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Cytotoxic chemotherapy: clinical aspects
SYSTEMIC THERAPY
Cytotoxic chemotherapy: clinical aspects
What’s new? C
Pippa G Corrie C
C
Abstract C
Cytotoxic chemotherapy drugs damage proliferating cells primarily by interfering with mitosis and we now know the molecular target of most of the drugs in clinical use. Even so, non-specificity of cytotoxic agents is a major drawback and their ability to damage normal as well as malignant cells means that cure with chemotherapy is not often achieved. Various strategies have been adopted to enhance the antitumour effect. These include combining drugs with different mechanisms of action, delivering drug directly to the tumour and overcoming cellular resistance mechanisms. With advances in science, rational drug design is now becoming a reality, and mechanism-driven, targeted anticancer agents are being used alongside conventional cytotoxic chemotherapy. Cancer treatment is therefore increasing in complexity, so the challenge for clinicians and scientists now is to manipulate the various treatment options to maximize benefit and minimize harm for individual patients.
C
C
The molecular targets of most cytotoxic chemotherapy drugs are well known Improved understanding of their action has widened their application Chemoresistance remains a problem and new strategies to overcome this are being developed Modern technology is providing the opportunity to identify those patients likely to respond to a given treatment based on individual tumour gene profiles Management of complications of cancer treatment is a key element of acute oncology services As cancer patients survive for longer, chronic life-changing effects are becoming evident; the national patients’ survivorship initiative aims to help growing numbers of cancer survivors return to and maintain as normal a life as possible
treatment of these diseases and is now used at some time during the course of the illness of most cancer patients.
Keywords cancer; chemotherapy; cytotoxic chemotherapy; cytotoxic drugs;
Clinical applications of cytotoxic chemotherapy
systemic anticancer therapy
Haematological malignancies By virtue of their high proliferative index, many haematological malignancies respond well to cytotoxic chemotherapy, at least in the first instance. High-grade leukaemias and lymphomas can be cured with aggressive treatment, while low-grade tumours can be controlled over many years with drug doses tailored to allow activities compatible with normal daily living. However, relapse carries a poor prognosis and re-treatment may not achieve durable remission.
The potential for developing cytotoxic chemotherapy dates back to the First World War, when soldiers treated for the irritant effects of exposure to sulphur mustard gas were noted also to develop lymphoid aplasia. The related nitrogen mustards were the first chemical agents to be tested in clinical studies and produced some dramatic regressions in lymphoma patients. These studies encouraged further efforts to find chemical agents with antitumour activity. Around 1950, researchers showed that aminopterin, a 4-amino analogue of folic acid, could inhibit proliferation of leukaemic cells and induce remissions in acute leukaemic patients. Nitrogen mustard and its derivatives were known to bond alkyl groups of molecules covalently, while folic acid vitamins were known to play a critical role in the synthesis of DNA precursors. To this day, alkylating agents and antifolates remain major classes of cytotoxic chemotherapy drugs in routine clinical use for the treatment of both haematological and other solid tumours. These early advances generated a new field of pharmacological research focussing on new drugs for the treatment of cancer. In the last 50 years, cancer chemotherapy has revolutionized
Advanced (metastatic) solid cancers Surgery and radiotherapy are the principal modalities used in the treatment of localized solid 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. Cytotoxic chemotherapy is commonly offered to patients with advanced cancer. In practice, it is seldom curative (Table 1). The best response to chemotherapy is most often a reduction in tumour volume, which may provide effective palliation in terms of life prolongation and/or symptom control compared with the natural course of the disease. Intrinsic or acquired mutations in tumourigenesis protect cancer cells from chemotherapy and drug resistance is the most common reason for treatment failure. Chemotherapy in early (primary) cancer as an adjunct to surgery Chemotherapy is most often tested first in advanced disease. If found to be active in this setting, it is usually adopted for treatment of early disease, in an attempt to improve cure rates following primary surgical intervention. Adjuvant chemotherapy is now offered routinely to patients at high risk of recurrence after surgical resection of many common cancers (e.g. primary breast and bowel
Pippa G Corrie PhD FRCP is Consultant Medical Oncologist and University Associate Lecturer at Cambridge University Hospitals NHS Foundation Trust. She qualified from Oxford University and trained in medical oncology in Birmingham. Her specialist interests are melanoma and hepatopancreaticobiliary malignancies, and the conduct of clinical trials. Competing interests: none declared.
MEDICINE 39:12
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Ó 2011 Elsevier Ltd. All rights reserved.
SYSTEMIC THERAPY
Benefits of current cytotoxic chemotherapy in terms of duration of survival in patients with common cancers
a
Curable (chemosensitive)
Clear survival benefit
Modest survival benefit
No survival gain (chemoresistant)
Teratoma Seminoma High-grade non-Hodgkin’s lymphoma Acute leukaemia Wilms’ tumour Myeloma
Colorectal cancer Small cell lung cancer Oesophageal cancer Ovarian cancer Breast cancer Cervical cancer Low-grade lymphoma Non-small cell lung cancer Chronic leukaemia
Pancreatic cancer Gastric cancer Sarcoma Bladder cancer Primary brain cancer Prostate cancer Nasopharyngeal carcinoma Cholangiocarcinoma
Melanomaa Renal cancera Hepatocellular carcinomaa
Based on randomized clinical trial evidence in early or advanced disease. Evidence of response to tyrosine kinase inhibitors and/or monoclonal antibodies.
Table 1
cancer), in the knowledge that treatment improves the likelihood of survival. Neoadjuvant chemotherapy is increasingly being used as a treatment for localized cancer before attempting 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 example, for localized oesophageal cancer compared with surgery alone.1 Chemotherapy combined with radiotherapy is sometimes more effective than either modality alone. The radiosensitization achieved by drugs such as fluorouracil is useful for shrinking bulky oesophageal and rectal cancers that might otherwise have been unresectable.
to the patient’s age, the type and total dose of drugs received, and the time of 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. Most cytotoxic drugs are teratogenic and potentially harmful to the fetus, so patients are counselled to use appropriate contraception for the duration of chemotherapy. There are two main medical emergencies associated with chemotherapy administration: extravasation and infection.
Dose–response curves for a chemotherapy drug that kills tumour cells and normal cells
Limitations of chemotherapy
Response (% of cells killed)
Cytotoxic drugs kill rapidly growing cells non-selectively The processes governing cell proliferation (i.e. mitosis and apoptosis) 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 (e.g. high-grade lymphoma) are highly proliferative relative to normal cells, 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 index is the ratio between the toxic dose and the therapeutic dose of a drug; for most conventional chemotherapy drugs, the index is close to one, and damage to normal tissues is dose-limiting (Figure 1).
Normal cells Tumour cells
C
Acute complications (during the treatment period) The rapidly dividing cells of the bone marrow, gastrointestinal mucosa, hair follicles and gonads are among the most sensitive tissues in the body. Thus, common immediate adverse effects of chemotherapy include myelosuppression, nausea and vomiting, hair loss and reduced fertility. Both spermatogenesis and oogenesis are susceptible to cytotoxic damage. Recovery of fertility after chemotherapy is possible, but appears to be related
MEDICINE 39:12
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. Figure 1
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Ó 2011 Elsevier Ltd. All rights reserved.
SYSTEMIC THERAPY
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. In 2006, the US National Cancer Institute reported that cancer survivors constituted 3.5% of the population, but second primary malignancies among this group accounted for 16% of all cancer incidence.4 Particularly high-risk groups include young patients cured of Hodgkin’s disease, acute leukaemia and testicular cancer. The problem of developing second cancers is now well documented, 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.5 Patients are informed that the risk exists, but this should not be a justification for declining curative treatment.6 Possibly of greater concern is the incidence of non-malignant chronic illness in cancer survivors, which is beginning to emerge. Almost 80% of children and adolescents treated for cancer can now expect to be cured; most of these will have received chemotherapy as part of their treatment. A recent survey of over 10,000 adult survivors of childhood cancer found that almost three-quarters of survivors had at least one chronic health condition 30 years after diagnosis, and almost half of these conditions were considered serious.7 The National Cancer
Some chemotherapy drugs e vincristine and doxorubicin in particular e are vesicants and can cause blistering and necrosis if extravasation occurs at the time of drug administration, with extensive tissue damage if appropriate action is not taken. For this reason, oncology staff are fully trained to identify and manage this complication on the rare occasion that it happens. Infection occurring in a myelosuppressed patient is a more common and life-threatening event. Fever in patients who have recently received chemotherapy indicates the need for urgent assessment and access to antibiotics, which may be life saving. In 2008, a national survey of patient deaths within 30 days of chemotherapy identified many shortfalls in the management of chemotherapy complications, especially relating to neutropenic sepsis.2 Acute oncology has now evolved as a new oncology subspeciality focussing on management of the complications of cancer and its treatment,3 aimed at improving patient safety and quality of care. There are many other adverse effects that are limited to particular drugs or groups of drugs with shared mechanisms of action (Figure 2 and Table 2). Most are transient, self-limiting and reversible on cessation of treatment. Late effects Direct adverse effects of cytotoxic chemotherapy can sometimes develop over many months; examples include cardiomyopathy
Severe painless hand-foot syndrome with nail dystrophy occurring after 7 months’ continuous infusional 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. Figure 2
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Ó 2011 Elsevier Ltd. All rights reserved.
SYSTEMIC THERAPY
Common adverse effects of cytotoxic chemotherapy
Reticuloendothelial
Gastrointestinal
Neurological Renal Hepatic Cardiac Respiratory Bladder Others
Manifestations
Agents likely to cause toxicity
Neutropenia Anaemia Thrombocytopenia Diarrhoea Oral mucositis Nausea and vomiting Peripheral sensory neuropathy Ototoxicity Acute renal failure Transaminitis Acute or chronic cardiomyopathy Cardiac ischaemic events Pulmonary fibrosis Haemorrhagic cystitis Handefoot syndrome Vesicant Anaphylaxis Alopecia, fatigue, lethargy Subfertility/infertility, increased risk of second malignancy
Alkylating agents, anthracyclines, taxanes Topoisomerase inhibitors Antifolates, fluoropyrimidines Various Vinca alkaloids, taxanes Cisplatin, oxaliplatin Cisplatin Raltitrexed Anthracyclines Fluoropyrimidines Bleomycin Cyclophosphamide Infusional fluorouracil, capecitabine Doxorubicin, vincristine Taxanes Particularly combination chemotherapy containing alkylating agents
The risk of adverse effects can be avoided or significantly reduced by careful monitoring of patients and use of appropriate prophylactic measures.
Table 2
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. In 2003, the oral fluoropyrimidines, capecitabine and tegafur with uracil, were approved to treat advanced colorectal8 and breast cancers.9 These two prodrugs were developed as substitutes for intravenous fluorouracil, and have proved highly attractive to patients and cost-effective for the health service. Oral anticancer drugs are on the increase and, whilst their use is convenient, there is potential for poor compliance as well as unintentional overdosage. Patient information and drug prescribing systems should be identical to parenteral chemotherapy, to ensure safety standards are maintained.10 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 minimize the risk of error.11
Survivorship Initiative (NCSI) was created in 2007 to improve services and support for those living with and beyond cancer e currently 2 million across the UK and growing by over 3% per year e by addressing medical, psychological, social, spiritual, financial and informational needs of cancer survivors, enabling them to lead as healthy and active a life as possible, for as long as possible.
Delivery of chemotherapy Patient selection Given that cytotoxic drugs can harm patients, the decision to treat needs to take into account potential to harm versus potential to benefit. Oncologists evaluate patient fitness for treatment by a performance status score (Table 3). Fitter patients tolerate treatment better, while patients with poor performance status may be offered treatment only if there is a high chance of benefit. Patients are monitored for evidence of toxicity throughout their treatment and chemotherapy doses are modified on an on-going basis, taking tolerance into account.
Targeted delivery systems For some chemosensitive haematological malignancies, 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 doseeresponse curve is sigmoid in shape (Figure 1). 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
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 determined primarily 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
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Ó 2011 Elsevier Ltd. All rights reserved.
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can be overcome by combining single agents with known activity against that particular tumour type. Combination chemotherapy (Table 4) is standard in the treatment of most malignancies and achieves significantly better outcomes than single-agent therapy. When combining drugs, different classes of drugs are selected to provide a broader coverage of activity against resistant cells and reduce the risk of outgrowth of new resistant subclones, and to avoid overlapping adverse effect profiles (Table 2). Chemotherapy drugs can be classified according to the mechanism by which they inhibit cell proliferation. Cyclophosphamide (C), methotrexate (M) and fluorouracil (F) exhibit single-agent activity against advanced breast cancer. When they are combined in the regimen termed ‘CMF’, the response rate is two- to threefold 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 anthracycline as second-line treatment, because cross-resistance should not have occurred.
WHO/ECOG score and Karnofsky scale for measuring performance status WHO/ECOG score
Karnofsky scale
Definition
0
90, 100%
1
70, 80%
2
50, 60%
3
30, 40%
4
10, 20%
5
0%
Fully active, able to carry out all pre-disease performance without restriction Restricted in physically strenuous activity, but ambulatory and able to carry out work of a light or sedentary nature Ambulatory and capable of all self-care, but unable to carry out any work activities. Up and about more than 50% of waking hours Capable of only limited self-care, confined to bed or chair more than 50% of waking hours Completely disabled. Cannot carry out any self-care. Totally confined to bed or chair Dead
Overcoming chemoresistance A major limitation of cytotoxic chemotherapy is intrinsic or acquired resistance of tumour cells to the drugs to which they are exposed. Biological resistance mechanisms are well recognized and include reduced drug uptake, enhanced intracellular detoxification, inadequate drug activation, up-regulation of DNA repair systems and increased drug efflux. Resistance modifiers are being developed for concomitant use with chemotherapy to potentiate tumour-selective cytotoxicity, albeit with limited success to date.14 More recently, delivery of gemcitabine in an animal model of pancreatic cancer identified that the problem was not intrinsic
ECOG, Eastern Cooperative Oncology Group; WHO, World Health Organization.
Table 3
such regimens. High-dose chemotherapy for breast cancer, popular in the 1980s, was abandoned when trials confirmed treatment-related mortality far exceeded patient benefits. Widening of the ‘therapeutic window’ by delivering chemotherapy directly to the region of the body most affected by the cancer has been tried with limited success. Studies of intraperitoneal cisplatin in ovarian cancer12 and intrahepatic arterial fluoropyrimidines in hepatic metastatic colorectal cancer13 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. Isolated limb perfusion of melphalan is offered in specialist centres to palliate metastatic melanoma confined to a single limb. Specially targeted delivery vehicles aim to increase the concentration of systemic chemotherapy drugs reaching tumour cells while reducing exposure of normal cells, the net effect being enhanced tumour kill with reduced adverse effects. The delivery system possesses a differentially higher affinity for tumour cells by interacting with tumour-specific or tumour-associated antigens. Examples of modified drugs now in clinical practice include doxorubicin encased in liposomes (liposomal doxorubicin; CaelyxÒ) and protein-bound paclitaxel (Abraxane, or nab-paclitaxel).
Some common established combination chemotherapy regimens Acronym
Drugs involved
Breast
CMF
Cyclophosphamide, methotrexate, fluorouracil AdriamycinÒ (doxorubicin), cyclophosphamide Mustine (nitrogen mustard), OncovinÒ (vincristine), procarbazine, prednisolone AdriamycinÒ (doxorubicin), bleomycin, vinblastine, dacarbazine Cyclophosphamide, hydroxydaunorubicin (doxorubicin), OncovinÒ (vincristine), prednisolone Bleomycin, etoposide, cisplatin Epirubicin, cisplatin, fluorouracil Epirubicin, cisplatin, capecitabine Methotrexate, vincristine, cisplatin Cyclophosphamide, AdriamycinÒ (doxorubicin), vincristine (etoposide) Fluorouracil, folinic acid, oxaliplatin
AC Hodgkin’s disease
MOPP
ABVD
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
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Cancer
Non-Hodgkin’s lymphoma
CHOP
Germ cell Stomach Bladder Lung
BEP ECF ECX MVAC CAV(E)
Colorectal
FOLFOX
Table 4
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5 Allan JM, Travis LB. Mechanisms of therapy-related carcinogenesis. Nat Rev Cancer 2005; 5: 943e55. 6 Matesich SM, Shapiro CL. Second cancers after breast cancer treatment. Semin Oncol 2003; 30: 740e8. 7 Oeffinger KC, Mertens AC, Sklar CA, et al. Chronic health conditions in adult survivors of childhood cancer. N Engl J Med 2006; 355: 1572e82. 8 National Institute for Health and Clinical Excellence. Guidance on the use of capecitabine and tegafur with uracil for metastatic colorectal cancer. Technology Appraisal 61. London: NICE, May 2003. 9 National Institute for Health and Clinical Excellence. Guidance on the use of capecitabine for the treatment of locally advanced or metastatic breast cancer. Technology Appraisal 62. London: NICE, May 2003. 10 Weingart SN, Flug J, Brouillard D, et al. Oral chemotherapy safety practices at US cancer centres: questionnaire survey. Br Med J 2007; 334: 407e9. 11 Department of Health. National guidance on the safe administration of intrathecal chemotherapy. London: DoH (HSC 2003/010). Available at: http://www.dh.gov.uk; October 2003. 12 Hamilton CA, Berek JS. Intraperitoneal chemotherapy for ovarian cancer. Curr Opin Oncol 2006; 18: 507e15. 13 Kerr DJ, McArdle CS, Ledermann J, et al. Intrahepatic arterial versus intravenous fluorouracil and folinic acid for colorectal cancer liver metastases: a multicentre randomised trial. Lancet 2003; 361: 368e73. 14 Nobili S, Landini I, Giglioni B, Mini E. Pharmacological strategies for overcoming multidrug resistance. Curr Drug Targets 2006; 7: 861e79. 15 Olive KP, Jacobetz MA, Davidson CJ, et al. Inhibition of hedgehog signalling enhances delivery of chemotherapy in a mouse model of pancreatic cancer. Science 2009; 324: 1457e61. 16 Quintieri L, Fantin M, Vizler C. Identification of molecular determinants of tumour sensitivity and resistance to anticancer drugs. Adv Exp Med Biol 2007; 593: 95e104. 17 Chang JC, Wooten EC, Tsimelzon A, et al. Gene expression profiling for the prediction of therapeutic response to docetaxel in patients with breast cancer. Lancet 2003; 362: 362e9. 18 Reya T, Morrison SJ, Clarke MF, Weissman IL. Stem cells, cancer, and cancer stem cell. Nature 2001; 414: 105e11. € Valdez R, Theisen BK, et al. Pten dependence distin19 Yilmaz OH, guishes haematopoietic stem cells from leukaemia-initiating cells. Nature 2006; 441: 475e82.
tumour cell resistance but the inability of the drug to access the tumour cells, due to the dense peritumoural stroma and lack of vascular access.15 Agents targeting stromal components are being combined with cytotoxic chemotherapy in clinical trials to ascertain whether they can enhance antitumour effect. Cancer is a genetic disease and, with modern sequencing technology, thousands of genes can be quantified simultaneously in tiny fragments of tumour tissue. It is hoped that these gene expression profiles might one day allow treatment strategies to be planned according to their probability of success in individual patients.16 So-called ‘stratified medicine’ is already beginning to use molecular abnormalities identified in tumours to select treatment with a targeted biological anticancer agent (such as monoclonal antibodies or tyrosine kinase inhibitors) with an expectation of a high chance of benefit. Similarly, it may be possible to identify gene fingerprints in a subset of tumours, which might predict for response to a particular cytotoxic drug. A variety of molecular markers of chemoresistance have been reported.17 For example, point mutations in the p53 gene appear to correlate with resistance to chemotherapy in many solid tumours. ErbB2, a member of the epidermal growth factor receptor family, is overexpressed in a small proportion of breast cancers; it is widely accepted to be a marker of poor prognosis generally, but has been implicated more recently as a predictor for resistance to anthracycline chemotherapy. Finally, recent evidence suggests that the capability of a tumour to grow and propagate depends on the presence of a small subset of cells within a tumour, termed cancer stem cells.18,19 These cells are inherently resistant to standard chemotherapy, suggesting that, in order to eradicate a cancer, new strategies will be needed to target these cancer stem cells selectively. A
REFERENCES 1 Clark P. Surgical resection with or without pre-operative chemotherapy in oesophageal cancer: an updated analysis of a randomised controlled trial conducted by the UK Medical Research Council Upper GI Tract Cancer Group. Lancet 2002; 359: 1727e33. 2 For better, for worse? A review of the care of patients who died within 30 days of receiving systemic anti-cancer therapy. National Confidential Enquiry into Patient Outcome and Death, November 2008. 3 Chemotherapy services in England: ensuring quality and safety. A report from the National Chemotherapy Advisory Group August 2009. 4 Travis LB, Rabkin CS, Brown LM, et al. Cancer survivorshipdgenetic susceptibility and second primary cancers: research strategies and recommendations. J Natl Cancer Inst 2006; 98: 15e25.
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FURTHER READING Devita VT, Hellman S, Rosenberg SA. Cancer: principles and practice of oncology. Philadelphia: Lippincott, Williams and Wilkin, 2007 (A comprehensive reference book for all aspects of oncology.). Rettig RA, Jacobson PD, Farquhar CM, Aubrey WM. False hope: bone marrow transplantation in breast cancer. Oxford University Press, 2007 (A sobering account of how clinicians and patients converged to propel a drastic treatment forward despite lack of clinical effectiveness.).
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Ó 2011 Elsevier Ltd. All rights reserved.
Cytotoxic chemotherapy: clinical aspects
What’s new? C
Pippa G Corrie C
C
Abstract C
Cytotoxic chemotherapy drugs damage proliferating cells primarily by interfering with mitosis and we now know the molecular target of most of the drugs in clinical use. Even so, non-specificity of cytotoxic agents is a major drawback and their ability to damage normal as well as malignant cells means that cure with chemotherapy is not often achieved. Various strategies have been adopted to enhance the antitumour effect. These include combining drugs with different mechanisms of action, delivering drug directly to the tumour and overcoming cellular resistance mechanisms. With advances in science, rational drug design is now becoming a reality, and mechanism-driven, targeted anticancer agents are being used alongside conventional cytotoxic chemotherapy. Cancer treatment is therefore increasing in complexity, so the challenge for clinicians and scientists now is to manipulate the various treatment options to maximize benefit and minimize harm for individual patients.
C
C
The molecular targets of most cytotoxic chemotherapy drugs are well known Improved understanding of their action has widened their application Chemoresistance remains a problem and new strategies to overcome this are being developed Modern technology is providing the opportunity to identify those patients likely to respond to a given treatment based on individual tumour gene profiles Management of complications of cancer treatment is a key element of acute oncology services As cancer patients survive for longer, chronic life-changing effects are becoming evident; the national patients’ survivorship initiative aims to help growing numbers of cancer survivors return to and maintain as normal a life as possible
treatment of these diseases and is now used at some time during the course of the illness of most cancer patients.
Keywords cancer; chemotherapy; cytotoxic chemotherapy; cytotoxic drugs;
Clinical applications of cytotoxic chemotherapy
systemic anticancer therapy
Haematological malignancies By virtue of their high proliferative index, many haematological malignancies respond well to cytotoxic chemotherapy, at least in the first instance. High-grade leukaemias and lymphomas can be cured with aggressive treatment, while low-grade tumours can be controlled over many years with drug doses tailored to allow activities compatible with normal daily living. However, relapse carries a poor prognosis and re-treatment may not achieve durable remission.
The potential for developing cytotoxic chemotherapy dates back to the First World War, when soldiers treated for the irritant effects of exposure to sulphur mustard gas were noted also to develop lymphoid aplasia. The related nitrogen mustards were the first chemical agents to be tested in clinical studies and produced some dramatic regressions in lymphoma patients. These studies encouraged further efforts to find chemical agents with antitumour activity. Around 1950, researchers showed that aminopterin, a 4-amino analogue of folic acid, could inhibit proliferation of leukaemic cells and induce remissions in acute leukaemic patients. Nitrogen mustard and its derivatives were known to bond alkyl groups of molecules covalently, while folic acid vitamins were known to play a critical role in the synthesis of DNA precursors. To this day, alkylating agents and antifolates remain major classes of cytotoxic chemotherapy drugs in routine clinical use for the treatment of both haematological and other solid tumours. These early advances generated a new field of pharmacological research focussing on new drugs for the treatment of cancer. In the last 50 years, cancer chemotherapy has revolutionized
Advanced (metastatic) solid cancers Surgery and radiotherapy are the principal modalities used in the treatment of localized solid 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. Cytotoxic chemotherapy is commonly offered to patients with advanced cancer. In practice, it is seldom curative (Table 1). The best response to chemotherapy is most often a reduction in tumour volume, which may provide effective palliation in terms of life prolongation and/or symptom control compared with the natural course of the disease. Intrinsic or acquired mutations in tumourigenesis protect cancer cells from chemotherapy and drug resistance is the most common reason for treatment failure. Chemotherapy in early (primary) cancer as an adjunct to surgery Chemotherapy is most often tested first in advanced disease. If found to be active in this setting, it is usually adopted for treatment of early disease, in an attempt to improve cure rates following primary surgical intervention. Adjuvant chemotherapy is now offered routinely to patients at high risk of recurrence after surgical resection of many common cancers (e.g. primary breast and bowel
Pippa G Corrie PhD FRCP is Consultant Medical Oncologist and University Associate Lecturer at Cambridge University Hospitals NHS Foundation Trust. She qualified from Oxford University and trained in medical oncology in Birmingham. Her specialist interests are melanoma and hepatopancreaticobiliary malignancies, and the conduct of clinical trials. Competing interests: none declared.
MEDICINE 39:12
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Ó 2011 Elsevier Ltd. All rights reserved.
SYSTEMIC THERAPY
Benefits of current cytotoxic chemotherapy in terms of duration of survival in patients with common cancers
a
Curable (chemosensitive)
Clear survival benefit
Modest survival benefit
No survival gain (chemoresistant)
Teratoma Seminoma High-grade non-Hodgkin’s lymphoma Acute leukaemia Wilms’ tumour Myeloma
Colorectal cancer Small cell lung cancer Oesophageal cancer Ovarian cancer Breast cancer Cervical cancer Low-grade lymphoma Non-small cell lung cancer Chronic leukaemia
Pancreatic cancer Gastric cancer Sarcoma Bladder cancer Primary brain cancer Prostate cancer Nasopharyngeal carcinoma Cholangiocarcinoma
Melanomaa Renal cancera Hepatocellular carcinomaa
Based on randomized clinical trial evidence in early or advanced disease. Evidence of response to tyrosine kinase inhibitors and/or monoclonal antibodies.
Table 1
cancer), in the knowledge that treatment improves the likelihood of survival. Neoadjuvant chemotherapy is increasingly being used as a treatment for localized cancer before attempting 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 example, for localized oesophageal cancer compared with surgery alone.1 Chemotherapy combined with radiotherapy is sometimes more effective than either modality alone. The radiosensitization achieved by drugs such as fluorouracil is useful for shrinking bulky oesophageal and rectal cancers that might otherwise have been unresectable.
to the patient’s age, the type and total dose of drugs received, and the time of 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. Most cytotoxic drugs are teratogenic and potentially harmful to the fetus, so patients are counselled to use appropriate contraception for the duration of chemotherapy. There are two main medical emergencies associated with chemotherapy administration: extravasation and infection.
Dose–response curves for a chemotherapy drug that kills tumour cells and normal cells
Limitations of chemotherapy
Response (% of cells killed)
Cytotoxic drugs kill rapidly growing cells non-selectively The processes governing cell proliferation (i.e. mitosis and apoptosis) 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 (e.g. high-grade lymphoma) are highly proliferative relative to normal cells, 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 index is the ratio between the toxic dose and the therapeutic dose of a drug; for most conventional chemotherapy drugs, the index is close to one, and damage to normal tissues is dose-limiting (Figure 1).
Normal cells Tumour cells
C
Acute complications (during the treatment period) The rapidly dividing cells of the bone marrow, gastrointestinal mucosa, hair follicles and gonads are among the most sensitive tissues in the body. Thus, common immediate adverse effects of chemotherapy include myelosuppression, nausea and vomiting, hair loss and reduced fertility. Both spermatogenesis and oogenesis are susceptible to cytotoxic damage. Recovery of fertility after chemotherapy is possible, but appears to be related
MEDICINE 39:12
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. Figure 1
718
Ó 2011 Elsevier Ltd. All rights reserved.
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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. In 2006, the US National Cancer Institute reported that cancer survivors constituted 3.5% of the population, but second primary malignancies among this group accounted for 16% of all cancer incidence.4 Particularly high-risk groups include young patients cured of Hodgkin’s disease, acute leukaemia and testicular cancer. The problem of developing second cancers is now well documented, 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.5 Patients are informed that the risk exists, but this should not be a justification for declining curative treatment.6 Possibly of greater concern is the incidence of non-malignant chronic illness in cancer survivors, which is beginning to emerge. Almost 80% of children and adolescents treated for cancer can now expect to be cured; most of these will have received chemotherapy as part of their treatment. A recent survey of over 10,000 adult survivors of childhood cancer found that almost three-quarters of survivors had at least one chronic health condition 30 years after diagnosis, and almost half of these conditions were considered serious.7 The National Cancer
Some chemotherapy drugs e vincristine and doxorubicin in particular e are vesicants and can cause blistering and necrosis if extravasation occurs at the time of drug administration, with extensive tissue damage if appropriate action is not taken. For this reason, oncology staff are fully trained to identify and manage this complication on the rare occasion that it happens. Infection occurring in a myelosuppressed patient is a more common and life-threatening event. Fever in patients who have recently received chemotherapy indicates the need for urgent assessment and access to antibiotics, which may be life saving. In 2008, a national survey of patient deaths within 30 days of chemotherapy identified many shortfalls in the management of chemotherapy complications, especially relating to neutropenic sepsis.2 Acute oncology has now evolved as a new oncology subspeciality focussing on management of the complications of cancer and its treatment,3 aimed at improving patient safety and quality of care. There are many other adverse effects that are limited to particular drugs or groups of drugs with shared mechanisms of action (Figure 2 and Table 2). Most are transient, self-limiting and reversible on cessation of treatment. Late effects Direct adverse effects of cytotoxic chemotherapy can sometimes develop over many months; examples include cardiomyopathy
Severe painless hand-foot syndrome with nail dystrophy occurring after 7 months’ continuous infusional 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. Figure 2
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Common adverse effects of cytotoxic chemotherapy
Reticuloendothelial
Gastrointestinal
Neurological Renal Hepatic Cardiac Respiratory Bladder Others
Manifestations
Agents likely to cause toxicity
Neutropenia Anaemia Thrombocytopenia Diarrhoea Oral mucositis Nausea and vomiting Peripheral sensory neuropathy Ototoxicity Acute renal failure Transaminitis Acute or chronic cardiomyopathy Cardiac ischaemic events Pulmonary fibrosis Haemorrhagic cystitis Handefoot syndrome Vesicant Anaphylaxis Alopecia, fatigue, lethargy Subfertility/infertility, increased risk of second malignancy
Alkylating agents, anthracyclines, taxanes Topoisomerase inhibitors Antifolates, fluoropyrimidines Various Vinca alkaloids, taxanes Cisplatin, oxaliplatin Cisplatin Raltitrexed Anthracyclines Fluoropyrimidines Bleomycin Cyclophosphamide Infusional fluorouracil, capecitabine Doxorubicin, vincristine Taxanes Particularly combination chemotherapy containing alkylating agents
The risk of adverse effects can be avoided or significantly reduced by careful monitoring of patients and use of appropriate prophylactic measures.
Table 2
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. In 2003, the oral fluoropyrimidines, capecitabine and tegafur with uracil, were approved to treat advanced colorectal8 and breast cancers.9 These two prodrugs were developed as substitutes for intravenous fluorouracil, and have proved highly attractive to patients and cost-effective for the health service. Oral anticancer drugs are on the increase and, whilst their use is convenient, there is potential for poor compliance as well as unintentional overdosage. Patient information and drug prescribing systems should be identical to parenteral chemotherapy, to ensure safety standards are maintained.10 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 minimize the risk of error.11
Survivorship Initiative (NCSI) was created in 2007 to improve services and support for those living with and beyond cancer e currently 2 million across the UK and growing by over 3% per year e by addressing medical, psychological, social, spiritual, financial and informational needs of cancer survivors, enabling them to lead as healthy and active a life as possible, for as long as possible.
Delivery of chemotherapy Patient selection Given that cytotoxic drugs can harm patients, the decision to treat needs to take into account potential to harm versus potential to benefit. Oncologists evaluate patient fitness for treatment by a performance status score (Table 3). Fitter patients tolerate treatment better, while patients with poor performance status may be offered treatment only if there is a high chance of benefit. Patients are monitored for evidence of toxicity throughout their treatment and chemotherapy doses are modified on an on-going basis, taking tolerance into account.
Targeted delivery systems For some chemosensitive haematological malignancies, 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 doseeresponse curve is sigmoid in shape (Figure 1). 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
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 determined primarily 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
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can be overcome by combining single agents with known activity against that particular tumour type. Combination chemotherapy (Table 4) is standard in the treatment of most malignancies and achieves significantly better outcomes than single-agent therapy. When combining drugs, different classes of drugs are selected to provide a broader coverage of activity against resistant cells and reduce the risk of outgrowth of new resistant subclones, and to avoid overlapping adverse effect profiles (Table 2). Chemotherapy drugs can be classified according to the mechanism by which they inhibit cell proliferation. Cyclophosphamide (C), methotrexate (M) and fluorouracil (F) exhibit single-agent activity against advanced breast cancer. When they are combined in the regimen termed ‘CMF’, the response rate is two- to threefold 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 anthracycline as second-line treatment, because cross-resistance should not have occurred.
WHO/ECOG score and Karnofsky scale for measuring performance status WHO/ECOG score
Karnofsky scale
Definition
0
90, 100%
1
70, 80%
2
50, 60%
3
30, 40%
4
10, 20%
5
0%
Fully active, able to carry out all pre-disease performance without restriction Restricted in physically strenuous activity, but ambulatory and able to carry out work of a light or sedentary nature Ambulatory and capable of all self-care, but unable to carry out any work activities. Up and about more than 50% of waking hours Capable of only limited self-care, confined to bed or chair more than 50% of waking hours Completely disabled. Cannot carry out any self-care. Totally confined to bed or chair Dead
Overcoming chemoresistance A major limitation of cytotoxic chemotherapy is intrinsic or acquired resistance of tumour cells to the drugs to which they are exposed. Biological resistance mechanisms are well recognized and include reduced drug uptake, enhanced intracellular detoxification, inadequate drug activation, up-regulation of DNA repair systems and increased drug efflux. Resistance modifiers are being developed for concomitant use with chemotherapy to potentiate tumour-selective cytotoxicity, albeit with limited success to date.14 More recently, delivery of gemcitabine in an animal model of pancreatic cancer identified that the problem was not intrinsic
ECOG, Eastern Cooperative Oncology Group; WHO, World Health Organization.
Table 3
such regimens. High-dose chemotherapy for breast cancer, popular in the 1980s, was abandoned when trials confirmed treatment-related mortality far exceeded patient benefits. Widening of the ‘therapeutic window’ by delivering chemotherapy directly to the region of the body most affected by the cancer has been tried with limited success. Studies of intraperitoneal cisplatin in ovarian cancer12 and intrahepatic arterial fluoropyrimidines in hepatic metastatic colorectal cancer13 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. Isolated limb perfusion of melphalan is offered in specialist centres to palliate metastatic melanoma confined to a single limb. Specially targeted delivery vehicles aim to increase the concentration of systemic chemotherapy drugs reaching tumour cells while reducing exposure of normal cells, the net effect being enhanced tumour kill with reduced adverse effects. The delivery system possesses a differentially higher affinity for tumour cells by interacting with tumour-specific or tumour-associated antigens. Examples of modified drugs now in clinical practice include doxorubicin encased in liposomes (liposomal doxorubicin; CaelyxÒ) and protein-bound paclitaxel (Abraxane, or nab-paclitaxel).
Some common established combination chemotherapy regimens Acronym
Drugs involved
Breast
CMF
Cyclophosphamide, methotrexate, fluorouracil AdriamycinÒ (doxorubicin), cyclophosphamide Mustine (nitrogen mustard), OncovinÒ (vincristine), procarbazine, prednisolone AdriamycinÒ (doxorubicin), bleomycin, vinblastine, dacarbazine Cyclophosphamide, hydroxydaunorubicin (doxorubicin), OncovinÒ (vincristine), prednisolone Bleomycin, etoposide, cisplatin Epirubicin, cisplatin, fluorouracil Epirubicin, cisplatin, capecitabine Methotrexate, vincristine, cisplatin Cyclophosphamide, AdriamycinÒ (doxorubicin), vincristine (etoposide) Fluorouracil, folinic acid, oxaliplatin
AC Hodgkin’s disease
MOPP
ABVD
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
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Cancer
Non-Hodgkin’s lymphoma
CHOP
Germ cell Stomach Bladder Lung
BEP ECF ECX MVAC CAV(E)
Colorectal
FOLFOX
Table 4
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5 Allan JM, Travis LB. Mechanisms of therapy-related carcinogenesis. Nat Rev Cancer 2005; 5: 943e55. 6 Matesich SM, Shapiro CL. Second cancers after breast cancer treatment. Semin Oncol 2003; 30: 740e8. 7 Oeffinger KC, Mertens AC, Sklar CA, et al. Chronic health conditions in adult survivors of childhood cancer. N Engl J Med 2006; 355: 1572e82. 8 National Institute for Health and Clinical Excellence. Guidance on the use of capecitabine and tegafur with uracil for metastatic colorectal cancer. Technology Appraisal 61. London: NICE, May 2003. 9 National Institute for Health and Clinical Excellence. Guidance on the use of capecitabine for the treatment of locally advanced or metastatic breast cancer. Technology Appraisal 62. London: NICE, May 2003. 10 Weingart SN, Flug J, Brouillard D, et al. Oral chemotherapy safety practices at US cancer centres: questionnaire survey. Br Med J 2007; 334: 407e9. 11 Department of Health. National guidance on the safe administration of intrathecal chemotherapy. London: DoH (HSC 2003/010). Available at: http://www.dh.gov.uk; October 2003. 12 Hamilton CA, Berek JS. Intraperitoneal chemotherapy for ovarian cancer. Curr Opin Oncol 2006; 18: 507e15. 13 Kerr DJ, McArdle CS, Ledermann J, et al. Intrahepatic arterial versus intravenous fluorouracil and folinic acid for colorectal cancer liver metastases: a multicentre randomised trial. Lancet 2003; 361: 368e73. 14 Nobili S, Landini I, Giglioni B, Mini E. Pharmacological strategies for overcoming multidrug resistance. Curr Drug Targets 2006; 7: 861e79. 15 Olive KP, Jacobetz MA, Davidson CJ, et al. Inhibition of hedgehog signalling enhances delivery of chemotherapy in a mouse model of pancreatic cancer. Science 2009; 324: 1457e61. 16 Quintieri L, Fantin M, Vizler C. Identification of molecular determinants of tumour sensitivity and resistance to anticancer drugs. Adv Exp Med Biol 2007; 593: 95e104. 17 Chang JC, Wooten EC, Tsimelzon A, et al. Gene expression profiling for the prediction of therapeutic response to docetaxel in patients with breast cancer. Lancet 2003; 362: 362e9. 18 Reya T, Morrison SJ, Clarke MF, Weissman IL. Stem cells, cancer, and cancer stem cell. Nature 2001; 414: 105e11. € Valdez R, Theisen BK, et al. Pten dependence distin19 Yilmaz OH, guishes haematopoietic stem cells from leukaemia-initiating cells. Nature 2006; 441: 475e82.
tumour cell resistance but the inability of the drug to access the tumour cells, due to the dense peritumoural stroma and lack of vascular access.15 Agents targeting stromal components are being combined with cytotoxic chemotherapy in clinical trials to ascertain whether they can enhance antitumour effect. Cancer is a genetic disease and, with modern sequencing technology, thousands of genes can be quantified simultaneously in tiny fragments of tumour tissue. It is hoped that these gene expression profiles might one day allow treatment strategies to be planned according to their probability of success in individual patients.16 So-called ‘stratified medicine’ is already beginning to use molecular abnormalities identified in tumours to select treatment with a targeted biological anticancer agent (such as monoclonal antibodies or tyrosine kinase inhibitors) with an expectation of a high chance of benefit. Similarly, it may be possible to identify gene fingerprints in a subset of tumours, which might predict for response to a particular cytotoxic drug. A variety of molecular markers of chemoresistance have been reported.17 For example, point mutations in the p53 gene appear to correlate with resistance to chemotherapy in many solid tumours. ErbB2, a member of the epidermal growth factor receptor family, is overexpressed in a small proportion of breast cancers; it is widely accepted to be a marker of poor prognosis generally, but has been implicated more recently as a predictor for resistance to anthracycline chemotherapy. Finally, recent evidence suggests that the capability of a tumour to grow and propagate depends on the presence of a small subset of cells within a tumour, termed cancer stem cells.18,19 These cells are inherently resistant to standard chemotherapy, suggesting that, in order to eradicate a cancer, new strategies will be needed to target these cancer stem cells selectively. A
REFERENCES 1 Clark P. Surgical resection with or without pre-operative chemotherapy in oesophageal cancer: an updated analysis of a randomised controlled trial conducted by the UK Medical Research Council Upper GI Tract Cancer Group. Lancet 2002; 359: 1727e33. 2 For better, for worse? A review of the care of patients who died within 30 days of receiving systemic anti-cancer therapy. National Confidential Enquiry into Patient Outcome and Death, November 2008. 3 Chemotherapy services in England: ensuring quality and safety. A report from the National Chemotherapy Advisory Group August 2009. 4 Travis LB, Rabkin CS, Brown LM, et al. Cancer survivorshipdgenetic susceptibility and second primary cancers: research strategies and recommendations. J Natl Cancer Inst 2006; 98: 15e25.
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FURTHER READING Devita VT, Hellman S, Rosenberg SA. Cancer: principles and practice of oncology. Philadelphia: Lippincott, Williams and Wilkin, 2007 (A comprehensive reference book for all aspects of oncology.). Rettig RA, Jacobson PD, Farquhar CM, Aubrey WM. False hope: bone marrow transplantation in breast cancer. Oxford University Press, 2007 (A sobering account of how clinicians and patients converged to propel a drastic treatment forward despite lack of clinical effectiveness.).
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