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Cytotoxic chemotherapy: clinical aspects
SYSTEMIC THERAPY
Cytotoxic chemotherapy: clinical aspects
What’s new? C
Rob Jones
C
Abstract
C
Chemotherapeutic drugs exert their effects by interfering with the processes involved in cell division. Their therapeutic use stems from their ability to cause a greater proportion of cell kill in cancer cells than normal cells. In this review we discuss the clinical uses of chemotherapeutic agents, their mechanisms of action, important toxicities and patterns of resistance.
C
Molecular characterization of tumours is leading to better personalization of systemic therapies Biopsying of multiple metastatic sites in the same patient has proven a high degree of tumour heterogeneity within each patient Understanding of tumour immunology has led to the development of immune checkpoint inhibitors Immune checkpoint inhibitors have improved survival in lung cancer and melanoma
In this article we review the clinical uses of conventional cytotoxic chemotherapy, important toxicities and patterns of resistance.
Keywords adjuvant; cell cycle; chemotherapy; clinical trials; palliative; resistance; toxicities
Combination chemotherapy Most chemotherapy regimens in clinical practice consist of several agents from different classes used in combination (see Principles of Systemic Anticancer Therapy on pages 00e00 of this issue). A summary of different drug classes and how they act on the cell cycle can be seen in Figure 1 and Table 1. There are a number of principles in generating an effective combination regimen: different phases of the cell cycle are targeted to achieve maximal cell kill and there is less likelihood of resistance emerging1 the drugs used in combination should have activity against the tumour when used alone, and those with maximal efficacy are preferred their mechanisms of action should be different to allow for additive or synergistic effects, and they should be dosed at their optimal dose and schedule the toxicities should also be minimally overlapping, thus reducing the risk of life-threatening toxicity to a single organ system. Chemotherapeutic drugs are given at repeated regular intervals known as treatment cycles. The scheduling of chemotherapy cycles is determined by the ability of normal tissues to recover and should be the shortest time possible.
Introduction Cancer treatment involves one or more of surgery, radiotherapy and systemic therapy. In early-stage disease, low-risk patients are often cured with surgery alone, but in many other cases a combination of treatments is required. In metastatic disease, systemic therapy is the principal therapeutic modality, as delivery through the bloodstream facilitates access to disseminated cancer sites. Systemic therapies include hormonal therapy, targeted therapy, immune therapy and chemotherapy. Hormone therapy plays a significant role in the treatment of breast and prostate cancer and is discussed in ‘Hormonal therapy for cancer’ in this issue. In addition targeted therapies, which have been developed from our understanding of cancer molecular biology and aberrant signalling pathways, are playing an increasingly important role in a number of tumour types (see The Biology of Cancer and Targeted Therapy in Cancer on pages 00e00 and 00e00 respectively of this issue). Tyrosine kinase inhibitors have shown promise for chemotherapy-resistant tumours, such as renal cell carcinoma, as has gefitinib for epidermal growth factor receptor (EGFR) mutation-positive lung cancer. Immune therapy has also seen some major recent developments and monoclonal antibodies now play a key role in treatment for several cancers including B cell lymphomas, human epidermal growth factor receptor-2 (HER-2)-positive breast cancer and colon cancer. New antibodies targeting inhibitors of the immune system itself are showing huge promise in several malignancies. Three classes of immunomodulatory antibodies targeting programmed death ligand-1 (PD-L1), programmed death-1 (PD-1) and cytotoxic T-lymphocyte-associated protein-4 (CTLA4) are entering clinical practice for lung cancer and metastatic melanoma types (see The Biology of Cancer and Targeted Therapy in Cancer on pages 00e00 and 00e00 respectively of this issue).
Clinical uses of chemotherapy From their introduction in the 1940s there are now over 50 licensed drugs for the management of malignant disease.2 The clinical uses of chemotherapy are determined by patient and tumour characteristics. In general cure is only possible when chemotherapy is used in combination with surgery, either in the adjuvant or neoadjuvant setting. Treatment of metastatic disease is mostly with palliative intent, although there are some notable exceptions. There is a wide spectrum of sensitivity to chemotherapy among different tumour types. As a general rule, rapidly dividing neoplasms are more chemosensitive. Although specific tumour sites such as testicular tumours are generally regarded as exquisitely chemosensitive, it is becoming increasingly clear that
Rob Jones BM BSc PhD MRCP is a Senior Lecturer and Consultant Medical Oncologist at Velindre Cancer Centre, Cardiff, UK. Competing interests: none declared.
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1
Ó 2015 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Jones R, Cytotoxic chemotherapy: clinical aspects, Medicine (2015), http://dx.doi.org/10.1016/ j.mpmed.2015.10.007
SYSTEMIC THERAPY
to hormonal therapy and trastuzumab and also provides prognostic information. In colorectal cancer, the absence of the RAS mutation can predict the response to cetuximab, an antibody targeting the EGFR.
Actions of chemotherapy agents on the cell cycle Anti-tumour Antibiotics
Anti-metabolites
Metastatic disease Taxoids
S (2–6 h)
Excluding germ cell tumours and lymphomas, most patients with solid tumours diagnosed with metastatic disease are not curable and treatment is with palliative intent. In the case of germ cell tumours and a number of haematological malignancies maintaining dose intensity during treatment is paramount, and in cases where conventional dose chemotherapy fails, high-dose chemotherapy is often used to try and enhance the chance of cure. For all other tumour types cure is not possible with chemotherapy alone. However in certain circumstances, such as those patients who have oligo-metastases, eradication of the cancer can be occasionally achieved if there is a good response to chemotherapy and a subsequent successful surgical resection. A good example of this is the treatment of potentially resectable liver metastases in colorectal cancer. For other cases of metastatic disease the aim of treatment is to prolong survival, delay the time to disease progression and improve quality of life. Examples of well-established palliative chemotherapy regimens are found for breast, colorectal, lung, ovarian, prostate, bladder and head and neck cancers. Response rates for single-agent therapy are usually around 15 e20%, and although there are some patients who have a substantial response with a significant improvement in symptoms and survival, there are also those who do not get any benefit from treatment and only suffer its adverse effects. Treatments are only continued if patients are genuinely benefitting and the toxicities are acceptable. Combination chemotherapy improves the response rates at the cost of increasing toxicity and is decided
G2 (2–32 h) M (0.5–2 h)
Alkylating agents
Vinca alkaloids
G1 (2– h)
Figure 1 The cell cycle is divided into a number of phases e G1, S, G2 and M e each of which can vary in length according to the type of cell and the growth rate of the cell. The activity of different classes of certain chemotherapeutic agents is optimal in different phases of the cell cycle, whereas alkylating agents are relatively non-phase-specific.
tumours of the same histological type can also display different patterns of chemosensitivity and behaviour. Cancer diagnosis is thus evolving from an emphasis on the organ and morphology, to include biological features based on the differential expression of proteins in or on cancer cells. This is of particular relevance to the new targeted therapies. For example, breast cancer patients are now routinely tested for the presence of the oestrogen receptor and expression of HER-2, which will predict their response
Biochemical classification of chemotherapy drugs Drug class
Mechanism of action
Examples
Alkylating agents
Impair cell function by forming covalent bonds on important molecules in proteins, DNA and RNA. Classified by their chemical structure and mechanism of covalent bonding. Structural analogues of naturally occurring metabolities involved in DNA and RNA synthesis. They either substitute for a metabolite that is normally incorporated into DNA or RNA or compete for the catalytic site of a key enzyme. Intercalate DNA at specific sequences, creating free radicals which cause strand breakage. Anthracyclines are products of the fungus Streptomyces, also have mechanism of action of topoisomerase I and II, required for the uncoiling of DNA required for DNA synthesis. Topoisomerases are enzymes that control the 3-D structure of DNA. Topoisomerase I and topoisomerase II are enzymes responsible for the uncoiling of DNA during replication. Vinca alkaloids bind to tubulin, and prevent the formation of the microtubule, which is important during mitosis, but also for cell shape, intracellular transport and axonal function. Taxanes prevent the disassembly of the microtubules, thereby inhibiting normal function.
Cisplatin, carboplatin, chlorambucil, cyclophosphamide, ifosfamide
Anti-metabolites
Antitumour antibiotics
Topoisomerase inhibitors Tubulin-binding drugs
5-Fluorouracil, methotrexate, pemetrexed, mercaptopurine, gemcitabine
Bleomycin, anthracyclines (doxorubicin, epirubicin)
Topoisomerase I inhibitors e irinotecan, topotecan Topoisomerase II inhibitors e etoposide Vinca alkaloids e vincristine, vinorelbine Taxanes e docetaxel, paclitaxel
Table 1
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Ó 2015 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Jones R, Cytotoxic chemotherapy: clinical aspects, Medicine (2015), http://dx.doi.org/10.1016/ j.mpmed.2015.10.007
SYSTEMIC THERAPY
Incremental improvements in median survival of colorectal cancer with combination therapy
Best supportive care – 6 months 12.1 months 5-FU / leucovorin3 17 months FOLFOX / FOLFIRI4 20.3 months IFL + bevacizumab5 25.6 months FOLFIRI + bevacizumab6 33.1 months FOLFIRI + cetuximab6
6
12
18
24
30
36
Median survival (months) Figure 2 The introduction of new drugs has led to improvements in overall survival. The addition of oxaliplatin (as part of FOLFOX) or irinotecan (as part of FOLFIRI) to 5-fluorouracil (5-FU) in combination is now the standard of care in the UK. The impact of the anti-vascular endothelial growth factor (VEGF) antibody bevacizumab (AvastinÒ) in addition to combination chemotherapy has led to its routine use in the USA and Europe, but it is only available through the Cancer Drugs Fund in England. The addition of cetuximab (anti-EGF receptor antibody) to chemotherapy has also led
An important part of the success of chemotherapy is the patients’ biological age and co-morbidity. Performance status is measured using the Eastern Cooperative Oncology Group performance status scale, and as a general rule those with a score of 3 or more are not offered treatment (because it is likely to be detrimental and shorten their survival) (Table 2).
on an individual basis. If the patient is becoming rapidly symptomatic due to disease, achieving a maximal response is clearly desirable. However, in the presence of minimal symptoms in a palliative setting, it may be preferable to use single-agent treatments sequentially. The evolving impact of incorporating new drugs into chemotherapy regimens in order to improve survival is well illustrated in colorectal cancer (Figure 2). Prior to the introduction of any chemotherapy a patient diagnosed with colorectal cancer could expect to survive for 6 months with best supportive care. With the introduction of single-agent 5-fluorouracil (5-FU) in the 1990s the median survival was approximately 1 year,3 increasing to 18 months when combined with irinotecan or oxaliplatin chemotherapy.4 By 2004, 20.3 months median survival was being reported with oxaliplatin, 5-FU and bevacizumab.5 Most recently in 2014, 25.6 months has been reported with irinotecan, 5-FU and bevacizumab, and 33.1 months with irinotecan, 5-FU and cetuximab.6 The number of effective chemotherapy regimens depends on the tumour type. For example, a patient with metastatic breast cancer may receive six or seven different regimens during their illness, but in colorectal cancer there are only two or three. The duration of palliative chemotherapy for patients has not been clearly defined and often depends on the individual circumstances and cumulative toxicity from treatments. In particular for colorectal cancer, several randomized studies have compared continuous versus intermittent chemotherapy. Although some of these suggest there may be a benefit to continuous treatment, a meta-analysis concluded no clear survival benefit to that approach.7 The decision must be individualized for each patient, taking into account quality of life in relation to either tumour symptoms or toxicity of treatment.
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Adjuvant chemotherapy Adjuvant chemotherapy is used after patients have had definitive treatment to eradicate the primary and loco-regional disease. The rationale for therapy is based on the hypothesis that relapses
Eastern Cooperative Oncology Group performance status scale Grade
Level of activity
0
Fully active, able to carry on all predisease performance without restriction Restricted in physically strenouous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g. light housework Ambulatory and capable of all self-care, but unable to carry out any work activities, up and about >50% of waking hours Capable of only limited self-care, confined to bed or chair >50% of waking hours Completely disabled, cannot carry out any self-care. Totally confined to bed or chair
1
2
3 4
Table 2
3
Ó 2015 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Jones R, Cytotoxic chemotherapy: clinical aspects, Medicine (2015), http://dx.doi.org/10.1016/ j.mpmed.2015.10.007
SYSTEMIC THERAPY
individual drugs or classes of drugs; for example ifosfamide can cause haemorrhagic cystitis and central nervous system toxicity. The National Cancer Institute in the USA has devised a standardized way of reporting toxicities using a graded scale, the Common toxicity criteria.11 This is used in clinical trials to allow a comparison between different chemotherapy drugs. Predictable toxicities can be prevented with appropriate prophylaxis, for example antiemetic combinations are prescribed according to the expected emetogenic potential of the regimen. Primary granulocyte colony-stimulating factor is used if the chemotherapy schedule has a greater than 20% risk of causing febrile neutropenia.12 However, if toxicity cannot be controlled with medical management, a reduction in the dose of chemotherapy is required. This is particularly relevant in palliative chemotherapy where symptom control and quality of life are at a premium. The late adverse effects of chemotherapy can be minimized by limiting doses where thresholds are known. However, in most instances they cannot be easily predicted and treatment is primarily symptomatic. Examples of late toxicities include the congestive cardiomyopathy seen with high total doses of anthracyclines, pulmonary fibrosis with bleomycin, neurotoxicity with platinum-based agents, vinca alkaloids and taxanes, and persistent cytopenias with alkylating agents. There is a small but increased risk of second malignancy in long-term survivors. NonHodgkin’s lymphoma and acute myeloid leukaemia, for example, have been reported as a late complication in patients treated for Hodgkin’s disease with chemotherapy and radiotherapy. Other late toxic sequelae include the risk of premature menopause in women and the risk of gonadal failure and dysfunction.13
occur due to occult micro-metastatic disease. Combination therapies give the greatest chance of cure and there is a greater emphasis on maintaining dose intensity. Clinical trials of adjuvant therapy have to be large to generate enough power to detect small differences in survival, which are usually of the order of around 5e10%. In the adjuvant setting treatment is focused on microscopic disease, so there is no disease response to measure and patients are offered treatment based on an assessment of risk. When evaluating suitable patients for adjuvant therapy, several patient and tumour characteristics are assessed. The tumour histology, its site, size, stage and biological features are important, as are the patients’ wishes, their biological age, comorbidities and performance status. In breast cancer, tools have been developed to aid the decision-making process. Adjuvant! is an online software tool that provides a survival estimate for chemotherapy or hormone therapy at 10 years, using the information gathered from large population databases.8 However, as a 5% survival advantage equates to a single patient being cured for every 20 who receive chemotherapy there is clearly a need to better define patients who will benefit from treatment. Gene assays such as Oncotype DXÒ have also been developed to give an estimate of risk by analysing the expression of gene sequences within a tumour. Their use is currently being assessed in prospective randomized trials but they should lead to improved outcomes and patient selection.9 Examples of cancer types for which adjuvant chemotherapy is well-established include breast, colorectal, ovarian and lung cancer.
Mechanisms of resistance Neoadjuvant chemotherapy
Resistance to chemotherapy is one of the main reasons for treatment failure, and in any given tumour type there are usually a combination of different mechanisms that contribute. Although there are strategies in development to try and reverse drug resistance, currently the only realistic choice for the clinician is to switch to an alternative cytotoxic drug or combination. The absence of a valid alternative normally heralds cessation of active drug therapy and a switch to symptomatic control. The only alternative would be to receive an experimental agent in the context of a clinical trial. A
There are potential advantages to giving adjuvant therapy as early as possible. When it is given before surgery, this is called ‘neoadjuvant’. Early treatment exposes the tumour and potential micro-metastases to therapy, thus avoiding the delay caused by surgery and recovery. The sensitivity of the primary tumour is easily assessed, and a reduction in bulk may allow for more conservative surgery. For example, in the treatment of low rectal cancer, preoperative chemoradiotherapy improves the rate of sphincter-sparing surgery.10 Locally advanced tumours which are initially unresectable may become resectable, increasing the possibility of cure and reducing the risk of local recurrence. Examples of where neoadjuvant chemotherapy is commonly used include inflammatory breast, rectal, bladder and bone cancers.
REFERENCES 1 Price P, Sikora K, Illidge T, eds. Treatment of cancer. 5th edn. London: Edward Arnold, 2008. 2 Brighton D, Wood W, eds. The Royal Marsden handbook of cancer chemotherapy. London: Churchill Livingstone, 2005. 3 Meta-Analysis Group in Cancer. Efficacy of intravenous continuous infusion of fluorouracil compared with bolus administration in advanced colorectal cancer. J Clin Oncol 1998; 16: 301e8. 4 Colucci G, Gebbia V, Paoletti G, et al. Phase III randomized trial of FOLFIRI versus FOLFOX4 in the treatment of advanced colorectal cancer: a multicenter study of the Gruppo Oncologico DellItalia Meridionale. J Clin Oncol 2005; 23: 4866e75. 5 Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 2004; 350: 2335.
Toxicity of chemotherapy The adverse effects of chemotherapy can be considerable, and it is important to educate and monitor patients carefully during treatment. Toxicities vary according to the specific agent, dose, route and schedule of administration and any predisposing patient factors, which may be known or unknown. Apart from nausea and vomiting and acute cholinergic gastrointestinal effects, most common toxicities occur because of the cytotoxic effects on normal dividing cells. These include myelosuppression with leucopenia, thrombocytopenia, anaemia, mucous membrane ulceration and alopecia. Other toxicities are less common and are specific to the
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Please cite this article in press as: Jones R, Cytotoxic chemotherapy: clinical aspects, Medicine (2015), http://dx.doi.org/10.1016/ j.mpmed.2015.10.007
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6 Heinemann V, von Weikersthal LW, Decker T, et al. FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer (FIRE-3): a randomized, open label, phase 3 trial. Lancet Oncol 2014; 15: 1065e75. 7 Berry SR, Cosby R, Asmis TR, et al. Randomized controlled trials (RCTs) examining continuous (CS) versus intermittent strategies (IS) of delivering systemic treatment (Tx) for untreated metastatic colorectal cancer (mCRC): a meta-analysis from the Cancer Care Ontario program in evidence-based care. J Clin Oncol 2013. Suppl 31: Abstract 3534. 8 http://www.adjuvantonline.com/index.jsp (accessed 22 Jul 2011). 9 Zujewski JA, Kamin L. Trial assessing individualized options for treatment for breast cancer: the TAILORx trial. Future Oncol 2008; 4: 603e10.
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10 Sauer R, Becker H, Hohenberger W, et al. German rectal cancer study group. Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med 2004; 351: 1731e40. 11 National Cancer Institute. http://ctep.cancer.gov/ protocolDevelopment/electronic_applications/ctc.htm (accessed 22 Jul 2011). 12 Smith TJ, Khatcheressian J, Lyman GH. 2006 update of recommendations for the use of white blood cell growth factors: an evidence-based, clinical practice guideline. J Clin Oncol 2006; 24: 3187e205. 13 Skeel RT. Handbook of cancer chemotherapy. 6th edn. Philadelphia: Lippincott Williams & Wilkins, 2003.
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Ó 2015 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Jones R, Cytotoxic chemotherapy: clinical aspects, Medicine (2015), http://dx.doi.org/10.1016/ j.mpmed.2015.10.007
Cytotoxic chemotherapy: clinical aspects
What’s new? C
Rob Jones
C
Abstract
C
Chemotherapeutic drugs exert their effects by interfering with the processes involved in cell division. Their therapeutic use stems from their ability to cause a greater proportion of cell kill in cancer cells than normal cells. In this review we discuss the clinical uses of chemotherapeutic agents, their mechanisms of action, important toxicities and patterns of resistance.
C
Molecular characterization of tumours is leading to better personalization of systemic therapies Biopsying of multiple metastatic sites in the same patient has proven a high degree of tumour heterogeneity within each patient Understanding of tumour immunology has led to the development of immune checkpoint inhibitors Immune checkpoint inhibitors have improved survival in lung cancer and melanoma
In this article we review the clinical uses of conventional cytotoxic chemotherapy, important toxicities and patterns of resistance.
Keywords adjuvant; cell cycle; chemotherapy; clinical trials; palliative; resistance; toxicities
Combination chemotherapy Most chemotherapy regimens in clinical practice consist of several agents from different classes used in combination (see Principles of Systemic Anticancer Therapy on pages 00e00 of this issue). A summary of different drug classes and how they act on the cell cycle can be seen in Figure 1 and Table 1. There are a number of principles in generating an effective combination regimen: different phases of the cell cycle are targeted to achieve maximal cell kill and there is less likelihood of resistance emerging1 the drugs used in combination should have activity against the tumour when used alone, and those with maximal efficacy are preferred their mechanisms of action should be different to allow for additive or synergistic effects, and they should be dosed at their optimal dose and schedule the toxicities should also be minimally overlapping, thus reducing the risk of life-threatening toxicity to a single organ system. Chemotherapeutic drugs are given at repeated regular intervals known as treatment cycles. The scheduling of chemotherapy cycles is determined by the ability of normal tissues to recover and should be the shortest time possible.
Introduction Cancer treatment involves one or more of surgery, radiotherapy and systemic therapy. In early-stage disease, low-risk patients are often cured with surgery alone, but in many other cases a combination of treatments is required. In metastatic disease, systemic therapy is the principal therapeutic modality, as delivery through the bloodstream facilitates access to disseminated cancer sites. Systemic therapies include hormonal therapy, targeted therapy, immune therapy and chemotherapy. Hormone therapy plays a significant role in the treatment of breast and prostate cancer and is discussed in ‘Hormonal therapy for cancer’ in this issue. In addition targeted therapies, which have been developed from our understanding of cancer molecular biology and aberrant signalling pathways, are playing an increasingly important role in a number of tumour types (see The Biology of Cancer and Targeted Therapy in Cancer on pages 00e00 and 00e00 respectively of this issue). Tyrosine kinase inhibitors have shown promise for chemotherapy-resistant tumours, such as renal cell carcinoma, as has gefitinib for epidermal growth factor receptor (EGFR) mutation-positive lung cancer. Immune therapy has also seen some major recent developments and monoclonal antibodies now play a key role in treatment for several cancers including B cell lymphomas, human epidermal growth factor receptor-2 (HER-2)-positive breast cancer and colon cancer. New antibodies targeting inhibitors of the immune system itself are showing huge promise in several malignancies. Three classes of immunomodulatory antibodies targeting programmed death ligand-1 (PD-L1), programmed death-1 (PD-1) and cytotoxic T-lymphocyte-associated protein-4 (CTLA4) are entering clinical practice for lung cancer and metastatic melanoma types (see The Biology of Cancer and Targeted Therapy in Cancer on pages 00e00 and 00e00 respectively of this issue).
Clinical uses of chemotherapy From their introduction in the 1940s there are now over 50 licensed drugs for the management of malignant disease.2 The clinical uses of chemotherapy are determined by patient and tumour characteristics. In general cure is only possible when chemotherapy is used in combination with surgery, either in the adjuvant or neoadjuvant setting. Treatment of metastatic disease is mostly with palliative intent, although there are some notable exceptions. There is a wide spectrum of sensitivity to chemotherapy among different tumour types. As a general rule, rapidly dividing neoplasms are more chemosensitive. Although specific tumour sites such as testicular tumours are generally regarded as exquisitely chemosensitive, it is becoming increasingly clear that
Rob Jones BM BSc PhD MRCP is a Senior Lecturer and Consultant Medical Oncologist at Velindre Cancer Centre, Cardiff, UK. Competing interests: none declared.
MEDICINE --:-
1
Ó 2015 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Jones R, Cytotoxic chemotherapy: clinical aspects, Medicine (2015), http://dx.doi.org/10.1016/ j.mpmed.2015.10.007
SYSTEMIC THERAPY
to hormonal therapy and trastuzumab and also provides prognostic information. In colorectal cancer, the absence of the RAS mutation can predict the response to cetuximab, an antibody targeting the EGFR.
Actions of chemotherapy agents on the cell cycle Anti-tumour Antibiotics
Anti-metabolites
Metastatic disease Taxoids
S (2–6 h)
Excluding germ cell tumours and lymphomas, most patients with solid tumours diagnosed with metastatic disease are not curable and treatment is with palliative intent. In the case of germ cell tumours and a number of haematological malignancies maintaining dose intensity during treatment is paramount, and in cases where conventional dose chemotherapy fails, high-dose chemotherapy is often used to try and enhance the chance of cure. For all other tumour types cure is not possible with chemotherapy alone. However in certain circumstances, such as those patients who have oligo-metastases, eradication of the cancer can be occasionally achieved if there is a good response to chemotherapy and a subsequent successful surgical resection. A good example of this is the treatment of potentially resectable liver metastases in colorectal cancer. For other cases of metastatic disease the aim of treatment is to prolong survival, delay the time to disease progression and improve quality of life. Examples of well-established palliative chemotherapy regimens are found for breast, colorectal, lung, ovarian, prostate, bladder and head and neck cancers. Response rates for single-agent therapy are usually around 15 e20%, and although there are some patients who have a substantial response with a significant improvement in symptoms and survival, there are also those who do not get any benefit from treatment and only suffer its adverse effects. Treatments are only continued if patients are genuinely benefitting and the toxicities are acceptable. Combination chemotherapy improves the response rates at the cost of increasing toxicity and is decided
G2 (2–32 h) M (0.5–2 h)
Alkylating agents
Vinca alkaloids
G1 (2– h)
Figure 1 The cell cycle is divided into a number of phases e G1, S, G2 and M e each of which can vary in length according to the type of cell and the growth rate of the cell. The activity of different classes of certain chemotherapeutic agents is optimal in different phases of the cell cycle, whereas alkylating agents are relatively non-phase-specific.
tumours of the same histological type can also display different patterns of chemosensitivity and behaviour. Cancer diagnosis is thus evolving from an emphasis on the organ and morphology, to include biological features based on the differential expression of proteins in or on cancer cells. This is of particular relevance to the new targeted therapies. For example, breast cancer patients are now routinely tested for the presence of the oestrogen receptor and expression of HER-2, which will predict their response
Biochemical classification of chemotherapy drugs Drug class
Mechanism of action
Examples
Alkylating agents
Impair cell function by forming covalent bonds on important molecules in proteins, DNA and RNA. Classified by their chemical structure and mechanism of covalent bonding. Structural analogues of naturally occurring metabolities involved in DNA and RNA synthesis. They either substitute for a metabolite that is normally incorporated into DNA or RNA or compete for the catalytic site of a key enzyme. Intercalate DNA at specific sequences, creating free radicals which cause strand breakage. Anthracyclines are products of the fungus Streptomyces, also have mechanism of action of topoisomerase I and II, required for the uncoiling of DNA required for DNA synthesis. Topoisomerases are enzymes that control the 3-D structure of DNA. Topoisomerase I and topoisomerase II are enzymes responsible for the uncoiling of DNA during replication. Vinca alkaloids bind to tubulin, and prevent the formation of the microtubule, which is important during mitosis, but also for cell shape, intracellular transport and axonal function. Taxanes prevent the disassembly of the microtubules, thereby inhibiting normal function.
Cisplatin, carboplatin, chlorambucil, cyclophosphamide, ifosfamide
Anti-metabolites
Antitumour antibiotics
Topoisomerase inhibitors Tubulin-binding drugs
5-Fluorouracil, methotrexate, pemetrexed, mercaptopurine, gemcitabine
Bleomycin, anthracyclines (doxorubicin, epirubicin)
Topoisomerase I inhibitors e irinotecan, topotecan Topoisomerase II inhibitors e etoposide Vinca alkaloids e vincristine, vinorelbine Taxanes e docetaxel, paclitaxel
Table 1
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Ó 2015 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Jones R, Cytotoxic chemotherapy: clinical aspects, Medicine (2015), http://dx.doi.org/10.1016/ j.mpmed.2015.10.007
SYSTEMIC THERAPY
Incremental improvements in median survival of colorectal cancer with combination therapy
Best supportive care – 6 months 12.1 months 5-FU / leucovorin3 17 months FOLFOX / FOLFIRI4 20.3 months IFL + bevacizumab5 25.6 months FOLFIRI + bevacizumab6 33.1 months FOLFIRI + cetuximab6
6
12
18
24
30
36
Median survival (months) Figure 2 The introduction of new drugs has led to improvements in overall survival. The addition of oxaliplatin (as part of FOLFOX) or irinotecan (as part of FOLFIRI) to 5-fluorouracil (5-FU) in combination is now the standard of care in the UK. The impact of the anti-vascular endothelial growth factor (VEGF) antibody bevacizumab (AvastinÒ) in addition to combination chemotherapy has led to its routine use in the USA and Europe, but it is only available through the Cancer Drugs Fund in England. The addition of cetuximab (anti-EGF receptor antibody) to chemotherapy has also led
An important part of the success of chemotherapy is the patients’ biological age and co-morbidity. Performance status is measured using the Eastern Cooperative Oncology Group performance status scale, and as a general rule those with a score of 3 or more are not offered treatment (because it is likely to be detrimental and shorten their survival) (Table 2).
on an individual basis. If the patient is becoming rapidly symptomatic due to disease, achieving a maximal response is clearly desirable. However, in the presence of minimal symptoms in a palliative setting, it may be preferable to use single-agent treatments sequentially. The evolving impact of incorporating new drugs into chemotherapy regimens in order to improve survival is well illustrated in colorectal cancer (Figure 2). Prior to the introduction of any chemotherapy a patient diagnosed with colorectal cancer could expect to survive for 6 months with best supportive care. With the introduction of single-agent 5-fluorouracil (5-FU) in the 1990s the median survival was approximately 1 year,3 increasing to 18 months when combined with irinotecan or oxaliplatin chemotherapy.4 By 2004, 20.3 months median survival was being reported with oxaliplatin, 5-FU and bevacizumab.5 Most recently in 2014, 25.6 months has been reported with irinotecan, 5-FU and bevacizumab, and 33.1 months with irinotecan, 5-FU and cetuximab.6 The number of effective chemotherapy regimens depends on the tumour type. For example, a patient with metastatic breast cancer may receive six or seven different regimens during their illness, but in colorectal cancer there are only two or three. The duration of palliative chemotherapy for patients has not been clearly defined and often depends on the individual circumstances and cumulative toxicity from treatments. In particular for colorectal cancer, several randomized studies have compared continuous versus intermittent chemotherapy. Although some of these suggest there may be a benefit to continuous treatment, a meta-analysis concluded no clear survival benefit to that approach.7 The decision must be individualized for each patient, taking into account quality of life in relation to either tumour symptoms or toxicity of treatment.
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Adjuvant chemotherapy Adjuvant chemotherapy is used after patients have had definitive treatment to eradicate the primary and loco-regional disease. The rationale for therapy is based on the hypothesis that relapses
Eastern Cooperative Oncology Group performance status scale Grade
Level of activity
0
Fully active, able to carry on all predisease performance without restriction Restricted in physically strenouous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g. light housework Ambulatory and capable of all self-care, but unable to carry out any work activities, up and about >50% of waking hours Capable of only limited self-care, confined to bed or chair >50% of waking hours Completely disabled, cannot carry out any self-care. Totally confined to bed or chair
1
2
3 4
Table 2
3
Ó 2015 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Jones R, Cytotoxic chemotherapy: clinical aspects, Medicine (2015), http://dx.doi.org/10.1016/ j.mpmed.2015.10.007
SYSTEMIC THERAPY
individual drugs or classes of drugs; for example ifosfamide can cause haemorrhagic cystitis and central nervous system toxicity. The National Cancer Institute in the USA has devised a standardized way of reporting toxicities using a graded scale, the Common toxicity criteria.11 This is used in clinical trials to allow a comparison between different chemotherapy drugs. Predictable toxicities can be prevented with appropriate prophylaxis, for example antiemetic combinations are prescribed according to the expected emetogenic potential of the regimen. Primary granulocyte colony-stimulating factor is used if the chemotherapy schedule has a greater than 20% risk of causing febrile neutropenia.12 However, if toxicity cannot be controlled with medical management, a reduction in the dose of chemotherapy is required. This is particularly relevant in palliative chemotherapy where symptom control and quality of life are at a premium. The late adverse effects of chemotherapy can be minimized by limiting doses where thresholds are known. However, in most instances they cannot be easily predicted and treatment is primarily symptomatic. Examples of late toxicities include the congestive cardiomyopathy seen with high total doses of anthracyclines, pulmonary fibrosis with bleomycin, neurotoxicity with platinum-based agents, vinca alkaloids and taxanes, and persistent cytopenias with alkylating agents. There is a small but increased risk of second malignancy in long-term survivors. NonHodgkin’s lymphoma and acute myeloid leukaemia, for example, have been reported as a late complication in patients treated for Hodgkin’s disease with chemotherapy and radiotherapy. Other late toxic sequelae include the risk of premature menopause in women and the risk of gonadal failure and dysfunction.13
occur due to occult micro-metastatic disease. Combination therapies give the greatest chance of cure and there is a greater emphasis on maintaining dose intensity. Clinical trials of adjuvant therapy have to be large to generate enough power to detect small differences in survival, which are usually of the order of around 5e10%. In the adjuvant setting treatment is focused on microscopic disease, so there is no disease response to measure and patients are offered treatment based on an assessment of risk. When evaluating suitable patients for adjuvant therapy, several patient and tumour characteristics are assessed. The tumour histology, its site, size, stage and biological features are important, as are the patients’ wishes, their biological age, comorbidities and performance status. In breast cancer, tools have been developed to aid the decision-making process. Adjuvant! is an online software tool that provides a survival estimate for chemotherapy or hormone therapy at 10 years, using the information gathered from large population databases.8 However, as a 5% survival advantage equates to a single patient being cured for every 20 who receive chemotherapy there is clearly a need to better define patients who will benefit from treatment. Gene assays such as Oncotype DXÒ have also been developed to give an estimate of risk by analysing the expression of gene sequences within a tumour. Their use is currently being assessed in prospective randomized trials but they should lead to improved outcomes and patient selection.9 Examples of cancer types for which adjuvant chemotherapy is well-established include breast, colorectal, ovarian and lung cancer.
Mechanisms of resistance Neoadjuvant chemotherapy
Resistance to chemotherapy is one of the main reasons for treatment failure, and in any given tumour type there are usually a combination of different mechanisms that contribute. Although there are strategies in development to try and reverse drug resistance, currently the only realistic choice for the clinician is to switch to an alternative cytotoxic drug or combination. The absence of a valid alternative normally heralds cessation of active drug therapy and a switch to symptomatic control. The only alternative would be to receive an experimental agent in the context of a clinical trial. A
There are potential advantages to giving adjuvant therapy as early as possible. When it is given before surgery, this is called ‘neoadjuvant’. Early treatment exposes the tumour and potential micro-metastases to therapy, thus avoiding the delay caused by surgery and recovery. The sensitivity of the primary tumour is easily assessed, and a reduction in bulk may allow for more conservative surgery. For example, in the treatment of low rectal cancer, preoperative chemoradiotherapy improves the rate of sphincter-sparing surgery.10 Locally advanced tumours which are initially unresectable may become resectable, increasing the possibility of cure and reducing the risk of local recurrence. Examples of where neoadjuvant chemotherapy is commonly used include inflammatory breast, rectal, bladder and bone cancers.
REFERENCES 1 Price P, Sikora K, Illidge T, eds. Treatment of cancer. 5th edn. London: Edward Arnold, 2008. 2 Brighton D, Wood W, eds. The Royal Marsden handbook of cancer chemotherapy. London: Churchill Livingstone, 2005. 3 Meta-Analysis Group in Cancer. Efficacy of intravenous continuous infusion of fluorouracil compared with bolus administration in advanced colorectal cancer. J Clin Oncol 1998; 16: 301e8. 4 Colucci G, Gebbia V, Paoletti G, et al. Phase III randomized trial of FOLFIRI versus FOLFOX4 in the treatment of advanced colorectal cancer: a multicenter study of the Gruppo Oncologico DellItalia Meridionale. J Clin Oncol 2005; 23: 4866e75. 5 Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 2004; 350: 2335.
Toxicity of chemotherapy The adverse effects of chemotherapy can be considerable, and it is important to educate and monitor patients carefully during treatment. Toxicities vary according to the specific agent, dose, route and schedule of administration and any predisposing patient factors, which may be known or unknown. Apart from nausea and vomiting and acute cholinergic gastrointestinal effects, most common toxicities occur because of the cytotoxic effects on normal dividing cells. These include myelosuppression with leucopenia, thrombocytopenia, anaemia, mucous membrane ulceration and alopecia. Other toxicities are less common and are specific to the
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6 Heinemann V, von Weikersthal LW, Decker T, et al. FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer (FIRE-3): a randomized, open label, phase 3 trial. Lancet Oncol 2014; 15: 1065e75. 7 Berry SR, Cosby R, Asmis TR, et al. Randomized controlled trials (RCTs) examining continuous (CS) versus intermittent strategies (IS) of delivering systemic treatment (Tx) for untreated metastatic colorectal cancer (mCRC): a meta-analysis from the Cancer Care Ontario program in evidence-based care. J Clin Oncol 2013. Suppl 31: Abstract 3534. 8 http://www.adjuvantonline.com/index.jsp (accessed 22 Jul 2011). 9 Zujewski JA, Kamin L. Trial assessing individualized options for treatment for breast cancer: the TAILORx trial. Future Oncol 2008; 4: 603e10.
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10 Sauer R, Becker H, Hohenberger W, et al. German rectal cancer study group. Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med 2004; 351: 1731e40. 11 National Cancer Institute. http://ctep.cancer.gov/ protocolDevelopment/electronic_applications/ctc.htm (accessed 22 Jul 2011). 12 Smith TJ, Khatcheressian J, Lyman GH. 2006 update of recommendations for the use of white blood cell growth factors: an evidence-based, clinical practice guideline. J Clin Oncol 2006; 24: 3187e205. 13 Skeel RT. Handbook of cancer chemotherapy. 6th edn. Philadelphia: Lippincott Williams & Wilkins, 2003.
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Please cite this article in press as: Jones R, Cytotoxic chemotherapy: clinical aspects, Medicine (2015), http://dx.doi.org/10.1016/ j.mpmed.2015.10.007