CLINICAL PHARMACOLOGY 2003 (PART 31)

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CLINICAL PHARMACOLOGY 2003 (PART 31)

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Neoplastic disease In most cases, the cause of cancer is multifactorial. About 75% of cancers are due to environmental factors, some of which are within the control of the individual, e.g. tobacco smoking, exposure to sunlight. Growing understanding of cancer genetics and inherited disease suggests that fewer than 10% of cancers are familial.The different systemic modalities used to treat cancer patients are discussed. Immunosuppressive drugs are described here as they share many characteristics with cytotoxics. ...

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  1. 30 Neoplastic disease and immunosuppression SYNOPSIS Neoplastic disease Neoplastic disease In most cases, the cause of cancer is multifactorial. About 75% of cancers are due to environmental factors, some of which are Cancer treatments and within the control of the individual, e.g. outcomes tobacco smoking, exposure to sunlight. Growing understanding of cancer genetics and Cancers share some common characteristics: inherited disease suggests that fewer than 10% Growth that is not subject to normal restrictions of cancers are familial.The different systemic for that tissue and fails to respond to apoptotic modalities used to treat cancer patients are signals (see later) or in which a high proportion discussed. Immunosuppressive drugs are of cells are dividing, i.e. there is a high 'growth described here as they share many fraction' characteristics with cytotoxics. Local invasiveness Cancer treatments and outcomes Tendency to spread to other parts of the body Rationale for cytotoxic chemotherapy1 (metastasise) Classes of cytotoxic chemotherapy drugs Less differentiated cell morphology Chemotherapy in clinical practice Tendency to retain some characteristics of the Endocrine therapy tissue of origin. Immunotherapy and biological therapies Cancer treatment employs six established princi- Emerging anticancer treatments pal modalities: Immunosuppression and immunosuppressive drugs 1. surgery 2. radiotherapy 3. chemotherapy 4. endocrine therapy 1 Although not in strict accord with the definition of Chapter 5. immunotherapy 11, the word 'chemotherapy' is in general use in this 6. biological therapy. connection and it would be pedantic to avoid it. It arose because some malignant cells can be cultured and the disease Details of the exploitation of all of these tech- transmitted by inoculation, as with bacteria. The more niques, whether alone, sequentially or concurrently precise term 'cytotoxic chemotherapy' is adopted here. is beyond the scope of a book on clinical phar- 603
  2. 30 N E O P L A S T I C D I S E A S E AND I M M U N O SU P PRESSI O N macology. This account will essentially be confined primary surgery. This strategy has improved over- to the use of drugs (see Table 30.1). It is important all survival for patients with, for example, breast however, to understand the context in which systemic and colorectal cancer. therapy is offered to patients. Most treatments currently available are associ- ated with unwanted effects of varying degrees of severity. The risk of causing harm must be weighed SYSTEMIC CANCER CHEMOTHERAPY against the potential to do good in each individual Cancers originating from different organs of the case. Chemotherapy depends on developing drugs body differ in their behaviour and in their response that kill malignant cells or modify their growth and to treatments. Primary surgery and/or radio- leave those of the host unharmed or, and more therapy to a localised cancer offer the best chance of usually, harmed but capable of recovery. When cure for patients. Drug treatments in the past were there is realistic expectation of cure or extensive life mainly restricted to patients with disseminated, prolongation of good quality life, then it is metastatic ('advanced') disease, where a systemic appropriate to risk severe drug toxicity, e.g. treat- effect is required. Cytotoxic chemotherapy for ment of testicular cancer patients with potentially advanced disease offers cure for only certain types life-threatening platinum-based combination chemo- of cancer, e.g. testicular cancers, Wilms tumour. therapy regimens offers a greater than 85% chance Most often, chemotherapy may prolong life, of cure, even for those with extensive, metastatic although patients ultimately die of their disease. disease. Palliation may be achieved by treatment in terms Where expectation is confined to palliation in of both increased survival and improved quality of terms of modest life prolongation of less certain life as a consequence of symptom control at least in quality, then the benefits and costs of treatment the short term. There remain a number of types of must be considered carefully. Preferably, palliative cancer which are unresponsive to currently avail- treatments should involve low risk of serious side able drugs. Patients with chemoresistant cancers effects, e.g. 5-fluorouracil-based chemotherapy for who are fit enough and willing may be offered advanced colorectal cancer is well tolerated by most experimental treatments within a clinical trial. patients while improving survival by around 6-9 Many cancer patients are not cured by their months. primary treatment, the disease often returning Clearly, patients must have the potential benefits months or years later even though at the time of and harm of treatment carefully explained to them completing their initial treatment there was no by skilled clinicians and nurses. They may them- visible evidence of cancer (complete remission). selves have strong views about aspects of quality Adjuvant therapy attempts to eradicate micro- and quantity of the life which should be taken into scopic cancer by treating patients usually after their consideration. TABLE 30. 1 Benefits achieved with cytotoxic chemotherapy for common cancers Curable: Improved survival: some degree Equivocal survival benefit: chemosensitive cancers of chemosensitivity chemoresistant cancers Teratoma Colorectal cancer Pancreatic cancer Seminoma Small cell lung cancer Gastric cancer High-grade non-Hodgkin's lymphoma Ovarian cancer Oesophageal cancer Breast cancer Non-small cell lung cancer Hodgkin's lymphoma Cervical cancer Sarcoma Wilm's tumour Endometrial cancer Bladder cancer Low-grade lymphoma Melanoma Myeloma Renal cancer Primary brain cancers Nasopharyngeal carcinoma Hepatoma Astrocytoma 604
  3. CLASSES OF CYTOTOXIC CHEMOTHERAPY DRUGS 30 cancer cell killing. Even so, cytotoxic chemotherapy Rationale for cytotoxic agents remain the mainstay of systemic anticancer treatment, since an understanding of their pharma- chemotherapy cology has enabled clinicians to exploit the benefits of these drugs by various means (see below). Cytotoxic chemotherapy began with sulphur mustards (oily vesicant liquids) which had been developed and used as chemical weapons in World War I (1914-18). Amongst their actions depression Classes of cytotoxic of haemopoiesis and of lymphoid tissues were observed. Preparations for World War II (1939-45) chemotherapy drugs included research to increase the potency and toxicity ('efficacy') of these odious substances. Sub- Cytotoxic chemotherapy drugs exert their effect by stitution of a nitrogen atom for the sulphur atom, inhibiting cell proliferation. All proliferating cells, i.e. making nitrogen mustards, had the desired whether normal and malignant, cycle through a result. The disappearance of lymphocytes and series of phases of: synthesis of DNA (S phase) granulocytes from the blood of rabbits was a useful mitosis (M phase) and rest (G1 phase). Noncycling marker of toxicity and gave rise to the idea of cells are quiescent in G0 phase (Fig. 30.1). Cytotoxic possible efficacy in lymphoid cancers. drugs interfere with cell division at various points of the cell cycle, e.g. synthesis of nucleotides from The problem was fundamental and simple: could purines and pyrimidines, of DNA and RNA, and one destroy a tumour with this group of cytotoxic interference with mitosis. They are potentially agents before destroying the host?2 mutagenic. Such drugs ultimately induce cell death Nitrogen mustards, as anticancer alkylating by the process of apoptosis.3 4 This is a process by agents, were first tested on experimental lymphoma which single cells are removed from the midst of in mice and the results were sufficiently encouraging living tissue by fragmentation into membrane- to warrant a therapeutic trial in man. The response bound particles and phagocytosed by other cells, of the first patient was as dramatic as that of the first without disturbing its architecture or function, or mouse', following 10 days treatment. But severe eliciting an inflammatory response. The instruc- bone marrow damage occurred and, disappointingly, tions for the response are built into the cell's genetic as the bone marrow recovered so did the tumour; in material, i.e. 'programmed cell death'.5 addition, with further courses, the tumour rapidly In general cytotoxics are most effective against became resistant. actively cycling cells and least effective against resting or quiescent cells. The latter are particularly Twenty years later (1963) we can appreciate how problematic in that, although inactive, they retain the accurately this first patient reflected the future capacity to proliferate and may start cycling again trials and tribulations of therapy with alkylating after a completed course of chemotherapy, often agents.2 leading to rapid regrowth of the cancer at a later date. Other classes of cytotoxic agents, e.g. anti- Cytotoxic drugs can be classified as either: metabolities, were subsequently identified and used • Cell cycle nonspecific: these kill cells whether to treat cancer patients. Their efficacy evidently was resting or actively cycling (as in a low growth limited by their relative nonselectivity for pro- liferating cells: the narrow therapeutic index of 3 Greek: apo, off; ptosis, a falling cytotoxic agents means that escalation of drug 4 Bellamy C O et al 1995 Cell death in health and disease: the doses is constrained by damage to normal cells and biology and regulation of apoptosis. Seminars in Cancer maximum doses which can be safely administered Biology 6 (1): 3-16. 5 to patients are often suboptimal to achieve total Dysregulated apoptosis is also involved in the pathogenesis of many forms of neoplastic disease, notably many lymphomas; understanding its mechanisms and the defective processes 2 Gilman A 1963 American Journal of Surgery 105: 574. offers scope for novel approaches to the treatment of cancer. 605
  4. 30 N E O P L A S T I C D I S E A S E AND I M M U N O SU P PRESSI O N Systemic adverse effects of alkylating agents include nausea and vomiting, and bone marrow depression (delayed with carmustine and lomustine), cystitis6 (cyclophosphamide, ifosfamide) and pul- monary fibrosis (especially busulfan). Male infertility and premature menopause may occur. Myelodysplasia and secondary neoplasia are par- ticularly associated with alkylator therapy (due to sublethal damage to normal cells) especially when accompanied by radiotherapy. These agents are used widely in the treatment of both haemato- logical and nonhaematological cancers, with varying degrees of success. PLATINUM DRUGS This family of drugs (including cisplatin, carbo- platin, oxaliplatin) crosslink DNA similarly to Most cytotoxic chemotherapy drugs inhibit the processes of DNA replication or mitosis alkylating agents. The parent drug, cisplatin, is Fig. 30.1 The cell cycle associated with a variety of adverse effects, including severe emetogenicity, nephrotoxicity and ototoxicity. Renal damage can be ameliorated by fraction cancer such as solid tumours, e.g. carefully hydrating patients and emetogenicity is alkylating agents, doxorubicin and allied now effectively controlled with 5-HT3-receptor (ser- anthracyclines) otonin) antagonists. Although second- (carboplatin) • Cell cycle (phase) specific: these kill only cells that and third- (oxaliplatin) generation platinum agents are actively cycling (often because their site of are now available with improved toxicity profiles, action is confined to one phase of the cell cycle, cisplatin remains a highly effective treatment for, in e.g. antimetabolite drugs). particular, germ cell tumours, when many patients A list of drugs currently in clinical use appears in may be cured. Table 30.2. Table 30.3 provides detail of toxicity of indi- ANTIMETABOLITES vidual agents. The following is an overview of the mode of action and toxicity and use of the principal Antimetabolites are synthetic analogues of normal groups of cytotoxic drugs. metabolites and act by competition, i.e. they 'deceive' or 'defraud' bodily processes. Methotrexate, for example, a folic acid antagonist, ALKYLATING AGENTS competitively inhibits dihydrofolate reductase, Alkylating agents (nitrogen mustards and ethy- preventing the synthesis of tetrahydrofolic acid (the eneimines) act by transferring alkyl groups to DNA coenzyme that is important in synthesis of amino in the N-7 position of guanine during cell division. and nucleic acids). This drug also provides a cogent There follows either DNA strand breakage or illustration of the need to exploit every possible crosslinking of the two strands so that normal syn- 6 thesis is prevented. A metabolite, acrolein, of cyclophosphamide and ifosfamide causes haemorrhagic cystitis. A high urine Examples include: busulfan, carmustine, chl- volume plus use of mesna (sodium 2-mercapto- orambucil, cyclophosphamide, ifosfamide, lomus- ethanesulphonate) which provides free thiol groups that tine, melphalan, mustine (mechlorethamine), thio- bind acrolein, are used to prevent this serious tepa, treosulfan. complication. 606
  5. CLASSES OF CYTOTOXIC CHEMOTHERAPY DRUGS 30 TABLE 30.2 Drugs commonly used as standard treatments for different types of cancer Cancer type Drugs of choice Bladder (urinary) Local: instillation of doxorubicin or BCG (Bacille Calmette-Guerin) Systemic: MVAC: methotrexate + vinblastine + doxorubicin + cisplatin Brain anaplastic astrocytoma Procarbazine + lomustine + vincristine glioblastoma Carmustine or lomustine Breast CMF: cyclophosphamide + methotrexate + S-fluorouracil AC: doxorubicin (Adriamycin) + cyclophosphamide Docetaxel; Paclitaxel ± trastuzumab (Herceptin) Tamoxifen Cervical Cisplatin + cyclophosphamide; Bleomycin + ifosfamide + cisplatin Choriocarcinoma Methotrexate + folinic acid Dactinomycin Colorectal 5-fluorouracil ± folinic acid Irinotecan ± 5-fluorouracil/folinic acid Oxaliplatin + 5-fluorouracil ± folinic acid Endometrial Doxorubicin + cisplatin + cyclophosphamide Ewing's sarcoma CAV: Cyclophosphamide (or ifosfamide) + doxorubicin (Adriamycin) + vincristine Gastric ECF:epirubicin + cisplatin + S-fluorouracil Head and neck, squamous cell Cisplatin + 5-fluorouracil; Methotrexate Islet cell (pancreas) Streptozotocin + 5-fluorouracil Kaposi's sarcoma Etoposide or interferon alfa or vinblastine ABV: doxorubicin (Adriamycin) + bleomycin + vincristine or vinblastine Leukaemias Acute lymphocytic leukaemia (ALL) Induction: vincristine + prednisolone + asparaginase ± doxorubicin CNS prophylaxis: intrathecal methotrexate with cranial irradiation + systemic high-dose methotrexate with folinic acid rescue ± intrathecal cytarabine ± intrathecal hydrocortisone Maintenance: methotrexate + mercaptopurine; bone marrow transplant Acute myelogenous leukaemia (AML) Induction: cytarabine + either daunorubicin or idarubicin Postinduction: high-dose cytarabine ± other drugs such as etoposide; bone marrow transplant Chronic lymphocytic leukaemia (CLL) Chlorambucil ± prednisolone; Fludarabine Chronic myelogenous leukaemia (CML) Chronic phase Hydroxyurea (hydroxycarbamide); imatinib; bone marrow transplant; interferon alfa Accelerated imatinib; Bone marrow transplant Hairy cell leukaemia Pentostatin or cladribine or interferon alfa Lung, small cell (oat cell) CAV: cyclophosphamide + doxorubicin (Adriamycin) + vincristine EP: etoposide + cisplatin Lung (non-small cell) MIC: mitomycin + ifosfamide + cisplatin MVP: mitomycin + vinblastine + cisplatin Cisplatin + gemcitabine;vinorelbine Lymphomas Hodgkin's disease MOPP: mustine (chlormethine) + vincristine + procarbazine + prednisolone; ABVD: doxorubicin (Adriamycin) + bleomycin + vinblastine + dacarbazine Non-Hodgkin's lymphoma Diffuse large-cell lymphoma CHOP: cyclophosphamide + doxorubicin* + vincristine (Oncovin) + prednisolone Follicular lymphoma Cyclophosphamide or chlorambucil + prednisolone; Rituximab Metastatic melanoma Dacarbazine Mycosis fungoides PUVA (psoralen + ultraviolet A) Mustine (topical); Interferon alfa; electron beam radiotherapy; methotrexate Myeloma Melphalan (or cyclophosphamide) + prednisolone; Vincristine + adriamycin + dexamethasone; high dose melphalan + autograft Oesophageal Cisplatin + 5-fluorouracil Osteogenic sarcoma Doxorubicin + cisplatin + etoposide + ifosfamide Ovary Carboplatin ± paclitaxel Topotecan; liposomal doxorubicin (caelyx) Pancreas Gemcitabine Prostate Leuprorelin (or goserelin) ± flutamide 607
  6. 30 NEOPLASTIC DISEASE AND I M M U N O SU P PRESSI O N TABLE 30.2 (continued) Renal Interferon alfa lnterleukin-2 Sarcomas, adult soft tissue Doxorubicin + dacarbazine ± cyclophosphamide ± ifosfamide Testicular BEP: bleomycin + etoposide + cisplatin Wilm's tumour Dactinomycin + vincristine ± doxorubicin ± cyclophosphamide Reproduced by courtesy of the Medical Letter on Drugs and Therapeutics, New York (abbreviated; numerous alternative regimens omitted). °° Drugs have major activity only when combined with surgical resection, radiotherapy or both. * The original name, hydroxydoxyrubicin.gave rise to this acronym. means of enhancing selectivity. Where it is desired mitozantrone), idarubicin, plicamycin (mithra- to maximise the effect of methotrexate a potentially mycin), mitomycin and streptozotocin (most often fatal dose is given and is followed 24 h later by a used to treat islet-cell pancreatic tumours). dose of tetrahydrofolic (folinic) acid as calcium Cytotoxic antibiotics depress the bone marrow, folinate (Ca Leucovorin), to bypass and terminate cause gastrointestinal upsets and stomatitis, alopecia, its action. This is called folinic acid 'rescue', since if it cardiomyopathy (daunorubicin and doxorubicin) is not given the patient will die. The therapeutic and pulmonary fibrosis and skin rashes (bleomycin). justification for this manoeuvre is that high con- Some of these effects are dose-dependent, for centrations of methotrexate are obtained and that example, doxorubicin-induced cardiomyopathy. the bone marrow cells recover better than the Others may be potentiated by concomitant use of tumour cells and some degree of useful selectivity radiotherapy. is achieved. Purine antagonists (azathioprine, mercaptopurine, TOPOISOMERASE INHIBITORS tioguanine) and pyrimidine antagonists (cytarabine, fludarabine, 5-fluorouracil) similarly deprive cells Doxorubicin is a nonspecific inhibitor of topoiso- of essential metabolites. merase I and II. Topotecan and irinotecan selec- Antimetabolites cause gastrointestinal toxicity tively inhibit topoisomerase I, an enzyme required including stomatitis and diarrhoea as well as bone for DNA replication. These agents have clinical marrow depression; renal impairment potentiates efficacy in relapsed ovarian and colorectal cancer, the toxicity of methotrexate. Active excretion of respectively. Dose limiting toxicity is bone marrow methotrexate by the renal tubule is blocked by depression and, in the case of irinotecan, delayed salicylate, which also displaces it from plasma diarrhoea. Administration of irinotecan may be protein, increasing the risk of toxicity. Hepatic dys- complicated by an acute cholinergic reaction, function potentiates the toxicity of 5-fluorouracil, reversible by administering atropine s.c. since it is primarily metabolised by the liver. 5-Fluorouracil has been the mainstay of treat- SPINDLE POISONS ment of gastrointestinal tract tumours for the last The plant alkaloids (vincristine, vinblastine, vindesine 50 years. Combined with cyclophosphamide and and vinorelbine) and taxoids (paclitaxel, docetaxel) methotrexate, the so-called CMF regimen is a gold inhibit microtubule assembly and cause cell cycle standard treatment for many women with either arrest in mitosis. They particularly cause bone early or advanced breast cancer. marrow depression, peripheral neuropathy (vin- cristine) and alopecia. Etoposide blocks the cell cycle CYTOTOXIC ANTIBIOTICS before mitosis. These antibiotics interfere with DNA and or RNA MISCELLANEOUS AGENTS synthesis. Examples include: bleomycin, dactinomycin, dau- Asparaginase starves tumour cells dependent upon a norubicin, doxorubicin, epirubicin (and the related supply of the amino acid, asparagine (except those 608
  7. CHEMOTHERAPY IN CLINICAL PRACTICE 30 able to synthesise it for themselves); its use is almost with more in the resting state (decrease in confined to acute lymphoblastic leukaemia. Other growth fraction) cytotoxic agents in clinical use include procarbazine, • Increased cell death within the tumour as it ages dacarbazine, hydroxyurea (hydroxycarbamide). • Overcrowding of cells leading to necrotic, avascular areas which cannot easily be penetrated by drugs. Chemotherapy in clinical Whilst selectivity of drugs for cancer cells is generally low compared with selectivity of anti- practice microbial drugs, in some tumours it can be sub- stantial, as in lymphoma, in which the tumour cell DRUG USE ANDTUMOUR CELL kill with some drugs is 10 000 times greater than KINETICS that of marrow cells. Cell destruction by cytotoxic Evidence from leukaemia in laboratory animals drugs follows first-order kinetics, i.e. a given dose shows that: of drug kills a constant fraction of cells (not a constant number} regardless of the number of cells • survival time is inversely related to the initial present. Thus treatment reducing a cell population number of leukaemia cells, or to the number from 1 000 000 to 10 000 (a two log cell kill) will remaining after treatment reduce a cell population of 100 to 1. Furthermore, • a single leukaemia cell is capable of multiplying cell chemosensitivity within a cancer is not homo- and eventually killing the host. geneous due to random mutations as the tumour grows and cells remaining after initial doses are Cytotoxic drugs act against all cells which are likely to become resistant to treatment. Therefore, multiplying. Bone marrow, mucosal surfaces (gut), combining several drugs may be more effective hair follicles, reticuloendothelial system, germ cells, than administration of a single agent, with repeated are all dividing more rapidly than many cancers administration to the limit of patient tolerance. and so are also damaged by cytotoxic drugs, as is shown by the occurrence of adverse effects ex- The selection of drugs in combination chemo- perienced by patients receiving chemotherapy. In therapy is influenced by: contrast to haematological cancers, most solid tumours in man divide slowly and recovery from • Choosing drugs which act at different cytotoxic agents is slow, while normal marrow and biochemical sites in the cell gut recover rapidly. This rapid recovery of normal • Using drugs that attack cells at different phases tissues is exploited in devising intermittent courses of the growth cycle (see Fig. 30.1) of chemotherapy. • The desirability of attaining synchronisation of In cancer, the normal feedback mechanisms cell cycling to achieve maximum cell kill. For which mediate cell growth are defective and cell example, cells are killed or are arrested in mitosis proliferation continues unchecked. Cancer cells by vincristine, which is then withdrawn. Cells continue to multiply, at first exponentially. Cancers then enter a new reproductive cycle more or less with high growth fractions (e.g. acute leukaemias, synchronously and when the majority are judged high-grade lymphomas) may visibly enlarge at an to be in a phase sensitive to a particular phase- alarming rate, but may also be highly sensitive to specific drug, e.g. methotrexate or cytarabine, it cytotoxic chemotherapy. In later stages, the growth is given. rate of many cancers slows and the volume- • Lack of evidence of cross-resistance (see below) doubling time becomes prolonged due to several • Non-overlapping adverse effect profiles factors, most of which conspire to render the • Empirical evidence of efficacy against a advanced cancer less susceptible to drugs: particular tumour type. • Increased cell cycle (division) time Considerations of pharmacokinetics in relation • Decrease in the number of cells actively dividing, to cell kinetics are of great importance, as drug 609
  8. 30 N E O P L A S T I C D I S E A S E AND I M M U N O SU P PRESSI O N treatment alters the activity of both malignant and IMPROVING EFFICACY OF normal cells. CHEMOTHERAPY In order to attain maximum selectivity for killing DRUG RESISTANCE cancer cells while limiting damage to the host, various methods have been adopted with a view to Resistance to a chemotherapy agent may be widening the narrow therapeutic index of cytotoxic present at the outset (primary resistance), or may agents: develop with repeated drug exposure (acquired resistance). Increasing dosage is limited by toxicity, • Regional (as opposed to systemic) e.g. to bone marrow, which does not become tolerant. administration of drugs: intrathecal, intra- Therefore combination chemotherapy is more com- arterial liver perfusion. monly used in an attempt to overcome the problems • Regional delivery of drug by altered formulation of resistance rendering a tumour unresponsive. e.g. Caelyx is a formulation comprising high concentrations of doxorubicin encased in Multiple drug resistance (MDR) of a cancer is not liposomes. uncommon. MDR is most frequently due to • High-dose chemotherapy which is bone marrow increased expression of an ATP-dependent mem- ablative can be administered if stem cells are brane efflux pump called P-glycoprotein (Pgp) which harvested prior to drug exposure and then is a member of a class of membrane proteins called returned to the patient on completion of the ATP-binding cassette superfamily. Pgp is a treatment. protective mechanism possessed by many normal • Circadian rhythms exist in cell metabolism and cells against environmental toxins and has broad proliferation and those of leukaemic cells differ specificity for hydrophobic compounds. Long-lived from normal leucocytes. Evidence is increasing cells such as the haemopoietic stem cell, cells on that the time of day at which therapy is excretory surfaces such as biliary hepatocytes, administered does influence the outcome; for proximal renal tubule and intestinal cells and the cells example, maintenance chemotherapy of some of the blood-brain barrier all have high expression of leukaemias is more effective if given in the Pgp and the protein is clearly an important protective evening (chronomodulation). mechanism for both individual cells and organisms. • In large solid tumours, the proportion of cells Pgp can be blocked by a number of agents including multiplying is often small. These may be better immunosuppressants (ciclosporin) and calcium removed by surgery (debulked) even if this is channel blockers (verapamil and nifedipine). The incomplete, and what remains treated by MDR phenomenon illustrates how tumour cells cytotoxic drugs. adapt and enhance normal cell mechanisms to deal with the effects of chemotherapy and how repeated cycles of chemotherapy select out a population of ADVERSE EFFECTS OF cells which have developed adaptive survival CHEMOTHERAPY mechanisms e.g. in myeloma where MDR proteins Principal adverse effects (see Table 30.3) are manifest are rare at diagnosis but common at progression. as, or follow damage to, the following: Cytotoxic drugs vary in their capacity to stimulate P-glycoprotein and some, e.g. cisplatin, • Nausea and vomiting do not induce this type of resistance. • Bone marrow and lymphoreticular system: In those tumours where cures can be achieved by pancytopenia and immunosuppression chemotherapy (acute lymphoblastic leukaemia in (depression of both antibody and cell-mediated childhood, Hodgkin's lymphoma, choriocarcinoma) immunity), leading to opportunistic microbial it is essential that optimal doses of chemotherapy infection be administered and dose intensity maintained in • Gut epithelium and other mucosal surfaces: order to avoid the emergence of chemoresistance. diarrhoea, mouth ulcers 610
  9. CHEMOTHERAPY IN CLINICAL PRACTICE 30 • Hair: alopecia due to effect on hair bulb e.g. the natural granulocyte colony stimulating (recovers 2-6 months after ceasing treatment); factor (filgrastim), are effective in neutropenia. prevention by scalp hypothermia helps with certain drugs, e.g. vindesine Septicaemia is often an opportunistic infection by • Delayed wound healing Gram-negative bacteria from the patient's own • Local toxicity if extravasation occurs flora, e.g. from the gut, which has been injured by • Specific organ damage the drugs. Vigorous antimicrobial prophylaxis and • Germ cells and reproduction: sterility, therapy, often in combination, are used. Infections teratogenesis, mutagenicity with virus (herpes zoster), fungus (candida) and • Second malignancies. protozoa (pneumocystis) are also prominent. Fever in a patient under this treatment requires collection The first six occur immediately or in the short of samples for microbiological studies and urgent term and are liable to be troublesome with any treatment. vigorously pursued regimen. Immune responses. Vigorous and prolonged chemo- Nausea and vomiting. This is common, can be therapy can impair the immune responsiveness of extremely severe and prolonged and cause patients patients for as long as 3 years after ceasing therapy. to refuse treatment. Effective management is of the Purine analogues (e.g. fludarabine), high dose utmost importance. Vomiting may be immediate, chemoradiotherapy and allogeneic bone marrow commonly beginning in 1-5 hours, or may be transplant produce profound immunosuppression delayed, lasting several days, depending on the with significant risk of opportunistic infection (e.g. agent. Since emetogenicity is largely predictable, herpes zoster, Pneumocystis carinii pneumonia) and preventive action can be taken. The most effective third party graft-versus-host disease following drugs are competitive antagonists at serotonin (5- unirradiated blood transfusion. Use of living HT3) receptors (ondansetron) and at the dopamine vaccines is contraindicated. D2-receptor (metoclopramide). They maybe used in Gonadal cells and reproduction. Sterility may combination with a benzodiazepine (anxiety is a occur. The mutagenic effects of anticancer drugs major factor in promoting emesis when the patient mean that reproduction should be avoided during knows that it will occur, as with cisplatin), or and for several months after therapy (but both men dexamethasone, which benefits by an unknown and women have reproduced normally whilst under- mechanism. Other effective agents include pro- going chemotherapy). When treatment may cause chlorperazine, domperidone and nabilone. permanent sterility, men are offered the facility for Combinations, e.g. benzodiazepine plus dexa- prior storage of sperm. Cryopreservation of ovarian methasone, plus a 5-HT3 (ondansetron) or dopa- tissue is now also feasible. Most cytotoxic drugs are mine D2-receptor blocker (metoclopramide) are teratogenic and should not be used during preg- often more effective than a single drug. nancy. Contraceptive advice should be given before Routes of administration are chosen as common- cancer chemotherapy begins. sense counsels, e.g. prophylaxis may be intra- venous or oral, but when vomiting occurs injections Urate nephropathy. Rapid destruction of malignant and suppositories are available. cells releases purines and pyrimidines, which are converted to uric acid and may crystallise in and Bone marrow suppression is the single most im- block the renal tubule (urate nephropathy). In portant dose-limiting factor with cytotoxic agents. practice this occurs only when there is a large cell Repeated blood monitoring is essential and mass and the tumour is very sensitive to drugs, e.g. transfusion of any/all formed elements of the blood acute leukaemias and high-grade lymphomas. may be needed, e.g. platelet transfusion for High fluid intake, alkalinisation of the urine and thrombocytopenic bleeding or where the platelet use of allopurinol (p. 296) during the early stages of count falls below 10 x 109/1. Cell growth factors, chemotherapy avert this outcome. 611
  10. 30 N E O P L A S T I C D I S E A S E AND I M M U N O SU PPRESSI O N TABLE 30.3 Adverse effects of some cytotoxic drugs, hormones and biological agents (reproduced and adapted by courtesy of the Medical Letter on Drugs and Therapeutics, New York) Drug Dose-limiting effects are in bold type Cytotoxic agents Acute toxicity Delayed toxicity Asparaginase Nausea and vomiting; fever, chills; headache; CNS depression or hyperexcitability; acute hypersensitivity; anaphylaxis; abdominal pain; haemorrhagic pancreatitis; coagulation defects; hyperglycaemia leading to coma thrombosis; renal damage; hepatic damage Bleomycin Nausea and vomiting; fever; anaphylaxis and other Pneumonitis and pulmonary fibrosis; rash and allergic reactions; phlebitis at injection site hyperpigmentation; stomatitis; alopecia; Raynaud's phenomenon; cavitating granulomas; haemorrhagic cystitis Busulfan Nausea and vomiting; rarely diarrhoea Bone marrow depression; pulmonary infiltrates and fibrosis; alopecia; gynaecomastia; ovarian failure; hyperpigmentation; azoospermia; leukaemia; chromosome aberrations; cataracts; hepatitis; seizures and veno-occlusive disease with high doses Carboplatin Nausea and vomiting Bone marrow depression; peripheral neuropathy (uncommon); hearing loss; transient cortical blindness; haemolytic anaemia Carmustine Nausea and vomiting; local phlebitis Delayed leukopenia and thrombocytopenia (may be prolonged); pulmonary fibrosis (may be irreversible); delayed renal damage; reversible liver damage; leukaemia; myocardial ischaemia Chlorambucil Nausea and vomiting; seizures Bone marrow depression; pulmonary infiltrates and fibrosis; leukaemia; hepatic toxicity; sterility Cisplatin Nausea and vomiting; diarrhoea; anaphylactic Renal damage; ototoxicity; bone marrow reactions depression; haemolysis; hypomagnesaemia; peripheral neuropathy; hypocalcaemia; hypokalamia; Raynaud's disease; sterility; teratogenesis; hypophosphataemia; hyperuricaemia Cyclophosphamide Nausea and vomiting; Type 1 (anaphylactoid) Bone marrow depression; alopecia; hypersensitivity; facial burning with i.v. haemorrhagic cystitis; sterility (may be temporary); administration; visual blurring pulmonary infiltrates and fibrosis; hyponatremia; leukaemia; bladder cancer, inappropriate antidiuretic hormone secretion; cardiac toxicity Cytarabine Nausea and vomiting; diarrhoea; anaphylaxis; Bone marrow depression; conjunctivitis; sudden respiratory distress with high doses megaloblastosis; oral ulceration; hepatic damage; fever; pulmonary oedema and central and peripheral neurotoxicity with high doses; rhabdomyolysis; pancreatitis when used with asparaginase; rash Dacarbazine Nausea and vomiting; diarrhoea; anaphylaxis, Bone marrow depression; alopecia; flu-like pain on administration syndrome; renal impairment; nepatic necrosis; facial flushing; paraesthesiae; photosensitivity; urticarial rash Dactinomycin Nausea and vomiting; hepatic toxicity with Stomatitis; oral ulceration; bone marrow ascites; diarrhoea; severe local tissue damage depression; alopecia folliculitis; dermatitis in and necrosis on extravasation; anaphylactic previously irradiated areas reaction Daunorubicin Nausea and vomiting; diarrhoea; red urine Bone marrow depression; cardiotoxicity (may (not haematuria); severe local tissue damage and be delayed for years); alopecia; stomatitis; anorexia; necrosis on extravasation; transient ECG diarrhoea; fever and chills; dermatitis in previously changes; anaphylactoid reaction irradiated areas; skin and nail pigmentation; photosensitivity Docetaxel Nausea and vomiting; hypersensitivity reactions Bone marrow depression; fluid retention; peripheral neuropathy; alopecia; arthralgias; myalgias; cardiac toxicity; mild Gl disturbances; mucositis 612
  11. CHEMOTHERAPY IN CLINICAL PRACTICE 30 TABLE 30.3 (continued) Drug Dose-limiting effects are in bold type C/totoxic agents Acute toxicity Delayed toxicity Doxorubicin Nausea and vomiting; red urine (not haematuria); Bone marrow depression; cardiotoxicity (may severe local tissue damage and necrosis on be delayed for years); alopecia; stomatitis; anorexia; extravasation; diarrhoea; fever; transient ECG conjunctivitis; acral (extremities) pigmentation; changes; ventricular arrhythmia; anaphylactoid dermatitis in previously irradiated areas; reaction hyperuricaemia Etoposide Nausea and vomiting; diarrhoea; fever; hypotension; Bone marrow depression; rashes; alopecia; anaphylactoid reactions; phlebitis at infusion site peripheral neuropathy; mucositis and hepatic damage with high doses; leukaemia Fludarabine Nausea and vomiting Bone marrow depression; CNS effects; visual disturbances; renal damage with higher doses; pulmonary infiltrates; tumour lysis syndrome (profound immunosuppression) 5-Fluorouracil Nausea and vomiting; diarrhoea; hypersensitivity Oral and Gl ulcers; bone marrow depression; reaction diarrhoea; neurological defects, usually cerebellar; cardiac arrhythmias; angina pectoris; alopecia; hyperpigmentation; palmar-plantar erythrodysaesthesia; conjunctivitis; heart failure; seizures Gemcitabine Mild nausea and vomiting; allergic reactions Bone marrow depression, mainly affecting platelets; rash; fluid retention; oedema Hydroxyurea Nausea and vomiting; allergic reactions to Bone marrow depression; stomatitis; dysuria; (hydroxycarbamide) tartrazine dye (e.g. in medicinal formulations) alopecia; rare neurological disturbances; pulmonary infiltrates Idarubicin Nausea and vomiting; tissue damage on Bone marrow depression; alopecia; stomatitis; extravasation myocardial toxicity; diarrhoea Ifosfamide Nausea and vomiting; confusion; coma; Bone marrow depression; haemorrhagic nephrotoxicity; metabolic acidosis and renal cystitis (prevented by concurrent mesna); alopecia; Fanconi's syndrome; cardiac toxicity with high inappropriate ADH secretion; neurotoxicity doses (somnolence, hallucinations, blurring of vision, coma) Irinotecan Nausea and vomiting; cholinergic syndrome; Bone marrow depression; diarrhoea; colitis; hypersensitivity reactions; anaphylaxis; diarrhoea ileus; alopecia; renal impairment; teratogenic Lomustine Nausea and vomiting Delayed (4-6 weeks) leukopenia and thrombocytopenia (may be prolonged); transient elevation of transaminase activity; neurological reactions; pulmonary fibrosis; renal damage; leukaemia Melphalan Mild nausea; hypersensitivity reactions Bone marrow depression (especially platelets); pulmonary infiltrates and fibrosis; amenorrhoea; sterility; leukaemia Methotrexate Nausea and vomiting; diarrhoea; fever; anaphylaxis; Oral and gastrointestinal ulceration, hepatic necrosis perforation may occur; bone marrow depression; hepatic toxicity including cirrhosis; renal toxicity; pulmonary infiltrates and fibrosis; osteoporosis; conjunctivitis; alopecia; depigmentation; menstrual dysfunction; encephalopathy; infertility; lymphoma; teratogenesis Mitomycin Nausea and vomiting; tissue necrosis; fever Bone marrow depression (cumulative); stomatitis; alopecia; acute pulmonary toxicity; pulmonary fibrosis; hepatotoxicity; renal toxicity; amenorrhoea; haemolytic-uraemic syndrome; bladder calcification (with intravesical administration) 613
  12. 30 N E O P L A S T I C D I S E A S E AND I M M U N O SU PPRESSI O N TABLE 30.3 (continued) Drug Dose-limiting effects are in bold type Cytotoxic agents Acute toxicity Delayed toxicity Mitoxantrone Blue-green pigment in urine; blue-green sclerae; Bone marrow depression; cardiotoxicity; nausea and vomiting; stomatitis; fever; phlebitis alopecia; white hair; skin lesions; hepatic damage; renal failure; extravasation necrosis Mustine (chlormethine) Nausea and vomiting; local reaction and phlebitis Bone marrow depression; alopecia; diarrhoea; oral ulcers; leukaemia; amenorrhoea; sterility; hyperuricaemia; teratogenic Oxaliplatin Nausea and vomiting; pharyngolaryngeal Bone marrow depression; diarrhoea; mucositis; dysaesthesia; allergic reaction liver function abnormalities; sensory peripheral neuropathy; cold dysaesthesia; renal impairment; fever; alopecia Paclitaxel Anaphylaxis, dyspnoea, hypotension, angioedema, Bone marrow depression; peripheral urticaria (probably due to vehicle) neuropathy; alopecia; arthralgias; myalgias; cardiac toxicity; mild Gl disturbances; mucositis Procarbazine Nausea and vomiting; CMS depression; Bone marrow depression; stomatitis; peripheral disulfiram-like effect with alcohol; adverse neuropathy; pneumonitis; leukaemia reactions typical of a MAO inhibitor Streptozotocin Nausea and vomiting; local pain Renal damage; hypoglycaemia; hyperglycaemia; liver damage; diarrhoea; bone marrow depression (uncommon); fever; eosinophilia; nephrogenic diabetes insipidus Topotecan Nausea and vomiting Bone marrow depression; alopecia; rash; dyspnoea; headache; paraesthesia; transient raised liver enzymes Vinblastine Nausea and vomiting; local reaction and phlebitis Bone marrow depression; alopecia; stomatitis; with extravasation loss of deep tendon reflexes; jaw pain; muscle pain; paralytic ileus Vincristine Tissue damage with extravasation Peripheral neuropathy; alopecia; mild bone marrow depression; constipation; paralytic ileus; jaw pain; inappropriate ADH secretion; optic atrophy Vinorelbine Nausea and vomiting Bone marrow depression; alopecia Hormones Aminoglutethimide Drowsiness; nausea; dizziness; rash Hypothyroidism (rare); bone marrow depression; fever; hypotension; masculinisation Flutamide Nausea; diarrhoea Gynaecomastia; hepatotoxicity Goserelin Transient increase in bone pain and urethral Impotence; testicular atrophy; gynaecomastia obstruction in patients with metastatic prostatic cancer; hot flushes Leuprolelin (LHRH analogue) Transient increase in bone pain and ureteral Impotence; testicular atrophy; gynaecomastia; obstruction in patients with metastatic prostatic peripheral oedema cancer; hot flushes Medroxyprogesterone Nausea; urticaria; headache; fatigue Menstrual changes; gynaecomastia; hot flushes; acetate weight gain; hirsutism; insomnia; fatigue; depression; oedema; weight gain thrombophlebitis and thromboembolism; sterile abscess Tamoxifen Hot flushes; nausea and vomiting; transiently Vaginal bleeding and discharge; rash; increased bone or tumour pain; hypercalcaemia; thrombocytopenia; peripheral oedema; depression; hyperglycaemia dizziness; headache; decreased visual acuity; corneal changes; retinopathy; purpuric vasculitis; thromboembolism; endometrial cancer 614
  13. CHEMOTHERAPY IN CLINICAL PRACTICE TABLE 30.3 (continued) Drug Dose-limiting effects are in bold type Biological agents Acute toxicity Delayed toxicity BCG Bladder irritation; nausea and vomiting; fever; Granulomatous pyelonephritis; hepatitis; urethral (Bacilli Calmette-Guerin) sepsis obstruction; epididymitis; renal abscess Trastuzumab (Herceptin) Fever; chills; nausea and vomiting; pain; Bone marrow depression; cardiomyopathy; hypersensitivity and pulmonary reactions ventricular dysfunction; congestive cardiac failure; diarrhoea Interferon alfa Fever; chills; myalgias; fatigue; headache; Bone marrow depression; anorexia; neutropenia; arthralgias; hypotension anaemia; confusion; depression; renal toxicity; hepatic toxicity; facial and peripheral oedema; cardiac arrhythmias lnterleukin-2 Fever; fluid retention; hypotension; respiratory Neuropsychiatric disorders; hypothyroidism; distress; rash, anaemia, thrombocytopenia; nausea nephrotic syndrome; possibly acute and vomiting; diarrhoea, capillary leak syndrome, leucoencephalopathy; brachial plexopathy; bowel nephrotoxicity; myocardial toxicity, hepatotoxicity; perforation erythema nodosum; neutrophil chemotactic defects Isotretinoin Fatigue; headache; nausea and vomiting; pruritis Teratogenic; cheilitis; xerostomia; rash; conjunctivitis and eye irritation; anorexia; hypertriglyceridaemia; pseudotumour cerebri Octreotide Nausea and vomiting; diarrhoea Steatorrhoea; gallstones Rituximab Fever; chills; rigors; hypotension; bronchospasm Bone marrow depression; angioedema; precipitation of angina or arrhythmia with pre-existing heart disease Carcinogenicity (second malignancies). Many stopped handling the drugs the contamination cytotoxic drugs are carcinogenic, and a patient may ceased. It can be assumed that absorption of even be cured of the primary disease only to succumb to small amounts of these drugs is harmful (muta- a second, treatment-induced cancer 5-20 years later. genesis, carcinogenesis), especially when it occurs Whether this is due to a mutagenic effect, to repeatedly over long periods. immunosuppression, or both, remains undecided. Contamination occurs from spilt drugs and Alkylating agents are particularly incriminated and carelessly handled syringes (there should be a swab also some antimetabolites (mercaptopurine) and on the tip of the needle when expelling air); even cytotoxic antibiotics (doxorubicin). The risk can be opening an ampoule can create an aerosol. Used as high as 10-20 times that of unexposed people ampoules, syringes and absorbent swabs constitute and the cancers include leukaemia, lymphoma and a hazard, as may body wastes of treated patients. squamous carcinoma. Precautions appropriate to different drugs range In Hodgkin's lymphoma life is greatly pro- from simply avoiding spillage, through gloves, longed by chemotherapy, but in ovarian cancer it is surgical masks, goggles and aprons, to the use of not; these aspects are plainly relevant to acceptance laminar flow cabinets. Special training of nomin- of risk of second tumours. ated drug handlers is essential. Pregnant staff should not handle these drugs. HAZARDSTO STAFF HANDLING CYTOTOXIC AGENTS INTERACTIONS OF CYTOTOXICS The urine of some nurses and of pharmacists who WITH OTHER DRUGS prepare infusions and injections of anticancer drugs Many examples of therapeutic interactions (drug was found to contain drugs even to the extent of combinations) are shown in Table 30.2. Non- being sometimes mutagenic to bacteria. When they therapeutic interactions can be serious. A com- 615
  14. 30 NEOPLASTIC D I S E A S E AND I M M U N O SU P P RESS I O N bination of cytotoxics causing dangerous degree of due to an abnormal ovarian stimulus and that immunosuppression represents an adverse phar- removal of the ovaries might have a therapeutic effect macodynamic interaction. There is also a general on cancer of the genital tract. case for alertness with drugs that inhibit the In 19418 it was shown that prostatic cancer with metabolism or renal excretion of other drugs. metastases was made worse by androgen and made Cimetidine, an inhibitor of several P450-mediated better by oestrogen (stilboestrol). Activity of this oxidation reactions, delays the breakdown and in- cancer is particularly readily observable since the creases the toxicity of 5-fluorouracil, and similarly, plasma prostate-specific antigen (PSA) concentra- the xanthine oxidase inhibitor allopurinol increases tion provides a reliable marker. Indeed the avail- toxicity of mercaptopurine and cyclophosphamide. ability of some means of reliably measuring effect is The renal tubular excretion of methotrexate is crucial to the use of drugs in cancer. reduced by competition with NSAIDs, leading to methotrexate toxicity. HORMONAL AGENTS The growth of some cancers is hormone-dependent and may be inhibited by surgical removal of Endocrine therapy gonads, adrenals and/or pituitary. The same effect is increasingly achievable, at less cost to the patient, HORMONAL INFLUENCE ON CANCER by administering hormones, or hormone antagonists, The possibility of interfering with cancer other than of oestrogens, androgens or progestogens and inhi- by surgery, e.g. by endocrine manipulation, was bitors of hormone synthesis. first tested in 1895 when a Scottish surgeon faced with a woman aged 33 years with advanced breast Breast cancer cells may have receptors for oestrogen, cancer. progesterone and androgen and hormonal mani- put it to her husband and herself as to whether she pulation benefits some 30% of patients with meta- should have performed the operation of removal of static disease; when a patient's tumour is oestrogen- the [fallopian] tubes and ovaries. Its nature was receptor positive the response is about 60%, and fully explained to them both, and also that it was a when negative it is only 10%. After treatment of the purely experimental one ... She readily consented primary cancer, endocrine therapy with tamoxifen, ... as she knew and felt her case was hopeless. 20 mg/d, is the adjuvant therapy of choice for [Eight months after operation] all vestiges of her postmenopausal women who have disease in the previous cancerous disease had disappeared. [The lymph nodes; both the interval before the develop- surgeon concluded, after treating two further cases, ment of metastases and overall survival are increased. that there may be ovarian influences in breast Adjuvant therapy with cytotoxic drugs and/or cancer and added that] whether [this is] accepted tamoxifen is recommended for node-negative or not, I am sure I shall be acquitted of having patients with large tumours or other adverse prog- acted thoughtlessly or recklessly.7 nostic factors. Cytotoxic chemotherapy is more useful in The treatment had indeed been based on reason. younger women, with tamoxifen, increasingly, as The author, 20 years previously, had agreed to take adjuvant therapy. The optimum duration of dosing charge of a Scottish landowner 'whose mind was with tamoxifen is not yet established, but is likely to affected'. His duties 'were at times exciting, but never be for 5 years or more. onerous', and, having the time and the interest to For those who do not respond to tamoxifen, observe the weaning of lambs on a local farm, he second-line therapy includes progestogens, e.g. observed a similarity 'up to a point' between the megestrol or medroxyprogesterone. Should fluid reten- proliferation of epithelial cells of the milk ducts in lactation and in cancer; he learned that some farmers 7 practised oophorectomy to prolong lactation in cows; Beatson G T 1896 Lancet 2:104,162. 8 and he had the idea that cancer of the breast might be Huggins C et al 1941 Cancer Research 1: 293. 616
  15. IM M U N O T H E R A P Y 30 tion prove a problem with these, formestane may be appears that the immune response to cancer substituted in postmenopausal women (it inhibits appears to be attenuated. Attempts have been made aromatase, an enzyme involved in the convertion of to stimulate the host's own immune system androgens to oestrogens). Aminoglutethimide and aspiring more effectively to kill cancer cells. trilostane, which similarly inhibit the conversion of Exploration of immunotherapy has involved: androgens to oestrogens (and have largely replaced • Nonspecific stimulation of active immunity with adrenalectomy for breast cancer), are also used for vaccines, e.g. BCG (Bacille Calmette-Guerin9) postmenopausal women; concurrent glucocorticoid instilled into the urinary bladder for bladder replacement therapy is, however, essential. cancer. More modern approaches involve the Prostatic cancer is androgen-dependent and meta- injection of rumour cells or tumour cell extracts static disease can be helped by orchidectomy, or by combined with an immune stimulant such as a gonadorelin analogue, e.g. buserelin, goserelin, BCG. leuprorelin or triptorelin. These cause a transient • Passive immunotherapy strategies with stimulation of luteinising hormone and thus testo- monoclonal antibodies raised against specific sterone release, before inhibition occurs; some tumour-associated antigens. Targeted antibodies patients may experience exacerbation of tumour have the advantage of high cancer specificity and effects, e.g. bone pain, spinal cord compression. low host toxicity. Examples include rituximab, an Where this can be anticipated, prior orchidectomy anti-CD20 monoclonal antibody licensed for the or antiandrogen treatment, e.g. with cyproterone or treatment of low-grade, follicular lymphomas flutamide, is protective. and trastuzumab (Herceptin), which specifically binds to the her2/neu (erbB2) receptor, which is Benign prostatic hypertrophy is also androgen- overexpressed by some breast cancers. In dependent and drug therapy includes use of combination with conventional cytotoxic finasteride, an inhibitor of the enzyme (5oc- chemotherapy, trastuzumab significantly reductase) which activates testosterone (see p. 544). improves the survival of advanced breast cancer patients when compared to cytotoxic Adrenocortical steroids are used for their action on chemotherapy alone. specific cancers and also to treat some of the complications of cancer, e.g. hypercalcaemia, raised intracranial pressure. Their principal use is in cancer of the lymphoid tissues and blood. In leukaemias Biological therapy they may also reduce the incidence of complications Naturally-occurring substances which regulate cell such as haemolytic anaemia and thrombocytopenia. function are increasingly used to treat cancer. They A glucocorticoid is preferred, e.g. prednisolone, as high doses are used and mineralocorticoid actions include: are not needed and cause fluid retention. Cytokines, produced in response to a variety of stimuli, such as antigens, e.g. virus, cancer. These In general, endocrine therapy carries less serious consequences for normal tissues than do cytotoxic substances regulate cell growth and activity, and agents. immune responses, and can be synthesised by recombinant DNA technology. They include: • Interleukins which stimulate proliferation of T-lymphocytes and activate natural killer cells. Immunotherapy Interleukin-2 is used in metastatic renal cell carcinoma. Immunotherapy derives from an observation in the 19th century that cancer sometimes regressed after 9 acute bacterial infections, i.e. in response to non- An attenuated strain of Mycobacterium bovis used to prepare specific immunostimulant effect. But, in general, it the BCG vaccine for immunisation against tuberculosis. 617
  16. 30 N E O P L A S T I C D I S E A S E AND I M M U N O S U P P RESSI O N • Interferons. Interferon alfa is used for chronic • Agents that promote apoptosis are being granulocytic leukaemia, hairy cell leukaemia, developed for clinical use. renal-cell carcinoma and Kaposi's sarcoma. It may also be an effective aduvant therapy for patients at high risk of melanoma recurrence. Chemoprevention of Haemopoietic growth factors or cell colony- cancer stimulating factors are used to assist recovery of leukopenic patients, e.g. filgrastim (recombinant Since many cancers are currently incurable, it human granulocyte colony stimulating factor, G- would seem preferable to prevent cancer occurring CSF) and molgramostim (recombinant human if possible. Individuals changing aspects of their granulocyte macrophage-colony stimulating factor, own lifestyles may significantly influence their risk GM-CSF) (see p. 598). of developing particular cancers. Chemical inter- ventions to reduce cancer risk may be considered for the population as a whole, or for groups at high risk of a specific cancer. Some vitamins and deriva- Emerging anticancer tives and dietary micronutrients may inhibit the treatments development of cancers, e.g. beta-carotene, iso- tretinoin, folic acid, ascorbic acid, alphatocopherol. Large-scale trials of these substances and deriva- Our understanding of the biological processes tives are in progress. Isotretinoin appears to prevent which govern carcinogenesis is growing rapidly second primary squamous cell tumours of the head and provides the basis for identifying novel cellular and neck. The antioestrogen, tamoxifen, when used targets for anticancer drug development. New as an adjuvant therapy in women undergoing approaches that are designed to exploit biological surgery for primary breast cancer, was shown to derangements unique to the cancer cell are being reduce the risk of cancer occurring in the contra- tested in clinical trials. Examples include: lateral breast. This oral agent with few unwanted • Matrix metalloproteinase inhibitors that are effects is now being tested in women at high risk of designed to inhibit invasion of cancer cells and developing breast cancer as a chemopreventive prevent formation of metastases. strategy. See also aspirin (p. 283). • Inhibitors of angiogenesis. Tumours require nutrition and produce angiogenic signals that CANCER 'CURES': UNPROVEN lead to new vessel formation; the strategy is to REMEDIES prevent new blood vessel formation essential for tumour growth. So long as conventional medicine cannot cure all • Signal transduction inhibitors. An example is patients with cancer some will be willing to try farnesyl transferase, an enzyme crucial for the anything that they think might help.10 activation of the oncogene, ras, which is frequently overexpressed in cancers. Inhibitors This is perfectly understandable and many patients of this enzyme appear effectively to inhibit use unproven methods, including medicines (see cancer cell growth. complementary medicine). Innumerable methods • Designer molecular therapy. A tyrosine kinase are and have been offered for cancer. A prominent inhibitor, imatinib, is specifically designed to remedy was laetrile, a preparation of apricot seeds block the dysregulated tyrosine kinase (pits, pips), which contains amygdalin (a (i-glucoside) hyperactivity produced by the Philadelphia which incorporates cyanide. It was claimed to chromosome that is specific for chronic relieve pain, prolong survival and even to induce granulocytic leukaemia; clinical trials support its complete remission of cancer. Benefit was reputed efficacy in this disease. to result from release of cyanide in the body which 618
  17. C H E M O P R EV E N T I O N O F C A N C E R 30 was claimed to kill cancer cells but not normal cells. • Adrenocortical steroids Although it was claimed that laetrile had no toxic • Azathioprine (see below) effects, an 11-month-old girl died after swallowing • Ciclosporin, tacrolimus (see below) tablets (1-5) being used by her father. The toxicity • Some alkylating agents: cyclophosphamide and was due to metabolic formation of hydrocyanic acid chlorambucil (see Table 30.2) in the intestine. There is no serious evidence that • Antilymphocyte immunoglobulin (see below). laetrile is effective. With the exception of cidosporin and tacrolimus, As has so often been the case in the past, and no all the above cause nonspecific immunosuppression doubt will continue to be in the future, the calm so that the general defences of the body against evaluation of such claims is obstructed by a mixture infection are impaired. of emotionalism and exploitation. Adrenal steroids destroy lymphocytes, reduce Interestingly, despite criticism of overpermissive inflammation and impair phagocytosis (see Ch. 34). laxity of the drug regulatory authority (FDA) in the Cytotoxic agents destroy immunologically com- USA, the public is unwilling to accept the opinion petent cells. Azathioprine, a prodrug for the purine of the FDA when it advises against the use of drugs antagonist mercaptopurine, is used in autoimmune such as laetrile. It is important that these inter- disease because it provides enhanced immuno- ventions be tested for efficacy and toxicity in the suppressive activity. Cyclophosphamide is a second same way as conventional drugs are subject to choice. Bone marrow is depressed as is to be expected. rigorous clinical trials. There is a long and generally dishonourable Ciclosporin history of the promotion of cancer 'cures', but as each new one appears the medical profession must Ciclosporin is polypeptide obtained from a soil yet again be willing to look dispassionately at the fungus. It acts selectively and reversibly by possibility that this time there really may be preventing the transcription of interleukin-2 and something in it, whilst avoiding the tragic raising of other lymphokine genes, thus inhibiting the hopes that will not be realised — a sad and difficult production of lymphokines by T-lymphocytes (that task. mediate specific recognition of alien molecules). Ciclosporin spares nonspecific function, e.g. of granulocytes, that are responsible for phagocytosis and metabolism of foreign substances. It does not Immunosuppression depress haemopoiesis. Suppression of immune responses mediated via Pharmacokinetics. Ciclosporin is about 40% mononuclear cells (lymphocytes, plasma cells) is absorbed from the gastrointestinal tract and is used in therapy of: extensively metabolised in the liver mainly by the cytochrome P450 3A system; the tl/2 is 27 h. • Autoimmune and collagen and connective tissue disease (see below) Uses. Ciclosporin is used to prevent and treat • Organ transplantation; to prevent immune rejection of organ transplants (kidney, liver, heart- rejection. lung) and bone marrow transplants. It may be Cytotoxic cancer chemotherapeutic agents are given orally or i.v. In the context of transplantation, immunosuppressive because they interfere with administration continues indefinitely and must be mononuclear cell multiplication and function. But carefully monitored, including measurement of they are generally too toxic for the above purposes plasma concentration and renal function. It is and the following are principally used for intended generally stopped after 6 months in patients who immunosuppression: have received a bone marrow transplant unless there is ongoing chronic graft-versus-host disease. Ciclosporin may also be used for severe, 10 Editorial. British Medical Journal 1977 1: 3. resistant psoriasis in hospitalised patients. 619
  18. 30 N E O P L A S T I C D I S E A S E AND I M M U N O SU P PRESSI O N Adverse reactions. Ciclosporin constricts the pre- involved; it is made by preparing antisera to human glomerular afferent arteriole and reduces glomerular lymphocytes in animals (horses or rabbits); allergic filtration; acute or chronic renal impairment may reactions are common. It largely spares the patient's develop if the trough plasma concentration con- response to infection. It is also used in the treatment sistently exceeds 250 mg/1. In the main, renal of severe aplastic anaemia and frequently changes resolve if the drug is withdrawn. Hyper- produces a good partial response either as a single tension develops in about 50% of patients, more agent or in combination with ciclosporin. It is commonly when a corticosteroid is co-administered the treatment of choice for patients with severe but possibly due in part to mineralocorticosteroid aplastic anaemia for whom no bone marrow donor action of ciclosporin. The blood pressure can be can be found or who are too old or unfit for bone controlled by standard antihypertensive therapy marrow transplant. without need to discontinue ciclosporin. Other adverse effects include gastrointestinal reactions, Mycophenolate selectively blocks the proliferation hepatotoxicity, hyperkalaemia, hypertichosis, gingival of T and B lymphocytes and acts like azathioprine; hypertrophy and convulsions. The clinical syn- it is being evaluated in combination immuno- drome of thrombotic thrombocytopenic purpura suppressive regimens for organ transplantation. may rarely follow cyclosporin therapy. USES Interactions. Careful attention to co-administered drugs is essential as many may interact. The plasma Diseases in which immunosuppression may be concentration of ciclosporin, and risk of toxicity, is useful include: tissue transplantation, inflammatory increased by drugs that include ketoconazole, ery- bowel disease, rheumatoid arthritis, chronic active thromycin, chloroquine, cimetidine, oral contra- hepatitis, systemic lupus erythematosus, glomerulo- ceptives, anabolic steroids and calcium channel nephritis, nephrotic syndrome, some haemolytic antagonists. Grapefruit juice also elevates plasma anaemias and thrombocytopenias, uveitis, myas- ciclosporin concentrations; flavonoids in the juice thenia gravis, polyarteritis, polymyositis, systemic inhibit the cytochrome that metabolises ciclosporin. sclerosis, Behc.et's syndrome. Drugs that reduce the plasma concentration of ciclosporin, risking loss of effect, include enzyme- HAZARDS OF LIFE ON inducing antiepileptics (e.g. phenytoin, carba- IMMUNOSUPPRESSIVE DRUGS mazepine, phenobarbital) and rifampicin. Inherently nephrotoxic drugs add to the risk of renal Impaired immune responses render the subject damage with ciclosporin, e.g. aminoglycoside more liable to bacterial and viral infections. Treat all antibiotics, amphotericin, NSAIDs (diclofenac). infection early and vigorously (using bactericidal Potassium-sparing diuretics add to the risk of drugs where practicable); use human gamma hyperkalaemia. globulin to protect if there is exposure to virus infections, e.g. measles, varicella. For example, Tacrolimus is a macrolide immunosuppressant patients who have not had chickenpox and are agent that is isolated from a bacterium. It acts like receiving therapeutic (as opposed to replacement) ciclosporin and is used to protect and treat liver and doses of corticosteroid are at risk of severe kidney grafts when conventional immunosup- chickenpox; they should receive varicella-zoster pressants fail. Such rescue treatment may be graft- immunoglobulin if there has been contact with the or life-saving. Tacrolimus may cause nephrotoxicity, disease within the previous 3 months. neurotoxicity, disturbance of glucose metabolism, hyperkalaemia and hypertrophic cardiomyopathy. Carcinogenicity is also a hazard, generally after 4-7 years of therapy. The cancers most likely to Antilymphocyte immunoglobin is used in organ occur are those thought to have viral origin graft rejection, a process in which lymphocytes are (leukaemia, lymphoma, skin). Where cytotoxics are 620
  19. CHEMO PREVENTION OF CANCER 30 used there is the additional hazard of mutagenicity, Crown J, O'Leary M 2000 The taxanes: an update. which may induce cancer. Lancet 355:1176-1178 Emery J, Lucassen A, Murphy M 2001 Common Hazards also include those of long-term cortico- hereditary cancers and implications for primary steroid therapy, and of cytotoxics in general (bone care. Lancet 358: 56-63 marrow depression, infertility and teratogenesis). Greenwald P 2002 Cancer chemoprevention. British Whilst the hazards may be acceptable to the Medical Journal 324: 714-718 patient who has grave life-endangering disease, Heaney M L, Golde D W 1999 Myelodysplsia. New they give more cause for concern when immuno- England Journal of Medicine 340:1649-1660 suppressive regimens are proposed in younger Janne P A, Mayer R J 2000 Chemoprevention of patients with less serious disease, e.g. rheumatoid colorectal cancer. New England Journal of arthritis, ulcerative colitis. Medicine 342:1960-1968 Lowenberg B, Downing J R, Burnett A1999 Acute myeloid luekaemia. New England Journal of ACTIVE IMMUNISATION DURING Medicine 341:1051-1062 IMMUNOSUPPRESSIVE THERAPY Mullan F 1985 Seasons of survival: reflections of a Response to nonliving antigens (tetanus, typhoid, (32-year-old) physician with cancer. New England poliomyelitis) is diminished and giving one or two Journal of Medicine 313: 270-273 extra doses may be wise. Living vaccines are contra- Pui C-H, Evans W E 1998 Acute lymphoblastic indicated in patients who are immunosuppressed by leukaemia. New England Journal of Medicine 399: drug therapy or indeed by disease (AIDS, leu- 605-615 kaemia, reticulosis) as there is a risk of serious Renehan A G, Booth C, Potten C S 2001 What is generalised infection. apoptosis, and why is it important? British Medical Journal 322:1536-1538 Savage D G, Antman K H 2002 Imatinib mesylate — a IMMUNOSTIMULATION new oral targeted therapy. New England Journal of See Immunotherapy, page 617. Medicine 346: 683-693 Shapiro C L, Recht A 2001 Side effects of adjuvant treatment of breast cancer. New England Journal of Medicine 344:1997-2008 GUIDETO FURTHER READING Stewart A K, Schuh A C 2000 White cells: impct of unerstanding the molecular basis of Bataille R, Harousseau J-L 1997 Multiple myeloma. haematological malignant disorders on clinical New England Journal of Medicine 336:1657-1664 practice. Lancet 355:1447-1453 demons M, Goss P 2001 Estrogen and the risk of Tamm I, Dorken B, Hartman G 2001 Antisense breast cancer. New England Journal of Medicine therapy in oncology: new hope for an old idea? 344: 276-285 Lancet 358: 489-497 Corrie P G 1999 Chemotherapy in practice. Medicine 27: 24-29 621
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