Carlo Palmieri and Anjana Singh discuss the available options

This second article deals with the non-surgical or medical treatments and aims to provide an overview of this area of medicine. Current medical treatments or modalities include chemotherapy, radiotherapy, endocrine therapy, immunotherapy, and monoclonal antibodies.

Chemotherapy

There are six basic facts you should know:

1. Chemotherapy or cytotoxic agents are drugs which interfere with cell division by preventing DNA synthesis or interacting with DNA leading to breaks in the structure.
2. They are non-selective and will affect any cell which is rapidly dividing, whether it is malignant or non-malignant.
3. Cytotoxics are usually given in combination, with drugs which interfere with replication at different phases of the cell cycle being used. This improves their effectiveness and reduces the likelihood of the development of drug resistance by the tumour.
4. Chemotherapy is given every 21 to 28 days to allow recovery of the bone marrow.
5. Each treatment is called a cycle and usually a course of chemotherapy involves a number of cycles.
6. Expected toxicities of each agent given in combination should not overlap.

Cautionary notes

Vinca alkaloids--for example, vincristine and vinblastine--are highly neurotoxic and are given only intravenously. They kill if given intrathecally.

Methotrexate accumulates in ascites and pleural effusions and can later leak back into the circulation causing toxicity. Hence these should be drained before treatment or a lower dose of drug should be used.

Taxanes--that is, docetaxel and paclitaxel--can cause hypersensitivity reactions, hence premedication with steroids and antihistamines is given.

Cytotoxics such as vinca alkaloids, anthracyclines, and mitomycin C are vesicants and if they extravasate--that is, leak into surrounding tissue--they can cause severe tissue damage.

Radiotherapy

There are five basic facts you should know:

1. Radiotherapy involves the use of high energy ionising radiation to cause DNA damage and ultimately cell death.
2. Dose of radiotherapy is measured in Grays (Gy)--this represents the amount of energy deposited in the tissue.
3. Radiotherapy is given in units called fractions over several days or weeks. To give the whole dose in one go is too toxic and would cause severe tissue damage and even death. Hence you may see written in patient notes, "For 50 Gy over 20 fractions." This means that the patient will be treated daily for four weeks with 2.5 Gy each day.
4. The area to be irradiated is referred to as the radiation field. This is always marked out on the skin before treatment and such markings often persist after treatment as tattooed dots. (Look out for these in exams.)
5. Each tissue in the body has a particular tolerance to radiation which will limit the total dose that can be administered to that area.

How is radiotherapy delivered?
There are three major ways in which ionising radiation is delivered.

External beam radiotherapy
This involves the use of a variety of machines to deliver external beam therapy. The source is at a distance from the body--for example, irradiation of bone metastasis.

Brachytherapy
In this the radioactive source is in or close to the area to be treated, or directly into the tumour.

Brachytherapy is administered in two ways: interstitial therapy, where radioactive wires are inserted directly into the tumour--for example, insertion of iridium-192 wires into a tongue carcinoma--or intracavitary therapy, where radioactive source is inserted into the body cavity--for example, insertion of caesium-137 into the vagina for treatment of cervical carcinoma.

Radioactive isotopes
This involves giving a radioactive isotope that is preferentially taken up the target organ. Radioactive isotopes can be delivered by the oral or intravenous route--for example, oral iodine-131 for the treatment of thyroid tumours and intravenous strontium-89 in palliative treatment of bone metastasis.

The use of chemotherapy and radiotherapy
Chemotherapy and radiotherapy can be used in several different clinical settings. The table on the next page summarises these and gives an example in each case.

Hormonal therapy
Endocrine therapy (or hormonal manipulation) is an important part of managing cancers whose growth is dependent on hormones, namely, breast and prostate cancer. The aim of such treatment is to reduce the amount or effect of circulating sex hormone.

Breast cancer
Hormonal manipulation is used when the breast tumour is positive for oestrogen receptor alpha (ER*)--that is, it will be sensitive to circulating oestradiol.

Luteinising hormone releasing hormone (LHRH) agonists--for example, goserelin--causes down regualtion of pituitary LHRH receptors and via a decrease in LH/FSH (luteinising hormone/follicle stimulating hormone) to a reduced plasma estradiol. It is used in the neoadjuvant, adjuvant, and palliative setting in premenopausal women.

Tamoxifen binds ER* and prevents oestradiol binding. It is used in the neoadjuvant, adjuvant, and palliative setting in postmenopausal women.

Aromatase inhibitors--for example, anastrozole--bind and inhibit aromatase enzyme in peripheral tissue--for example, adipose tissue, which is the major source of oestradiol synthesis in postmenopausal women. They are used in the palliative setting for women whose disease progresses on tamoxifen.

All the above drugs can cause menopausal symptoms, namely hot flushes, sweats, and vaginal dryness.

Specific and important adverse effects of tamoxifen are thromboembolic disease and uterine carcinoma. The benefits far outweigh the risks.

Prostate cancer
The growth of prostatic carcinoma is under the control of androgens, hence the aim of hormonal therapy is to reduce testosterone levels or prevent it binding to the androgen receptor.

Luteinising hormone realeasing hormone agonists cause down regulation of pituitary LHRH receptors and via a decrease in LH to a reduced plasma dihydrotestosterone. The adverse effects are impotence, loss of libido, gynaecomastia, hot flushes.

Tumour flare--that is, increase in tumour size which can cause symptoms such as increase in bone pain and spinal cord compression--can occur with the initial use of these drugs, due to an initial increase in testosterone. Therefore an antiandrogen should be prescribed for a few weeks before, and after commencement of, a LHRH agonists to prevent this happening.

Antiandrogens--for example, cyproterone, flutamide, bicalutamide--bind to the androgen receptor and prevent dihydrotestosterone binding.

The adverse effects are hepatotoxcity, gyanecomastia and diarrhoea, abdominal pain, gynaecomastia.

Combined androgen blockade (or maximal androgen blockade) is a term used to describe the use of an LHRH agonist and androgen receptor antagonist together.

These agents are used alone or in combination for either locally advanced or metastatic prostate cancer.

Immunotherapy
Immunotherapy involves trying to stimulate the immune system to mount a response to the tumour by effects on the tumour and the immune system effector cells or both.

Interferons are naturally occurring proteins produced in response to viral infections. Three interferons are known to exist *, ß, and *. Only interferon alpha is used in malignant diseases.

Interferon alpha is used in hairy cell leukaemia, metastatic renal cell carcinoma, metastatic malignant melanoma, and AIDS related Kaposi's sarcoma. The adverse effects are flu-like symptoms, fatigue, and myelosuppression.

Interleukins are a large group of secretory proteins that are produced by T cells during an immune response.

Interleukin-2 (IL-2) is used in the treatment of metastatic renal cell carcinoma. The adverse effects are fluid retention, multiorgan dysfunction, and bone marrow and hepatic toxicity.

Monoclonal antibody treatment

A monoclonal antibody is an antibody produced by a single clone of B cells. Two monoclonal antibodies are currently used in oncology: rituximab and trastuzumab.

Rituximab is directed against CD20, a protein which is expressed on pre-B and mature B cells. This is non-specific as it will ablate both normal and malignant B cells. However, the normal cells are subsequently regenerated by the bone marrow from normal stem cells. It is effective in low grade and follicular non-Hodgkin's lymphoma.

Trastuzumab is directed against human epidermal growth factor receptor 2 (HER2), which is overexpressed in 30% of breast cancers and is associated with a poorer prognosis. It is used in metastatic breast cancer which is HER2 positive.

Both these drugs can cause flu-like symptoms on infusion, such as chills and pyrexia. In addition, trastuzumab has been noted to be cardiotoxic especially when given with anthracyclines.

We would like to thank Elizabeth Selvadurai, specialist registrar in clinical oncology, for her advice.