Mechanisms and groups

Alkylating agents contain alkyl groups (e.g. methyl, ethyl) and form highly reactive chemical structures that react rapidly with an electron donor group, such as a nitrogen atom in a guanine base of DNA, forming strong bonds as the alkyl group is ‘donated’ to the DNA base (see Figure 42-1). The alkylating agents usually are bifunctional, i.e. they have two active ‘arms’ that can link across or along the strands of DNA chains. This effectively ties the double helix together (like a zipper that has become stuck by having thread caught in it and cannot be unzipped), and interferes with the unwinding of the DNA strands in the processes of transcription to RNA and replication of DNA. Thus the cell cycle (Figure 41-1) is blocked mainly at the S phase, before the G₂ phase, and cell proliferation is slowed or stopped. Some alkylating agents are considered cell-cycle-specific, others are cell-cycle-non-specific.

Figure 42-1 Chemical structures of representative antineoplastic agents. A Alkylating agent (cyclophosphamide) and cisplatin. B Antimetabolites: mercaptopurine, fluorouracil (FU) and methotrexate (MTX); compare with endogenous compounds adenine, thymine and folate and see also Figure 41-3.

Various types of alkylating agents are available, such as the nitrogen mustards (including chlorambucil, cyclophosphamide [Drug Monograph 42-1 and Figure 42-1], melphalan and ifosfamide) and nitrosoureas (carmustine, fotemustine and lomustine). Nitrosoureas are highly lipophilic alkylating agents that readily cross the blood–brain barrier and are thus useful for treating primary brain tumours. Other alkylating agents include busulfan, dacarbazine (and its orally active analogue temozolomide) and thiotepa.

Groups of antimetabolites

The chemical structures of three typical antimetabolites (*) are shown in Figure 42-1. The antimetabolites fall into three main groups:

Folic acid antagonists

Folic acid is an essential co-factor in many biochemical reactions, particularly in one-carbon transfers, and is essential for the synthesis of purines and the methylation of uracil. An enzyme essential for the activation of folate to tetrahydrofolate is dihydrofolate reductase. This enzyme is inhibited by the folic acid antagonist methotrexate (MTX; see Drug Monograph 42-2). MTX has a structure very similar to folic acid (as shown in Figure 42-1B) so it competes with dihydrofolate for the active site on the enzyme. The blockade of biochemical reactions dependent on the co-factor activities of folic acid impairs synthesis of macromolecules required for cell proliferation, and halts cell cycling. (The sulfonamide antibacterial drugs have a similar mechanism of action and are also classed as antifolate drugs, but are more specific for bacterial metabolic pathways than those in neoplastic cells.) Pemetrexed, a new antifolate drug, also inhibits folatedependent enzymes.

Purine and pyrimidine antagonists

The purine and pyrimidine base analogues can be incorporated into DNA strands in place of the true bases, forming permanently modified DNA and leading to improper base pairing during replication of DNA and improper transcription to RNA. They may also act as specific inhibitors of enzymes involved in DNA synthesis. Thus macromolecular synthesis and cell duplication are impaired. The antimetabolites are considered to be phasespecific agents, as they act particularly at the S phase of the cell cycle.

A cunning technique for making anticancer drugs more specific for neoplastic cells is exemplified in the new drug capecitabine, which is a prodrug for fluorouracil (FU). It has been rationally designed to be ‘tumour-activated’: after oral administration it is metabolised in three stages, the last of which involves the enzyme thymidine phosphorylase, which is more active in the liver and tumour cells than in normal cells. Hence 2.5-fold higher levels of active FU are reached in tumour cells than in adjacent tissue, which optimises therapeutic effects and minimises adverse effects. Capecitabine is proving particularly effective in breast and colorectal cancers.

Antibiotic antitumour drugs

The third main group of cytotoxic agents is the antibiotic antitumour agents, such as the anthracyclines and bleomycins. These drugs are defined as antibiotics because they are compounds that are isolated from one type of organism (usually fungi) and act against another type of organism. In this context the antibiotic activity is against neoplastic cells, rather than bacterial cells as for traditional antibiotics such as penicillins. The early agents in this class (daunorubicin, doxorubicin) caused the clinically limiting adverse effect of irreversible cardiomyopathy; newer agents are being sought that lack this cardiac toxicity. (See Table 42-1 for the drugs in this classification, primary indications and major toxicities.)

Mechanisms of action

Mechanisms of action

During the metaphase stage of mitotic division (see Figure 41-1), the replicated chromosomes line up on a spindle formed from microtubules. Mitotic inhibitors bind to the protein tubulin, a constituent of microtubules, which inhibits its polymerisation into microtubules, disrupts spindle formation and arrests mitosis in metaphase. Thus they are said to be cell-cycle-phase-specific agents, inhibiting cell cycling during the late G₂ and M phases. (Inhibition of microtubule actions also impairs other processes in cells, including chemotaxis, phagocytosis and axonal transport of neurotransmitters.) The mitotic inhibitors may also have other actions that contribute to their cytotoxic effects; e.g. the vinca alkaloids impair uridine incorporation into mRNA.

Drug groups

Platinum compounds

The platinum-containing compounds cisplatin, carboplatin and oxaliplatin are sometimes considered as alkylating agents, as they have a rather similar mechanism of action. In cisplatin, the platinum atom is bonded to two amine groups, which cross-link between DNA strands (see Figure 42-1). Cell division is inhibited, leading to apoptosis; these compounds are cell-cycle-non-specific. Cisplatin is particularly emetogenic, and most likely to cause nephroand neurotoxicities. The three platinum compounds have different indications, contraindications, adverse drug reactions, and dosage and administration guidelines, so individual specialist oncology protocols should be consulted for these details.

Podophyllotoxins

The podophyllin-type compounds etoposide and teniposide are sometimes included with mitotic inhibitors as they can cause metaphase arrest; however, their mechanisms of action are not simple, as they also kill cells in the S and G₂ phases of the cell cycle and may inhibit topoisomerase II (see Clinical Interest Box 42-2). They are used mainly in leukaemias and lymphomas.

Topoisomerase I inhibitors

The topoisomerase type I enzymes are involved in the untwisting, nicking and resealing of DNA strands during the processes of DNA duplication. Agents that inhibit these enzymes cause breaks in double-stranded DNA, blocking macromolecular synthesis in the cell cycle and leading to tumour cell death. Two new antineoplastic agents with this mechanism of action are derivatives of the plant Camptotheca accuminata and have been given the generic name camptothecins. They are S phase-specific.

Topotecan, a topoisomerase I inhibitor, is indicated for the treatment of relapsed or refractory metastatic carcinoma of the ovary after failure of other therapies, and also for small-cell lung cancer. Adverse reactions include neutropenia (a dose-limiting toxicity), leucopenia, thrombocytopenia, anaemia, headache, GI tract disturbances, alopecia, tiredness, dyspnoea and neuromuscular pain. The usual dose is 1.5 mg/m² by IV infusion over 30 minutes daily for 5 days.

Irinotecan, another topoisomerase I inhibitor, is indicated for the treatment of metastatic colorectal cancer that has occurred or progressed after FU chemotherapy. Irinotecan can cause severe diarrhoea, which requires immediate treatment with atropine or loperamide. Severe myelosuppression, nausea and vomiting may also occur.

Colaspase (formerly known as asparaginase)

The enzyme asparaginase hydrolyses the amino acid L-asparagine to L-aspartic acid and ammonia. Asparagine is necessary for cell survival and, because normal body cells are capable of synthesising adequate supplies of asparagine, they are not affected by an asparagine deficiency. Certain cancer cells, however, are unable to synthesise asparagine and depend on a circulating supply of asparagine within the blood; administration of asparaginase enhances the breakdown of asparagine, so the cancer cells will die. Colaspase is sometimes classed as an antimetabolite, as it exploits differences between metabolic pathways in normal and neoplastic cells.

Colaspase is a form of asparaginase produced from cultures of Escherichia coli; as it is a protein, it cannot be given orally, but is administered by IM injection or IV infusion to treat leukaemias and lymphoma. Adverse reactions include allergic reactions (including anaphylaxis), a decrease in the blood clotting factors, hyperammonaemia (headache, anorexia, nausea, vomiting and abdominal cramps), liver toxicity and nervous system dysfunction. The drug should be administered only in hospital settings because of the risk of anaphylaxis.

Altretamine

Altretamine is a cytotoxic agent for the palliative treatment of persistent or recurrent ovarian cancer. Its mechanism of action is unknown, although chemically it resembles the alkylating agents. Clinically, however, it is effective for ovarian tumours that are resistant to the previously marketed alkylating agents. Its main adverse reactions are bone marrow suppression, GIT dysfunction and neurotoxicity.

Hydroxyurea

Hydroxyurea inhibits DNA synthesis by interfering with the conversion of ribonucleotides to deoxyribonucleotides; it is sometimes classified with the antimetabolites. It is indicated for the treatment of ovarian carcinoma, chronic myelocytic leukaemia and malignant melanoma. Adverse reactions include bone marrow suppression and GI tract dysfunctions.

Prostate cancer

For example, prostate cancer may be treated by:

Breast cancer

Breast cancer, the commonest cancer in Australian women (27% of all diagnoses) may be genetic, but more commonly occurs sporadically and the risk is related to length of oestrogen exposure. The risk of developing breast cancer can be reduced by adopting a healthy lifestyle (low alcohol consumption, low-fat and high-fibre diet, exercise and low weight) and by early detection of cancer (regular breast selfexamination and mammography). Women at high genetic risk for breast cancer can reduce the risk by prophylactic use of antioestrogens (tamoxifen or raloxifene), or even by pre-emptive surgery to remove the breasts.

If breast cancer develops, the initial treatment is usually surgery and radiation therapy, then chemotherapy with an antioestrogen or SERM and possibly cytotoxic agents. Biopsies can be taken and tested for levels of oestrogen and progesterone receptors and for levels of the proto-oncogene c-her2/neu, which encodes the protein EGF receptor 2; if the latter levels are high, the drug trastuzumab (Herceptin), a monoclonal antibody against the her2 protein, can be effective.

Androgens

Androgens such as testosterone (Drug Monograph 39-1) and fluoxymesterone are used to treat advanced breast carcinoma if surgery, radiation and other therapies are inappropriate or ineffective.

Antiandrogens

The group of antiandrogenic agents includes flutamide, bicalutamide, nilutamide and cyproterone (a partial agonist). These drugs inhibit the uptake or the binding of androgens at their target cells or receptors. The result is suppression of ovarian and testicular steroidogenesis, thus inducing a ‘medical castration’. They are indicated in combination with surgery and a GnRH analogue (see below) for treatment of advanced prostate cancer. This combination has been reported to prolong survival by at least 25% compared with GnRH therapy alone. Adverse reactions include diarrhoea, impotence and other symptoms of low testosterone levels, and hepato-toxicity.

In many men with prostate cancer, the tumour becomes resistant to the actions of antineoplastics, so-called ‘castration-resistant prostate cancer’, due to mutations in or increased expression of the androgen receptor, increased synthesis of androgens or alteration or upregulation of some TK pathways. Second-generation antiandrogens attempt to overcome this resistance; one new analogue under clinical trial in advanced prostate cancer, the drug MDV3100, has greater relative affinity for the androgen receptor than bicalutamide and shows sustained declines in levels of PSA, a marker for prostate overactivity. Other drugs being tested in resistant prostate cancer include drugs that reduce androgen synthesis, inhibit transcription of androgen receptors or enhance androgen receptor degradation.

Oestrogens

Oestrogens may be used to treat androgen-sensitive prostatic carcinomas or advanced breast carcinoma in postmenopausal women. Oestrogens such as diethylstilboestrol and ethinyloestradiol, for example, have been used to treat advanced prostatic carcinoma; however, they are rarely used for this indication now due to adverse cardiovascular effects (see Chapter 38 and Drug Monograph 38-2 for typical oestrogenic actions).

Oestrogens may occasionally be used in breast cancer to ‘recruit’ resting cells from the G₀ phase into active cell cycling again (G₁ phase), so the cells will be sensitive to cytotoxic agents.

Anti-oestrogens

Anti-oestrogens are useful in treatment of postmenopausal breast cancers that are oestrogen receptor (ER)-positive, i.e. tumours that contain high concentrations of ERs. They have replaced both androgens and oestrogens as the initial approach in breast cancer therapy. (Anti-oestrogens are less useful in premenopausal women because their effects would be swamped by the high levels of oestrogens produced by the ovaries.)

Selective ER modulators

Selective ER modulators (SERMs) have been designed to block ERs in breast cancers but maintain ER agonist actions in other tissues such as bone and cardiovascular system where oestrogen has protective actions. Tamoxifen and toremifene can in fact be classed as SERMs.

Raloxifene is a SERM currently used to prevent postmenopausal osteoporosis, as it has oestrogenic effects in bone, but anti-oestrogenic effects in uterus and breast tissues (see Chapter 38). It is also being studied for the treatment of breast cancer, with results showing a significant decrease in invasive breast cancer in women at increased risk of breast cancer (see Vogel et al [2006]; Sengupta and Jordan [2008]).

Aromatase inhibitors

In the biochemical pathways for the synthesis of oestrogens, a critical stage is the ‘aromatisation’ of the steroid A ring, from testosterone to oestradiol (see Figures 33-3 and 35-1); this step was difficult in the early attempts to synthesise oestrogens in the laboratory. In postmenopausal women, the main source of oestrogens in the body is from androgens via the aromatase enzyme actions in peripheral (non-ovary) tissues. Various compounds that inhibit the aromatase enzyme have been synthesised, including anastrozole, letrozole and exemestane. They are indicated for use in women with natural or induced postmenopausal status, whose breast cancer has progressed despite anti-oestrogen therapy. Aromatase inhibitors do not block the synthesis of glucocorticoids or mineralocorticoids.

Trastuzumab

Trastuzumab targets a growth factor receptor. It is a monoclonal antibody against the receptor for epidermal growth factor (EGF), a protein encoded by an oncogene (known as her-2) overexpressed in about 30% of women with breast cancer.¹ By blocking the EGF receptor, trastuzumab slows breast cancer progression and increases tumour reduction in women with this altered gene. It is used as monotherapy or has synergistic effects when used in combination with paclitaxel or with an antitumour antibiotic and cyclophosphamide. The antibody is administered by IV infusion. It has a very long half-life (about 6 days), but steady state is not reached for 4–8 months as the pharmacokinetics are non-linear. Hypersensitivity reactions and cardiotoxicity can occur.

Panitumumab is also an antibody against the EGF receptor, hence it inhibits cell growth and production of some cytokines and growth factors and induces apoptosis. It is indicated for use in patients with EGFR-positive metastatic colorectal cancer whose tumours have progressed despite treatment with cytotoxic chemotherapy; it is most effective in tumours expressing the wild-type KRAS gene. Skin-related toxicity is common, due to impairment of epidermal growth factor actions; other serious adverse effects include thromboembolism and hypomagnesaemia.

Rituximab

Rituximab is another genetically engineered monoclonal antibody, this one specific against an antigen (CD20) located on the surface of both normal and malignant B lymphocytes. The CD20 antigen governs the early steps in cell cycle initiation and differentiation, and it is found on more than 90% of B-cell non-Hodgkin’s lymphomas. Rituximab is indicated in treatment of B-cell non-Hodgkin’s lymphoma and is usually administered with the CHOP regimen: cyclophosphamide/hydroxydaunomycin/Oncovin (vincristine)/prednisone.

Others

Other new monoclonal antibodies include bevacizumab, specific against a vascular EGF, hence useful in slowing growth of new blood vessels supplying a tumour (angiogenesis); it is proving useful in treatment of renal cell carcinoma, which has previously been resistant to treatment with the usual antineoplastic drugs. Cetuximab is useful as an antibody against an EGF receptor overexpressed in many patients with colorectal cancer. Gemtuzumab is an antibody against CD33, a transmembrane receptor associated with myeloid cells; the antibody has antineoplastic activity in CD33-positive acute myeloid leukaemias and may be administered attached to a cytotoxic antibiotic (ozogamicin) to enhance the effects. Alemtuzumab, an antilymphocyte antibody, is used in treatment of chronic lymphocytic leukaemia; it binds to the CD52 glycoprotein and induces cell lysis. Infusion reactions are common, so dosage starts low, and premedication with steroids, an analgesic and an antihistamine is recommended. Most patients develop cytopenia and may require transfusion of blood or platelets; fatal infections have occurred.

Imatinib and gefitinib

Two such tyrosine kinase inhibitors (-tinibs) are imatinib and gefitinib. They are relatively new drugs, so clinical experience with their use is still accumulating. Imatinib (Drug Monograph 42-4) inhibits the TK in the receptor for Philadelphia chromosomal platelet-derived growth factor, and was the first anticancer drug targeted to a signal transduction protein unique to cancer cells. It is indicated for use in chronic myelocytic leukaemia (CML), various other leukaemias and gastrointestinal tumours. Adverse reactions including bone marrow suppression, gastrointestinal disorders and fluid retention are com mon. Gefitinib inhibits the TK associated with the receptor for EGF, which occurs particularly in solid tumours derived from epithelial tissues, such as non-small-cell lung cancers. Its major adverse reactions are interstitial pneumonitis and gastrointestinal and skin disorders. Drug interactions common to TK inhibitors are summarised in Drug Interactions 42-3.

Newer TK inhibitors

Several other new TK inhibitors are becoming available, such as lapatinib, nilotinib, sorafenib, erlotinib and sunitinib; each targets a particular TK and thus has specific indications for use in particular cancers, and specific adverse effects, depending on the TK inhibited. Sorafenib and sunitinib are oral TK inhibitors effective in some cases of renal cell carcinoma. Lapatinib is active against breast cancers overexpressing the HER-2 growth factor receptor and, when used in combination chemotherapy with capecitabine, it prolongs the time to disease progression. Nilotinib has been designed to bind to a specific TK in CML cells with the mutant Philadelphia chromosome and shows benefits in patients who have developed resistance to imatinib; sudden cardiovascular deaths have occurred due to prolongation of the QT interval. Dasatinib binds to a broader range of TKs than does imatinib, so is proving effective in some leukaemias that have developed resistance to the latter drug. Myelosuppression is common, so blood counts should be monitored regularly. Erlotinib is indicated in specialist protocols for non-small-cell lung cancer and pancreatic cancer. It has many serious adverse effects, including rashes, abnormal hair and nail growth, diarrhoea, GIT and liver disorders and, rarely, corneal or GIT perforation and interstitial lung diseases.

mTOR inhibitors

The mTOR (mammalian target of rapamycin) protein complex functions as an integration centre for various intracellular signalling pathways. For example, inhibition of the mTOR complex by sirolimus (aka rapamycin) is an important target for anticancer drugs (see review by Figlin et al [2008]).

Temsirolimus has an indirect mechanism of action, binding to an intracellular protein and blocking a target of a kinase and inhibiting the mTOR pathway; cell cycling is arrested and angiogenesis inhibited, leading to tumour suppression. It is used in treatment of renal cell carcinoma. Serious adverse effects include infusion reactions and hypersensitivity reactions, delayed wound healing and infections due to leucopenia. A similar drug, everolimus, has been approved in the USA for use in advanced kidney cancer. (Other -limus drugs such as tacrolimus are more selective for immunosuppressant actions, via blocking the action of calcineurin in activated T-cells, and are used in immune disorders and to prevent transplant rejection; see Chapter 47.)

BRAF inhibitors

The BRAF gene in humans encodes a protein B-RAF, belonging to a family of serine/threonine protein kinases. This protein is involved in regulating a pathway affecting cell division and differentiation and secretion; mutations in the gene are associated with various cancers, including colorectal, thyroid and lung and malignant melanoma. In late 2009, a breakthrough in the treatment of melanoma was announced when results from the first phase I clinical trial with a BRAF inhibitor were reported: whereas traditional chemotherapy often has little effect on melanomas, the BRAF inhibitor caused marked shrinkage of melanomas; larger scale trials are to be carried out in New York, Sydney and Melbourne.

Tumour vaccines

Immune surveillance² by T-cells against non-self cells implies that the specific defence systems in the body can mount an immune response against antigens expressed on the surface of tumour cells and destroy the cells. Only when the immune system is depressed and/or the load of mutated tumour cells becomes too great for the immune system to dispose of them, do cancers continue to develop (see Figure 41-4). This raises the hope that vaccines can be developed against cancers (see again Clinical Interest Box 41-7). The field of cancer immunology is beyond the scope of this chapter; however, it is worth noting that many anti-tumour vaccines are being developed, including against some oncogenic viruses. A notable recent vaccine against the human papilloma virus (HPV) is the non-live vaccine (Gardasil or Cervarix) developed in Australia. It is already in large-scale use in teenage girls and young women in many countries and provides effective protection against various strains of HPV.

Other strategies in cancer immunotherapy include the following (see review by Mastini et al [2009]):

Proteasome inhibitors

Proteasomes are large protease-containing complexes in cells, in which ubiquitinated proteins are degraded. There are hundreds of ubiquitin-protein ligases by which chains of poly-ubiquitinated proteins can be formed and thus proteins can be targeted for destruction by proteolysis in proteasomes. Complete inhibition of proteasome functions kills cells, so researchers have sought small-molecule specific inhibitors for regulatory proteins in the proteasome complex.

Bortezomib

Bortezomib, a new anticancer drug, is a proteasome inhibitor; it can be classed with cytotoxic agents. By blocking the targeted proteolysis normally performed by the proteasome, bortezomib disrupts various cell signalling pathways, leading to cell cycle arrest, apoptosis and inhibition of angiogenesis. Specifically, the agent inhibits nuclear factor (NF)-kappa B, a protein that is constitutively activated in some cancers. The drug thus interferes with NF-kappa B-mediated cell survival, tumor growth and angiogenesis. In vivo, bortezomib delays tumour growth and enhances the cytotoxic effects of radiation and chemotherapy.

It is being used in treatment of multiple myeloma, a cancer of the plasma cells (a type of B-lymphocyte) in which large amounts of useless immunoglobulins are formed. Multiple myeloma is characterised by bone lesions and pain, renal failure, anaemia and elevated calcium levels, and has been resistant to treatment by usual chemotherapeutic agents (previously melphalan and prednisolone, plus autologous stem cell transplantation). The relative roles of bortezomib, thalidomide and lenalidomide in treatment of multiple myeloma are still being established.

Radioactive isotopes

As described in Chapter 41 under ‘Treatment modalities’, radioactive isotopes may be used in cancer therapy. Radiopharmaceuticals used include iodine-131 (see Drug Monograph 34-3 and Clinical Interest Box 41-3), phophorus-32 and strontium-89. Preparing and administering these isotopes is a highly specialised area of hospital pharmacy practice.

Anagrelide

Anagrelide is a different type of agent; it has specific actions in reducing the platelet count and so is useful in essen tial thrombocytopenia, a condition in which platelets proliferate.

Methyl aminolevulinate

This unusual drug is a photosensitising agent that is applied as a cream to skin lesions (actinic keratoses or basal cell carcinomas) for 3 hours, then the area is exposed to red light, which activates the chemical to produce reactive oxygen radicals that selectively destroy tumour cells. Common adverse reactions include burning pain and ulceration at the site of application. The drug is a porphyrin precursor, and is related to verteporfin, used in a similar way as a photosensitiser to treat ocular macular degeneration (see Chapter 31).

Potentially toxic chemicals

Treatment of nausea and vomiting

The commonest and most distressing adverse reactions to cytotoxic drugs include nausea and vomiting. The chemoreceptor trigger zone in the medulla oblongata is sensitive to chemical stimuli, including emetogenic substances produced by cytotoxics, and to endogenous substances produced in radiation sickness and in the tumour lysis syndrome. Cytotoxics can be compared in terms of their emetogenic potential (see Table 41-2).

Nausea and vomiting are treated with antiemetic drugs, preferably prophylactically (see Chapter 29, and Drug Monographs 29-3 [metoclopramide] and 29-4 [ondansetron]); for low-risk agents, metoclopramide is given when necessary; for intermediate-risk agents, metoclopramide 20 mg IV or orally plus dexamethasone 20 mg IV or orally. For drugs with high emetic risk, a stronger antiemetic is required, such as an oral 5-hydroxytryptamine (5-HT³) antagonist (e.g. ondansetron) plus dexamethasone before chemotherapy. Other similar antiemetics are dolasetron, tropisetron and granisetron (also usefully available in a transdermal formulation). Phenothiazine antiemetic drugs (e.g. prochlorperazine) and antianxiety agents may also be helpful. For severe delayed emesis (>24 hours after chemotherapy), regular administration of IV antiemetics for 2–4 days may be necessary.

Aprepitant is a new antiemetic acting by a different mechanism: it inhibits substance P-mediated vomiting by selectively antagonising the neurokinin-1 receptor. Currently, it is recommended for use only with highly emetogenic cytotoxics such as high-dose cisplatin or cyclophosphamide plus an anthracycline. Fosaprepitant, a prodrug, is an IV formulation producing higher concentrations of aprepitant; it is effective in stopping delayed emesis.

Treatment of myelosuppression (bone marrow depression)

Bone marrow depression is usually the limiting factor in the clinical use of cytotoxics, causing treatment delays and dose reductions. White cells and platelets are the first affected, leading to immunosuppression, infections, bruising and bleeding. Neutrophil counts and platelet counts are monitored to indicate when, after cessation of chemotherapy, levels have risen high enough for another cycle of chemotherapy to commence. The main risk from thrombocytopenia (low platelet count) is haemorrhage; this may be treated or prevented with infusions of platelets or with haemostatic agents.

Hydration therapy and treatment of tumour lysis syndrome

Rehydration, to prevent renal tubular damage or hyperuricaemia, requires vigorous IV fluid infusion. During therapy with high-dose cisplatin, for example, about 2.5 litres of fluids (saline, mannitol and/or glucose) are infused before chemotherapy over 2–3 hours, with frusemide to encourage diuresis if necessary; then, after the chemotherapy, 2 litres of fluids are given over the next 10 hours.

Treatment of mucositis

Mouth ulcers from chemotherapy have traditionally been treated with mouthwashes of antiseptics and zinc.

Preservation of fertility

By far the majority of cancers develop in people over the age of 70 years, for whom adverse effects of cytotoxic agents on germ cells (ova, spermatozoa) are usually not an issue. However, with the increased survival rate of children from childhood cancers such as leukaemias and lymphomas, it is estimated now that one in every 250 adults is a childhood cancer survivor, and may have impaired fertility from earlier treatments. Also, with women in many societies delaying childbearing into their 30s, there are more women with early-onset cancers (breast, melanoma, cervical, leukaemias and lymphomas) anxious to preserve their fertility. Assisted reproduction technologies are helpful in preserving fertility, but require interdisciplinary cooperation between the various medical specialists involved in a woman’s treatment.

Interferons

Interferons are naturally occurring small protein molecules that have antiviral, antiproliferative and immunostimulating actions. They can be produced by recombinant technology, resulting in highly purified proteins that have effects similar to the interferon subtypes produced by human leucocytes. Interferons are expensive, however, and the cost of treatment courses is often prohibitive.

Immunomodulatory properties include enhanced phagocyte activity and increased cytotoxic properties of lymphocytes for target cells. Their mechanism of action as antineoplastic agents is unknown, but may be the result of one or more of the three properties identified above. In some types of cancer, for example, interferon appears to have a dual effect of both cytotoxicity and immune stimulation. Some patients demonstrate an increase in haematological factors, granulocytes, platelets and haemoglobin plasma levels.

Interferons alfa-2a and alfa-2b are indicated for the treatment of some leukaemias and lymphomas, genital warts, AIDS-related Kaposi’s sarcoma, bladder cancer, osteosarcoma and chronic active hepatitis. Toxicities reported include a flu-like syndrome with fever, chills, muscle pain, loss of appetite and lethargy. At higher doses, myelosuppression, nausea, vomiting, neurotoxicity and cardiotoxicity can occur. (Other interferons are more selective in actions against multiple sclerosis or viral infections.)

Levamisole

Levamisole was initially used clinically as a treatment for intestinal worm infestations. It was also found to have useful immunostimulant effects, enhancing T-cellmediated immunity and macrophage actions. Levamisole is used in combination with FU to treat colorectal carcinoma. This combination has resulted in a lengthened survival time (decreased mortality) and lowered risk of cancer recurrence. Levamisole can be administered orally, and adverse effects are usually mild; however, reversible bone marrow sup pression and a flu-like syndrome can occur.

Aldesleukin

Aldesleukin is another immunoregulatory lymphokine that stimulates immune function and is a recombinant version of human interleukin-2 (IL-2). This substance appears to stimulate T-cell proliferation and is a co-factor in enhancing growth of the body’s natural killer cells and the lymphokine-activated killer cells; it also increases production of interferons. Aldesleukin is indicated for the treatment of metastatic renal cell carcinoma, melanoma and thymoma, and after bone marrow transplant. Adverse effects of aldesleukin include oedema, anaemia, thrombocytopenia and hypotension. It is not generally available in Australia, but may be via the Special Access Scheme.

Colony-stimulating factors

Granulocyte colony-stimulating factors (G-CSFs: filgrastim, lenograstim, pegfilgrastim) are recombinant versions of bone marrow-stimulating factors with immunomodulatory actions. G-CSFs are used to mobilise stem cells to stimulate the production of phagocytes and thus decrease the potential for infection in people receiving myelosuppressant agents (such as cytotoxics) that are associated with severe neutropenia and fever. Neutrophil counts are closely monitored after the nadir (lowest level) induced by bone marrow transplant or chemotherapy. G-CSFs should be discontinued when the absolute neutrophil count reaches 10,000/mm³ or higher. The major adverse reactions include splenomegaly, hair loss, diarrhoea, fevers, mucositis, anorexia and fatigue. Bone pain has been reported about 2–3 days before the increase in neutrophil count. This pain is usually controlled with non-opioid analgesics. The usual doses are in the range 1–20 mcg/kg per day by SC injection.

BCG (non-vaccine)

BCG stands for bacille Calmette–Guérin, or the Mycobacterium bovis bacillus. The BCG vaccine is a live bacterial vaccine for immunisation against tuberculosis; when commonly used in the early 20th century it was found that BCG vaccine reduced risk of some cancers including bladder cancer (see Clinical Interest Box 41-7). The non-vaccine formulation is also a preparation of an attenuated strain of the bacterium; however, it is administered for its immunostimulatory effects rather than to produce immunity against the particular organism. The mechanism whereby BCG reduces cancerous lesions of the urinary bladder is unknown; it promotes a local inflammatory response and white cell infiltration of tissue.

It is administered not intradermally (as is the vaccine) but instilled by urethral catheter into the urinary bladder of patients with bladder carcinoma, to reduce tumour recurrence. Patients who are immunocompromised are at risk of systemic tuberculosis infection; other adverse effects include urinary tract pain and dysfunction and fever and malaise.

Other immunostimulating therapy

Bisphosphonates

The bisphosphonates (including pamidronate, zoledronic acid, ibandronic acid and sodium clodronate; see Chapter 37) bind to hydroxyapatite in bone and specifically inhibit osteoclast-mediated bone resorption. They are used to improve bone mineral density in osteoporosis and Paget’s disease of bone, and to prevent corticosteroid-induced osteoporosis (see Drug Monograph 37-5). In cancers, they are used to reduce the skeletal morbidity that occurs with bony metastases and to reduce tumour-induced hypercalcaemia.

Radioactive isotopes

The radioisotopes strontium-89 and samarium-153 are used for palliation of bone pain in osteoblastic skeletal metastases (secondary cancers in the bone).

Pharmacological aspects of palliative care

As well as the drugs used to treat the disease for which the patient is receiving care, many other drugs may be useful in providing improved quality of life and comfort, such as analgesics for pain and dyspnoea and drugs to treat side effects of the primary drugs (e.g. antiemetics, immunostimulants, GCSFs). Decisions may also need to be made as to whether or for how long to continue with drugs being administered for other concurrent chronic conditions, such as diabetes mellitus, hypertension, arthritis or asthma.

Drugs commonly administered in palliative care situations include:

Special Access Scheme

The Special Access Scheme (SAS) is a process administered in Australia by the Therapeutic Goods Administration of the Commonwealth Department of Health and Ageing (see www.tga.gov.au/index.htm). It refers to arrangements whereby an unapproved therapeutic good (e.g. drug or device) can be imported or supplied for a single patient on a case-by-case basis. The medical practitioner must provide details of the patient, the product and the prescriber, and give clinical justification for the requirement for the product. The SAS may be applied in the case of seriously ill patients who may benefit from a new anticancer agent that is being used overseas but has not yet been approved for general use in Australia. Some drugs included in the SAS in 2010 are the antineoplastic agents aldesleukin, amsacrine and gemtuzumab; sufentanil for pain relief and cyclizine for nausea and vomiting.

Drugs targeting hypoxic cells

Tumour cells that have become hypoxic are resistant to killing by radiation therapy or by most antineoplastic drugs; this limits the success of therapy of most large solid tumours. Tirapazamine is a novel anticancer drug that targets hypoxic cells. Its mechanism of action is to be reduced in hypoxic cells to a toxic free radical that decays to oxidising free radicals that damage DNA or damage topoisomerase II enzymes. Early clinical trials of tirapazamine in lung or head and neck cancers looked promising; however, later trials showed little benefit in survival times when added to chemo- or radiation therapy. Trials are ongoing (see review by Reddy and Williamson [2009]).

Similar ‘hypoxic cytotoxins’ that are activated in hypoxic cells from prodrugs are banoxantrone and a new class of benzamide mustards. Other techniques targeting hypoxic cells include using drugs that sensitise hypoxic cells to radiation therapy (metronidazole and related compound nimorazole are being trialled), and targeting hypoxia-associated genes and proteins (see review by Bache et al [2008]).

Smart drug delivery systems

CAM in cancer

Sadly, many people with cancer rely on unproven ‘natural remedies’ until a tumour has grown so large that it is too late for conventional anticancer treatments (surgery, radiation, drugs) to be effective.

With respect to prevention of cancer, it is worth recalling that up to 80% of cancers are initiated by or exacerbated by natural causes, including carcinogens in the environment (e.g. tars and other hydrocarbons, UV radiation) or dietary or lifestyle factors (high-fat/low-fibre diets, nitrosamines, aflatoxins, cigarettes, alcohol). We cannot alter our genotype, which may endow us with oncogenes or predisposition to particular cancers, but some of the environmental factors are avoidable.

Patients often use both prescribed medical therapies and complementary and alternative therapies concurrently. It is becoming apparent that drug interactions between conventional medical treatments and CAM do occur and can have adverse effects, so it is important that patients discuss with their physicians what other remedies they are using. Some unorthodox methods tried in treatment of cancer are listed in Clinical Interest Box 42-5. Complementary and alternative techniques have also been used to treat the symptoms of cancer and the adverse effects of conventional treatments, such as pain, breathlessness, nausea and vomiting and mucositis. Relaxation training and hypnosis have been shown to improve patients’ coping skills.