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Topoisomerase inhibitors
Cytotoxic chemotherapy: clinical aspects
The topoisomerases are a group of enzymes that control the three-dimensional structure of DNA. They allow strand passage of DNA during replication and transcription, by cleavage followed by religation (Figure 5). • Type I topoisomerase is a monomeric protein found in mammalian cells. This enzyme preferentially binds to dsDNA and causes a single-strand DNA break; this allows the unbroken strand to pass through the nick, releasing torsional stress. Topoisomerase I levels have been found to be elevated in several tumour types. Type I topoisomerase inhibitors include topotecan and irinotecan. These agents are active in colorectal and ovarian cancer. • Topoisomerase II exists as two dimeric isoenzymes, α and β. These enzymes bind covalently to complementary strands of dsDNA, cleaving both strands and allowing a second dsDNA strand to pass through. Type II topoisomerase inhibitors stabilize this cleavable complex, thereby maintaining the strand breaks. The epipodophyllotoxins (e.g. etoposide, teniposide) are the major inhibitors of topoisomerase II.
Pippa G Corrie
Aims of chemotherapy Most cytotoxic chemotherapy drugs exert their effect by inhibiting one or more of the processes involved in cell division. It appears that the fate of cells damaged by chemotherapy is to die primarily by induction of apoptosis (programmed cell death). Chemotherapy is generally used to treat cancer at an advanced or early stage. Advanced (metastatic) cancer Surgery and radiotherapy are the principal modalities used in the treatment of localized cancers, but many patients present with metastatic spread or develop recurrent disease locally or at distant sites that cannot be dealt with by these means. Chemotherapy is a systemic treatment commonly offered to patients with advanced cancer. In practice, it is seldom curative (Figure 1). The best response to chemotherapy is most often a reduction in tumour volume, which may provide effective palliation in terms of duration of survival and/or symptom control compared with the natural course of the disease. Acquired mutations in tumorigenesis protect
Tubulin-binding drugs Tubulin is the basic subunit of microtubules, which have many important, diverse roles in cell function including maintenance of cell shape, mitosis, meiosis, secretion, intracellular transport and axonal function. Several classes of anticancer drugs are known to interfere with tubulin function (Figure 6). • The vinca alkaloids (vincristine, vindesine, vinorelbine and vinblastine) bind to tubulin dimers and prevent their assembly into microtubules. • The taxanes (paclitaxel and taxotere) and epothilones A and B bind to microtubules and prevent their disassembly, thereby inhibiting normal microtubule function.
What’s new ? • Cytotoxic chemotherapy is increasingly used as an adjunct to surgery in early stages of cancer • Side-effects can usually be controlled by use of additional drugs such as anti-emetics, antidiarrhoeals and antihistamines • As cancer patients survive for longer, long-term side-effects are becoming evident; risks of infertility and carcinogenesis must be discussed to enable the patient to make an informed choice
FURTHER READING DeVita V T, Hellman S, Rosenberg S A. Cancer – principles and practice of oncology. 6th ed. Philadelphia: Lippincott, 2001. Holland J F, Frei E, Bast R C et al. Cancer medicine. 5th ed. Philadelphia: Lea & Feiberger, 2000. Perry M C. The chemotherapy source book. 3rd ed. Philadelphia: Williams & Wilkins, 2001.
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Pippa G Corrie is Consultant and Associate Lecturer in Medical Oncology at Addenbrooke’s Hospital, Cambridge, UK. She qualified from the University of Oxford, and trained in medical oncology in Birmingham. Her research interests include developmental therapeutics in the prevention of tumour invasion and metastasis. She is Lead Clinician for the West Anglia Cancer Research Network.
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Benefits of current chemotherapy in terms of duration of survival in patients with common cancers Curable (chemosensitive) • Teratoma • Seminoma • High-grade non-Hodgkin’s lymphoma • Hodgkin’s disease • Wilms’ tumour • Myeloma
Clear survival benefit • Colorectal cancer • Small cell lung cancer • Oesophageal cancer • Ovarian cancer • Breast cancer • Cervical cancer • Low-grade lymphoma • Non-small cell lung cancer
Modest/equivocal survival benefit • Pancreatic cancer • Gastric cancer • Hepatoma • Sarcoma • Bladder cancer • Primary brain cancer • Nasopharyngeal carcinoma
No survival gain (chemoresistant) • Melanoma • Renal cancer • Cholangiocarcinoma
Based on randomized clinical trial evidence in early or advanced disease
1
Acute complications The rapidly dividing cells of the bone marrow, gastrointestinal mucosa and hair follicles are among the most sensitive tissues in the body. Thus, common immediate side-effects of chemotherapy include myelosuppression, nausea, vomiting and hair loss. Druginduced damage to the bone marrow is probably the most lifethreatening risk. Other side-effects are idiosyncratic to particular drugs or groups of drugs with shared mechanisms of action (Figures 3 and 4). Most are transient, self-limiting and reversible on cessation of treatment.
cancer cells from chemotherapy, and drug resistance is the most common reason for treatment failure. Some cancers are intrinsically resistant to treatment, and in these patients the likelihood of any benefit from chemotherapy is low.
Chemotherapy in early (primary) cancer as an adjunct to surgery Chemotherapy first tested in advanced disease and found to be active is usually adopted for treatment of early disease, in expectation of more effective cancer control. • Adjuvant chemotherapy is now routinely offered to patients at high risk of recurrence after surgical resection of, for example, primary breast or bowel cancer. • Neoadjuvant chemotherapy is increasingly used as a treatment in localized cancer before planned curative surgery. This approach has enabled more conservative surgical resection of large primary breast cancers, and has been shown to improve overall survival in patients undergoing surgery for localized oesophageal cancer compared with surgery alone. • Chemotherapy combined with radiotherapy is sometimes more effective than either modality alone. The radiosensitization achieved by drugs such as 5-fluorouracil is useful for shrinking bulky oesophageal and rectal cancers that might otherwise be unresectable.
Response (% of cells killed)
Dose response curves for a chemotherapy drug that kills tumour cells and normal cells
Limitations of chemotherapy Cytotoxic drugs non-selectively kill rapidly growing cells The processes governing cell proliferation are common to normal and cancer cells; thus, both cell populations are susceptible to damage by chemotherapy. However, selectivity towards cancer cells is seen because some tumours are highly proliferative relative to normal cells (e.g. high-grade lymphoma), or are defective in their ability to repair DNA damage and so cannot repopulate after cytotoxic injury. The aim of chemotherapy is to achieve maximum tumour cell killing while accepting a certain degree of toxicity to normal tissues. The therapeutic ratio is the ratio between the toxic dose and the therapeutic dose of a drug; for most conventional chemotherapy drugs, the ratio is close to 1, and damage to normal tissues is dose-limiting (Figure 2).
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Normal cells Tumour cells
C
A
B
Drug concentration The therapeutic dose (A) is so close to the toxic dose (B) (therapeutic index 1) that it is unsafe to give this drug at the therapeutic dose. A safe dose (C) is chosen for administration to patients. 2
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Common side-effects of chemotherapeutic agents Manifestations • Neutropenia • Anaemia • Thrombocytopenia
Agents likely to cause toxicity Alkylating agents, anthracyclines, taxanes Topoisomerase inhibitors
• Diarrhoea • Oral mucositis • Nausea and vomiting
Antifolates, fluoropyrimidines
Neurological
• Peripheral sensory neuropathy • Ototoxicity
Vinca alkaloids, taxanes Cisplatin, oxaliplatin
Renal
• Acute renal failure
Cisplatin
Hepatic
• Transaminitis
Raltitrexed
Cardiac
• Acute or chronic cardiomyopathy
Anthracyclines
Respiratory
• Pulmonary fibrosis
Bleomycin
Bladder
• Haemorrhagic cystitis
Cyclosphamide
Others
• • • •
Infusional 5-fluorouracil, capecitabine Doxorubicin Taxanes Particularly combination chemotherapy containing alkylating agents
Reticuloendothelial
Gastrointestinal
Hand–foot syndrome Vesicant Anaphylaxis Alopecia, fatigue, lethargy
Various
• Subfertility/infertility, increased risk of second malignancy The risk of side-effects can be avoided or significantly reduced by careful monitoring of patients and use of appropriate prophylactic measures
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but it is difficult to define the risk; randomized trials comparing adjuvant chemotherapy with no treatment suggest that it is likely to be extremely small. Patients are informed that the risk exists, but it should not be a justification for declining curative treatment.
Delayed complications Delayed side-effects of cytotoxic chemotherapy include cardiomyopathy induced by doxorubicin and pulmonary fibrosis associated with bleomycin. To avoid such problems, checks have been established to limit the amount of drug that can be prescribed over time. As cancer care improves, patients are now surviving longer after their treatment, and previously unrecognized long-term effects are emerging. Infertility and carcinogenicity are of particular concern in young patients cured of, for example, Hodgkin’s disease, acute leukaemia or testicular cancer. • Both spermatogenesis and oogenesis are susceptible to cytotoxic damage. Recovery of fertility after chemotherapy is possible, but appears to be related to the patient’s age, the type and total dose of drugs received, and the time off treatment. Many men and women are subsequently able to conceive by natural means, but it is routine practice, before treatment begins, to offer semen or ovarian tissue storage to young patients at high risk of chemotherapy-induced infertility. • The potential for cytotoxic drugs to induce second malignancies was suggested in 1947. The problem is now well documented,
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Delivery of chemotherapy Administration Drug-related toxicity to normal tissues limits the frequency with which chemotherapy can be delivered. Most drugs are administered intermittently in, for example, 2-week, 3-week or 4-week cycles; the time to re-treatment is primarily determined by the need to allow recovery of major organs such as the bone marrow. Chemotherapy is given by various routes including intravenous, intramuscular and oral; the route used depends largely on the pharmacological properties of the drug in vivo (e.g. absorption, metabolism, half-life). Most chemotherapeutic drugs exhibit poor oral bioavailability and are therefore administered intravenously. The recent demand for the oral fluoropyrimidine capecitabine (which is rapidly replacing the traditional 5-fluorouracil) is likely
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4 Severe (painless) hand–foot syndrome with nail dystrophy occurring after 7 months’ continuous infusional 5-fluorouracil in a 64-year-old man with responsive metastatic colorectal cancer. Daily oral pyridoxine was introduced to ameliorate skin exfoliation, and chemotherapy was continued successfully.
Some common established combination chemotherapy regimens Cancer • Breast
Acronym CMF AC
Drugs involved Cyclophosphamide, methotrexate, 5-fluorouracil Doxorubicin, cyclophosphamide
• Hodgkin’s disease
MOPP ABVD
Mustine (nitrogen mustard), vincristine, procarbazine, prednisolone Doxorubicin, bleomycin, vinblastine, dacarbazine
• Non-Hodgkin’s lymphoma
CHOP
Cyclophosphamide, doxorubicin, vincristine, prednisolone
• Germ cell
BEP
Bleomycin, etoposide, cisplatin
• Stomach
ECF
Epirubicin, cisplatin, 5-fluorouracil
• Bladder
CMV
Cisplatin, methotrexate, vinblastine
• Lung
CAV(E) MIC
Cyclophosphamide, doxorubicin, vincristine (, etoposide) Mitomycin, ifosfamide, cisplatin
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to encourage pharmaceutical companies to develop oral analogues of standard intravenous drugs. Chemotherapy may be administered intrathecally in the presence of proven meningeal disease or to treat certain haematological cancers with a high likelihood of nervous system involvement. In the UK, stringent national guidelines have been established to ensure the safety of patients receiving intrathecal drugs and to minimize the risk of error.
chemical damage. Tumour cells may over-express P-glycoprotein and are therefore highly resistant to various chemotherapy drugs. p53 protein is an important intracellular mediator of apoptosis and is often mutated in transformed cells. Point mutations in the p53 gene appear to correlate with resistance to chemotherapy in many solid tumours. The complex interrelationship between the mechanism of action of chemotherapy drugs and induction of cell death is the subject of intensive research. Resistance modifiers are being developed for concomitant use with chemotherapy to potentiate its efficacy. Ability to predict sensitivity is limited by the artificial nature of the experimental models commonly used in cancer research. For example, the growing of tumour cells in tissue culture cannot take into account the micro-environment of the intact host, in which blood supply, interactions with surrounding stromal cells and immune factors have a significant effect on cancer cell survival and response to systemic treatment. Recent developments in molecular biology coupled with modern computer technology enable tiny fragments of tumour tissue to be analysed for their level of expression of thousands of genes at any one time. Scientists hope that, in the future, gene expression profiling of individual tumours will enable clinicians to accurately predict response to chemotherapy.
Rationale for combining drugs Single-agent chemotherapy seldom cures. Although cancers probably arise from clonal expansion of a single mutated cell, most tumours have acquired polyclonality by the time of detection. Heterogeneity of cell chemosensitivity within a single cancer may be overcome by combining single agents with known activity against that particular tumour type. Combination chemotherapy (Figure 5) is standard clinical practice in the treatment of high-grade lymphomas and testicular teratomas, and achieves a significantly higher cure rate than single-agent therapy. When combining drugs, it is preferable to select different classes (to provide a broader coverage of activity against resistant cells and to reduce the risk of outgrowth of new resistant subclones) and non-overlapping side-effect profiles (Figure 3). Drugs for chemotherapy can be classified according to the mechanism by which they inhibit cell proliferation. Cyclophosphamide (C), methotrexate (M) and 5-fluorouracil (F) exhibit single-agent activity against advanced breast cancer. When they are combined in the regimen termed ‘CMF’, the response rate is 2–3-fold greater than with any of the single agents and the treatment is well tolerated by most patients. Patients in whom CMF fails may respond to an anthracyline as second-line treatment, because cross-resistance should not have occurred. Overcoming chemoresistance For some chemosensitive tumours (e.g. high-grade lymphoma, acute leukaemia), very high doses of drugs offer a potential cure if the patient is supported through unpleasant but transient side-effects. For most drugs and tumours, the dose–response curve is sigmoid in shape (Figure 2). The doses used in clinical practice lie on the steep, linear part of the curve. At higher doses, the curve reaches a plateau; thus, even if very high doses could be administered safely, it is unlikely that all cancer cells would be eliminated by such regimens. Widening of the ‘therapeutic window’ by delivering chemotherapy directly to the region of the body most affected by the cancer has not been successful. Studies of intraperitoneal cisplatin in ovarian cancer and intrahepatic arterial fluoropyrimidines in hepatic metastatic colorectal cancer have shown that large doses can be administered safely and may achieve higher response rates than conventional doses administered intravenously, but delivering treatment by these routes is largely impractical.
Practice points • Most cytotoxic chemotherapy drugs exert their effect by killing actively dividing cells • Chemotherapy achieves a cure in a small proportion of cancer patients, but prolongs life in many more • Chemotherapy-induced damage to normal cells causes side-effects that may be life-threatening and are dose-limiting • Common immediate side-effects are usually transient and manageable using prophylactic agents • Delayed effects of chemotherapy are rare; they include infertility and second malignancies
Alternative strategies There are many mechanisms of tumour cell chemoresistance, including reduced drug uptake, enhanced intracellular detoxification, inadequate drug activation, up-regulation of DNA repair systems and increased drug efflux. The MDR gene encodes P-glycoprotein, a membrane-associated, energy-dependent efflux pump that protects normal cells of the kidney and testis from
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