or chair >50% of waking hours 4  Completely disabled. Significant anaemia (Hb <10 g/dl) is managed with blood transfusions or recombinant erythropoietin. doxorubicin). Chemotherapy toxicity Chemotherapy is associated with a wide variety of side effects. Totally confined to bed or chair 5 Dead Karnofsky and WHO performance scales can also be used. The provision of wigs may ease the distress felt by many patients. Severe neutropenia (neutrophils <1. A more formal assessment of response.g. Patients may complain of soreness of the mouth due to ulceration or oral candida: this can be severe and affect oral intake. granisetron) are given to patients in whom standard antiemetics fail or those receiving highly emetogenic drugs (e. required in many clinical trials. Cyclophosphamide can cause haemorrhagic cystitis. growth factors such as granulocyte colony-stimulating factor may be used to maintain dose intensity if treatment is given with curative intent (e. carcinoembryonic protein. which would make further chemotherapy inappropriate. although hair usually starts to regrow within weeks of stopping chemotherapy. Severe neutropenia is often an indication for dose modification with subsequent cycles of treatment.g.g.g. A chest radiograph may also be done to monitor response to treatment. for immediate admission to hospital and adminstration of broad-spectrum antibiotics. Scalp cooling may reduce the delivery of chemotherapy to the hair follicles and may significantly reduce the severity of hair loss. and require adequate renal function to be excreted efficiently. dose reduction or discontinuation of the chemotherapy regimen. many of these patients experienced intolerable vomiting. Vinca alkaloids can cause an autonomic neuropathy which can be present as a late effect of chemotherapy. Neurological – many drugs can cause a peripheral neuropathy that may require dose reduction or a discontinuation of treatment. Platelet counts of > 50 × 109/l are rarely associated with clinical problems. cisplatin. and thus is highly susceptible to chemotherapy. particularly a temperature of >38 °C. and frequently done in routine clinical practice to accurately define the degree of response. Alopecia – many chemotherapy agents result in total alopecia. Additional oral antiemetics are given to ease symptoms over the next 5–7 days.0 × 109/l) associated with an infection is a serious and potentially life-threatening risk. Routine blood tests (including full blood count. office work) 2 Ambulatory and capable of all self-care. Before their introduction. hence they are one of the most significant advances in cancer care in the last 20 years. dexamethasone) are given intravenously routinely before chemotherapy. many of these drugs can affect renal function. 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.g. Diarrhoea or constipation is common. tests of renal and hepatic function) may show changes that reflect a response to chemotherapy. germ cell tumours) or a highly chemotherapysensitive tumour (e. α-fetoprotein.CANcER TREAtMENt Eastern Cooperative Oncology Group Performance Status 0  Fully active. Care must be taken to distinguish a fall in performance status due to disease progression from that due to chemotherapy toxicity. Patients with a poor performance status usually receive chemotherapy only if they have a chance of cure (e. In clinical trials. A combination of clinical assessment and measurement of tumour markers usually provides an accurate assessment of response. Gastrointestinal – the epithelium covering the entire gastrointestinal tract is rapidly dividing. WHO) define response and allow direct comparison of results from different centres. lymphomas. light housework. able to carry on all pre-disease performance without restriction 1 Restricted in physically strenuous activity. which often improves after stopping the drug. The 5-hydrotryptamine-3 antagonists (ondansetron. Genitourinary – platinum chemotherapy drugs are excreted by the kidneys. Table 2 disease progression. internationally agreed standards (e. the blood count drops to its lowest point about 10–14 days later (depending on the drugs and cycle length). 3 (severe). metoclopramide. Up and about >50% of waking hours 3  Capable of only limited self-care. Patients must be carefully counselled of the need to contact the Cancer Unit immediately if they develop signs of an infection. Performance status is one of the key determinants of chemotherapy tolerability. but unable to carry out any work activities. The decision to continue with chemotherapy should be carefully reviewed if there is a progressive deterioration in performance status while receiving chemotherapy.g. Myelosupression – after chemotherapy. Platelet counts less severely affected require ­transfusion in active bleeding or concurrent infection. 175 4 (life-threatening) or 5 (death) according to an internationally agreed standard (Common Terminology Criteria for Adverse Events. Measuring specific tumour markers (e. Cisplatin results in high-tone hearing loss and tinnitus. cancer antigen125. .

and cyclophosphamide given as six cycles every three weeks achieves a 20–38% reduction in the risk of death.cancer.5  ×  109/l <50. A combination of oxaliplatin and 5-fluorouracil produces response rates of about 40%. Colorectal cancer Neoadjuvant chemotherapy is routinely used in patients with potentially operable liver metastases. doxorubicin) can affect cardiac function. Anthracycline drugs (e.5 g/dl <1. tube feeding or TPN for 24 hours or more 6 or more episodes in 24 hours: i. fluids indicated for <24 hours Patchy ulcerations or pseudomembranes Grade 3 Severe fatigue interfering with ADL Inadequate oral caloric or fluid intake. Infertility – many chemotherapy agents can impair fertility to some extent. This drug is avoided in patients with uncontrolled angina. ­ Secondary malignancies – many chemotherapy agents can induce a second malignancy. ADL: Activities of daily living. sarcomas) occurring many years later. Left ventricular function must be measured before and during treatment in patients with a cardiac history.0  ×  109/l LLN: Lower limit of normal. The appropriate use of chemotherapy in combination with hormones and radiotherapy has approximately halved the risk of death from breast cancer. Leukaemias tend to occur after a few years with solid tumours (e. epirubicin SURGERY 27:4 © 2009 Published by Elsevier Ltd. septic shock) <6.5  ×  109/l <25. Metastatic disease – a number of chemotherapy drugs and hormonal agents can be used in patients with metastatic disease.0 to 50. Sperm donation is routinely offered to young men undergoing chemotherapy for haematological malignancies or germ-cell tumours. Myopathy – paclitaxel commonly causes myalgia and generalized arthralgia.5  ×  109/l <LLN to 75.0  ×  109/l <8.0 g/dl <1. with about 20% of patients becoming operable. About 25% of women who were initially thought require a mastectomy achieved sufficient response to chemotherapy to undergo breast-conservation surgery instead. fluids indicated for <24 hours 2–5 episodes in 24 hours: i. patients with metastatic breast cancer live for 18–24 months with treatment.v. Chemotherapy is used in addition to hormone therapy (see page 59) in patients with hormone receptor-positive tumours.5 to 1. in general. dehydration or malnutrition: i.0  ×  109/l <10 to 8.v. Infertility caused by chemotherapy is unusual and. Cardiac – 5-fluorouracil can cause coronary artery spasm. 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.g. Neoadjuvant chemotherapy (e.ctep.gov. those achieving very good. Combination chemotherapy such as 5-fluorouracil. 176 Chemotherapy in breast and colorectal cancer Breast cancer Adjuvant chemotherapy for breast cancer is well established.v.0 to 6.g. .v. Table 3 Hepatic – many drugs require adequate liver function to be metabolized.CANcER TREAtMENt 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 difficulty in doing ADL Oral intake decreased without significant weight loss. i. significant spontaneous bleeding. TPN: Total parenteral nutrition.0 to 0.0 to 25.g. On average.g. fluids. resulting in cardiac ischaemia. Lethargy – most chemotherapy drugs cause lethargy independently of any anaemia they may cause.5 g/dl <0. prolonged responses to treatment may improve their survival significantly. epirubicin/cyclophosphamide) may be given to women with large tumours in whom a mastectomy would otherwise be required.0  ×  109/l <75. Source: www. Some chemotherapy agents can transiently affect liver enzymes. fluids or TPN indicated for 24 hours or more Confluent ulcerations or pseudomembranes. lifethreatening consequences Life-threatening consequences (e.0  ×  109/l Tissue necrosis. is associated with alkylating agents (particularly in high-dose regimens). 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.

and second-line settings. the number needed to treat is 1:10 (i.e. ◆ SURGERY 27:4 177 © 2009 Published by Elsevier Ltd. Oxaliplatin or irinotecan in combination with 5-fluorouracil are used in the first. one patient is saved from developing recurrence within 5 years). Adjuvant chemotherapy provides a 22–30% reduction in mortality at 5 years. depending on the chemotherapy the patient has already received. for every ten patients treated. Median survival with first. Metastatic disease – the aim of chemotherapy in the metastatic setting is to palliate symptoms and prolong survival.CANcER TREAtMENt Adjuvant chemotherapy with six months of 5-fluorouracil and folinic acid is the standard regimen in patients with stage III disease.and second-line chemotherapy is about 18–20 months. .