A new paradigm and novel therapies

The current model for treating cancer is based on the belief that cure can be achieved only by the eradication of each and every cancer cell. This model, which is derived from the need to destroy invading microorganisms, may not necessarily apply to cancer cells which are derived from their host. It has been suggested that the malignant cell should be regarded as part of a biological communications network where processes of cell growth, division and migration take place in an environment of impaired regulation. While conventional antineo-plastic approaches, such as surgery, radiation therapy and cytotoxic chemotherapy, still play a part in treatment, the essential need is to reassert normal controlling mechanisms so that re-regulation of critical processes in the growth, invasion and metastatic process can occur. This will entail reversal of inducing and promoting events, blocking the action of defective or false transmitters, overriding inefficient enzymes or receptors and inducing alternative metabolic pathways.

Over 100 separate protocols for 'gene therapy' are now under investigation worldwide. These do not necessarily indicate a direct attack on a defective gene; rather current use investigations of 'gene therapy' rather have focussed on the use of DNA constructs to augment existing therapies. Examples of such strategies include the following:

• The infusion of genetically modified immuno-competent cells which overexpress cytokines (e.g. interleukin-2, IL-2) and mount an exaggerated immune response against the tumour. Initially it was believed that those lymphocytes found within the tumour (tumour-infiltrating lymphocytes, TIL cells) would prove ideal for this purpose, as they could be readily extracted from the tumour, their population expanded in laboratory culture, transfected with an IL-2 gene and re-infused. However, subsequent studies in which a 'marker' gene was inserted into TIL-cells indicated that they were not selectively taken up or retained by the tumour. Alternative strategies include the use of autologous tumour cells transduced with a cytokine gene as a vaccine; or tumour cells which have been genetically modified (e.g. by transfection with HLA genes) to increase their immuno-genicity.

• The enhancement of protection against the toxic effects of chemotherapeutic agents by the insertion, into normal cells, of a drug-resistance gene. This applies particularly to bone-marrow stem cells into which the mdr-1 gene can be inserted. Through stimulation of the P-glycoprotein efflux pump, daughter cells expressing this gene are protected against the cytotoxic effects of the drug which can then be given in higher dose.

• The development of strategies to enable tumour cells to selectively activate a 'pro-drug', normally inert, into a highly toxic metabolite. An example is the insertion of the thymidine kinase gene, the product of which can convert ganciclovir into its cytotoxic triphosphates. This gene can be inserted into neurological tumours using a herpes simplex virus vector.

• The synthesis of 'antisense' DNA oligonucleotides which have complimentary coding to mRNA but which, being inert, block the normal process of translation (Fig. 9.16).

Figure 9.16. Mechanism of action of antisense oligonucleotides.

• siRNA which potently inhibits gene expression at a post-transcriptional level which an apparently high degree of potency and specificity.

• The development of inhibitors of enzymes such as topoi-somerase and telomerase which are concerned with repair and integrity of the genome. Drugs which override the check-points in the cell cycle apparently sensitize the cells to DNA damaging agents.

It is obvious that the ideal form of gene therapy is that which allows replacement or correction of a defective oncogene or tumour-suppressor gene which is causally associated with the cancer in question. But difficulties arise in the delivery of the replacement gene, which must be transduced into the tumour cells by a suitable vector. To date most attention has focussed on the use of virus vector, particularly retrovirus, but alternative non-viral vectors are also being studied. These include liposomes, synthetic molecular complexes as well as 'naked' and modified oligonucleotides. It is hoped that by the attachment to these vectors of ligands, which bind to tumour cell antigens, selectivity can be achieved.

Other forms of non-genetic biological therapy are under study. These include the use of monoclonal antibodies (Fig. 9.17) specific for tumour antigens, which carry a radioactive isotope (e.g. yttrium-90) or a cell toxin (e.g. saporin) which can penetrate the cell membrane. Inhibitors of those 'downstream events' that affect the metabolism, proliferation of the cancer cell and its invasive properties are also being developed. Examples are antagonists to growth factors, collagenase activity and angiogenesis. The promotion of apop-tosis is another area of interest.

The development of new cytotoxic drugs is an ongoing process leading to new effective agents such as taxol, suramin and imatinib.

Whatever the outcome of research into these approaches, the 'take-home' message is that, unlike infecting parasites

Figure 9.17. Monoclonal antibody therapy.

and microorganisms, cancer cells are not new invaders but aberrations of the proliferation, growth and migration of normal host cells.

RELIEF OF CANCER PAIN Palliative care

Palliative care, is commonly regarded as synonymous with terminal care; that is, the management of patients with advanced disease for whom curative treatment is not appropriate and who are approaching death. It has been converted from a passive form of care practised as an alternative to radical or curative care to one that includes active measures to counteract symptoms and provide support. At times, this may include aggressive treatment, for example by chemotherapy or surgery. Palliative care is now 'holistic' and all embracing and therefore requires a multidisciplinary approach.

Four broad domains of palliative care are described -physical, psychological, social (cultural) and spiritual. Of these physical needs are most likely to concern the surgeon, whose services may be required to relieve a mechanical dysfunction. He must also understand the principles of modern pain control.

Principles of cancer pain control

Pain at diagnosis is experienced by 20-50% of cancer patients. By the time the disease is advanced, this proportion has risen to 75%. Considering that worldwide some 7 million new cases are diagnosed every year and that 8% of all deaths are due to cancer (25% in developed countries), some 4 million persons require treatment of cancer pain at any one time.

Pain may be acute or chronic. Acute pain is severe, may be catastrophic and accompanied by autonomic and psychological responses, drawing attention to an acute pathological process which needs to be remedied. Chronic pain is continuous, recurring at intervals of months or years, and is associated with vegetative disturbances such as lack of sleep, anorexia, decreased libido and personality change. Unlike acute pain it does not serve any useful purpose.

Pain associated with cancer may be caused by the cancer itself, when it may be somatic or visceral in origin, or due to associated factors such as muscle spasm, bedsores, constipation or complications of treatment. It may also arise from an unrelated disorder. Cancer pain can be differentiated from other forms of pain by its chronicity and by overwhelming associated features of insomnia, reduced appetite, irritability, depression, rage and spiritual or social disturbance. It is described as 'total pain' (Fig. 9.18). A number of typical cancer pain syndromes have been described for particular sites of primary or metastatic disease, which must be recognized.

The mainstay of the successful treatment of cancer pain is the use of non-opioid, opioid and a number of adjuvant drugs. The WHO 'ladder' ascends from the prescription of non-opioid drugs, through 'weak opioids' to 'strong opioids' as control is lost (Fig. 9.19). Opioid is a generic term which refers to codeine, morphine and other natural and synthetic drugs which act on specific receptors in the central and peripheral nervous systems. With correct administration of appropriate drugs, pain can be controlled in 90% of cases. In the remainder, it will be reduced to acceptable proportions. Inappropriate use of opioids is due to lack of availability or incorrect prescribing by physician or surgeon who may equate need with the prescription of opioids for benign conditions. Unwarranted fear of addiction and lack of knowledge of alternative remedies also contribute to this.

Patient factors may constrain appropriate pain control. Believing that cancer pain is inevitable and untreatable, a patient may put on a brave face to their doctor who then falsely believes that their pain is well controlled. Noncompliance with prescribed medication may be a problem, either because of adverse effects or a desire to keep 'strong drugs' for a time when things get worse. The key to successful control is that the dose and duration of opioid treatment is determined solely by the needs of the patient. Peripheral nerve blocks, cordotomy and intrathecal blocks are now required only for drug resistant or certain specific forms of pain.

Evaluation of the patient

As with all forms of patient management, diagnosis and evaluation of symptoms must precede treatment. This requires knowledge of the pathological processes that give rise to pain, sites of referral and the anatomy of the central and peripheral nervous systems. When evaluation is complete, the physician or surgeon should have ascertained

Other symptoms Adverse effects of treatment

Loss of social position-

Loss of job, prestige and income Loss of role in family

Insomnia and chronic fatigue -

Sense of helplessness-

Disfigurement-

Physical ( Total A

Depression pain Anxiety

Anger

Bureaucratic bungling Delays in diagnosis — Unavailable physicians

Uncommunicative physicians _ Failure of therapy

Friends who do not visit

Fear of hospital or nursing-home

Fear of pain Worry about family and finances Fear of death Spiritual unrest, uncertainty about future

Figure 9.18. Total pain as described by Twycross (1994).

Figure 9.19. WHO 'ladder' for treatment of pain.

whether the pain is caused by the cancer or another (possibly remedial) disorder, whether it constitutes a specific cancer pain syndrome and whether it is of somatic or visceral type. He also should recognize neuropathic pain due to irritation or compression of central or peripheral nerves.

A specific plan should be identified for each patient, which must be fully discussed with him and his family. The aim of treatment and the risk of adverse effects should be explained. Optimum requirements for non-opioids and opioids, laxatives and psychotropic drugs are planned. As these will require adjustment, continuing assessment is necessary. A particular pathological process (e.g. bone metastases) may respond to direct treatment by radiotherapy or bisphosphonates. Mobility must be preserved. Muscular spasm and other pains associated with immobility can be as severe as cancer pain.

The analgesic ladder

The World Health Organization ladder for the relief of cancer pain consists of three steps at each of which the right drug is given in the right dose and at the right time intervals for a particular patient. For other than transient pain, analgesics should not be used 'as needed' but prescribed at time intervals appropriate to their duration of action. To allow pain to re-emerge before the next dose causes unnecessary pain and encourages tolerance. At each step a number of adjuvant drugs are included to relieve the adverse effects of pain control.

The Insomnia Battle

The Insomnia Battle

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