Chemotherapy and related treatments

Published on 03/04/2015 by admin

Filed under Hematology, Oncology and Palliative Medicine

Last modified 22/04/2025

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Chemotherapy and related treatments

General principles

The life cycle of the normal cell is shown schematically in Figure 27.1. Conventional anti-leukaemic and lymphoma cytotoxic drugs can be broadly divided into those agents active during only one phase of the cell cycle (‘phase-specific’) and those acting at all stages (‘phase non-specific’). In practice, most anti-leukaemic drugs act predominantly against proliferating cells and therefore affect a fraction of the malignant cell population. Thus, if in advanced acute leukaemia the total number of malignant cells is 10¹⁰, a single course of chemotherapy could be expected to kill between 2 and 5 log of cells, leaving between 10⁵ and 10⁸ residual leukaemic cells. It can be seen that the chance of eradication of the disease by chemotherapy is favoured by early treatment when the leukaemic mass is small and by repeated courses of cytotoxic drugs. It is also logical to combine different agents to maximise the anti-leukaemic activity and exploit different toxicities (‘combination chemotherapy’).

Fig 27.1 The cell cycle.

Major classes of conventional cytotoxic drugs

Alkylating agents

Despite their variable structure, all alkylating agents appear to have a common mechanism with cross-linking of DNA the principal cytotoxic action. Agents commonly used in haematological practice include melphalan, chlorambucil, cyclophosphamide, busulfan and bendamustine. These are toxic to rapidly proliferating cells and the dose-limiting toxicity is myelosuppression. Other side-effects include infertility, haemorrhagic cystitis (cyclophosphamide) and an increased risk of secondary malignancy.

Antimetabolites

These drugs are compounds which interfere with the utilisation of a natural metabolite by virtue of the similarity of their chemical structure. Most are analogues of nucleic acid precursors. Commonly used examples are the folinic acid analogue methotrexate, the purine analogues 6-mercaptopurine and fludarabine, and the pyrimidine analogue cytosine arabinoside. The alkylating agent bendamustine also has some antimetabolic activity. The main toxic effect of the group is myelosuppression. Fludarabine is significantly immunosuppressive.

Topoisomerase poisons and inhibitors

This broad class of drugs includes the anthracyclines (doxorubicin, daunorubicin, mitoxantrone, idarubicin) and the epipodophyllotoxins (etoposide). The anthracyclines are cell cycle non-specific drugs. The acute dose-limiting toxicity is bone marrow suppression but the cumulative dosage is limited by cardiotoxicity. Etoposide is a phase-specific drug (active in G₂) with myelosuppression the major toxicity.

Spindle poisons

Key agents in this group are the two vinca alkaloids, vincristine and vinblastine. They are cell-cycle phase-specific, exerting a cytotoxic effect by binding to cellular microtubular protein and inhibiting mitosis. Vincristine’s major adverse effects are mixed motor-sensory and autonomic neuropathies (patients usually initially complain of ‘pins and needles’ in the fingers or toes and constipation); vinblastine is less neurotoxic but causes more bone marrow suppression.

Side-effects of conventional cytotoxic drugs

Some toxic effects are common to many cytotoxic drugs and must be discussed with all patients receiving a relevant single agent or combination chemotherapy (Table 27.1). Myelosuppression and alopecia are often unavoidable. However, nausea and vomiting can usually be minimised or even completely avoided by modern antiemetic protocols. The probability of infertility is influenced by the agents used, the total dosage, the duration of administration and the age and sex of the patient. Strategies to minimise infertility include prechemotherapy storage of germ cells (unfortunately, fertility is often abnormal at presentation) or choice of regimens which are relatively non-sterilising. Gonadal failure occurs more commonly in women and may be managed by hormone replacement therapy; androgens are used in men. Chemotherapy is associated with an increased risk of secondary malignancy including leukaemia and solid tumours. Alkylating agents are particularly leukaemogenic.

Table 27.1

Common adverse effects of cytotoxic drugs

Short-term effects	Long-term effects
Myelosuppression	Infertility
Nausea and vomiting	Secondary malignancy
Alopecia
Mucositis

Note: If extravasated from the vein some drugs can cause severe tissue injury.

Multi-drug resistance

The major problem in the treatment of leukaemia and other haematological malignancies is the emergence of cells resistant to chemotherapy. Genes capable of conferring resistance to cytotoxic drugs have been characterised. Of particular note is the P-glycoprotein or multi-drug resistance gene (MDR1), as its over-expression can lead to resistance to many of the agents used in the treatment of leukaemia. The MDR1 gene encodes a membrane protein which acts as an ATP-dependent efflux pump transporting organic compounds out of the cell. Elevated MDR1 levels appear to predict a poor prognosis in acute myeloid leukaemia. A number of MDR-reversing agents (e.g. ciclosporin, PSC-833, zosuquidar) have been given in conjunction with normal chemotherapy in AML but so far with little benefit.

Other treatments for haematological malignancy

Conventional chemotherapy currently plays the major role in the treatment of most haematological malignancies but, as these selected examples demonstrate, there is increasing emphasis on more targeted therapies which exploit particular characteristics of tumour cells and cause fewer systemic side-effects.

Differentiating agents

In most cases, attempts to induce maturation of malignant cells have been disappointing. One notable exception is the drug all-trans-retinoic acid (ATRA) in acute promyelocytic leukaemia (associated with t(15;17)). At pharmacological concentrations ATRA overcomes the suppressive effect of the PML-RARα fusion protein, allowing leukaemic promyelocytes to differentiate into neutrophils. Addition of ATRA to normal chemotherapy reduces the severity of APL-related coagulopathy and gives a significantly better survival than chemotherapy alone. The major side-effect is ‘ATRA syndrome’ where a rising white blood cell count accompanies systemic upset with cardiopulmonary and renal problems.

Monoclonal antibodies

Monoclonal antibodies (MoAbs) promise tumour-targeted therapy with minimal toxicity. They may be unconjugated or conjugated to a toxin or radioisotope. One potential target is the CD20 antigen which is present in over 90% of B-cell lymphomas. An unconjugated chimeric human-mouse anti-CD20 MoAb (rituximab) is widely used in association with chemotherapy in follicular and diffuse large B-cell non-Hodgkin’s lymphomas. Newer anti-CD20 agents (e.g. ofatumumab) are being investigated. The linking of a radionucleotide to anti-CD20 may improve efficacy. Other MoAbs in clinical practice include anti-CD52 (alemtuzumab) in chronic lymphocytic leukaemia, anti-CD33 (Mylotarg) in acute myeloid leukaemia and anti-CD30 (brentuximab) in Hodgkin’s lymphoma.

Tyrosine kinase inhibitors (TKIs)

Imatinib mesilate (Glivec), a specific small molecule inhibitor of BCR-ABL, is very effective drug therapy for chronic myeloid leukaemia (CML) (see also p. 45). In patients who develop resistance to imatinib more potent BCR-ABL inhibitors (e.g. dasatinib, nilotinib) can give good responses. Other TKIs entering clinical practice include JAK2 inhibitors (e.g. ruxolitinib) in myeloproliferative neoplasms and FLT3 inhibitors in acute myeloid leukaemia.

Proteosome inhibitors

The proteosome is an enzyme complex that plays a crucial part in cell-cycle control and gene expression by regulating cellular protein degradation. Inhibition of the proteosome ultimately results in cell death. Bortezomib (Velcade) is a proteosome inhibitor that is able to kill tumour cells selectively. It is effective in myeloma and it also has activity in non-Hodgkin’s lymphomas. The most troublesome side-effect is peripheral neuropathy.

Epigenetic therapies

The term ‘epigenetics’ refers to heritable changes in gene expression which are not coded in the DNA sequence. Epigenetic mechanisms, including DNA and histone modifications, are potentially reversible. The hypomethylating agents azacitidine and decitabine have activity in myelodysplastic syndrome and acute myeloid leukaemia.

Anti-angiogenic agents

Myeloma is known to be associated with increased angiogenesis in the bone marrow. The anti-angiogenic agents thalidomide and lenalidomide now play key roles in the treatment of this malignancy. Both drugs have other mechanisms of action including alteration of tumour cell cycle progression and immunomodulation.

Interferon alfa

Interferon alfa is an antiviral protein with immunomodulatory and anti-cancer activities. It has been extensively used in CML and hairy cell leukaemia but is now being largely supplanted by more effective and better tolerated agents.

Haematopoietic growth factor therapy

Several haematopoietic growth factors are routinely used in clinical haematology. Their main use is in haematological malignancy.

Supportive care in patients with blood cytopenia

G-CSF (see p. 2) is most commonly used to accelerate the production of neutrophils following chemotherapy or stem cell transplantation. The shortened period of neutropenia reduces the incidence of infections and the length of stay in hospital. It can also help maintain the dose intensity of chemotherapy. Erythropoietin is mainly used to treat the anaemia of renal failure but may ameliorate anaemia in selected patients with myelodysplastic syndrome and myeloma. Early trials of thrombopoietin-like agents to treat thrombocytopenia were unsuccessful due to the development of neutralising antibodies. Thrombopoietin receptor agonists are used in immune thrombocytopenia (see p. 69) but they have no definite role in thrombocytopenia due to marrow failure.

Stem cell mobilisation

G-CSF is used in conjunction with chemotherapy to ‘mobilise’ stem cells from the bone marrow to the blood prior to harvesting (see also p. 56).

Chemotherapy and related treatments

There are several classes of conventional cytotoxic drugs with different mechanisms of action.

In leukaemia and lymphoma it is usual to combine cytotoxic drugs in repeated courses to maximise anti-tumour activity and exploit different toxicities.

Cytotoxic drugs have predictable short-term and long-term side-effects.

Conventional chemotherapy is increasingly being supplemented, or even replaced, by therapies targeting particular characteristics of tumour cells (e.g. tyrosine kinase inhibitors in CML).

Erythropoietin may be used to treat anaemia in selected patients with haematological malignancy.

G-CSF is used to shorten the duration of neutropenia after intensive chemotherapy and to mobilise stem cells for harvesting.

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