Chemotherapy

• Introduction to chemotherapy
• Chemotherapeutic classes
  • Alkylating agents
  • Anthracyclines
  • Taxanes
• Chemotherapeutic classes
  • Vinca alkaloids
  • Anti-metabolites
    • Folate antagonists
    • Purine antagonists
    • Pyrimidine antagonists

Introduction to chemotherapy

Cancer is a disease characterised by disturbances in cell survival, proliferation, and differentiation (maturation of cells so they can carry out specified functions). Cancer cells have a special ability to rapidly proliferate (often leading to the production of a tumour mass) and metastasise (or spread) to distant tissues.
Chemotherapy refers to the use of cytotoxic (cell killing) drugs in the treatment of cancer. Tumour cells are more sensitive than normal cells to chemotherapeutic drugs because they are rapidly dividing cells. Chemotherapy treatment disrupts the cell cycle in an attempt to cause enough changes in the cellular makeup so that the cell cannot divide, or damages the cellular makeup enough to cause the cell to die. Some chemotherapeutic agents are cell cycle specific (meaning they act on cells at a specific stage of growth and division) while others can be given at any time in a cells life and cause these terminal changes.
Chemotherapy drugs are sometimes given with the intent to cure your disease. In other instances they may be used after surgery to prevent recurrence or may be used as a palliative measure to control symptoms and improve quality of life, rather than actually curing disease (if this is not possible).
Chemotherapy often requires a combination of a number of drugs in conjunction with other treatments such as surgery and radiation therapy. Depending on the type of drug used, it may be administered by mouth, intravenously or directly into the affected organ. Chemotherapy regimens vary greatly and may require several cycles of treatment with drug-free periods in between. Your medical oncologist can provide detailed information about the specific regimen recommended for you.

Chemotherapeutic classes

There are five chemotherapeutic classes:

• Alkylating agents;
• Anthracyclines;
• Taxanes;
• Vinca alkaloids; and
• Anti-metabolites.

Alkylating agents

Alkylating agents cause cell death by interacting with DNA during cell synthesis. DNA is the component of cells containing all the genetic information the cell needs to grow, divide and function. The DNA is like the blue-print of living cells and has a special helical ladder structure. Alkylating agents work by directly interacting with exposed DNA and adding alkyl groups. The resulting permanent DNA damage ultimately results in death of the cells.
Cyclophosphamide (cycloblastin, endoxan) was the first clinically effective cancer chemotherapy agent and is the most commonly used alkylating agent. As well as its anti-tumour effects, it also has immunosuppressant activity as it also disrupts the function of lymphocytes (immune cells).
Other alkylating agents include chlorambucil (leukeran), carmustine, lomustine and cisplatin. The latter is sometimes classed as a platinum compound and has been responsible for the massive advances in the treatment of testicular cancer as well as being effective against a range of other cancers including lung, ovarian and head and neck cancers.

Side effects of alkylating agents
All alkylating agents depress bone marrow function and cause gastrointestinal disturbances such as nausea and vomiting. As bone marrow is responsible for the production of red blood cells, white blood cells and platelets when it is depressed symptoms of anaemia, infection and bleeding respectively, may occur. Therefore regular monitoring of blood counts is required during treatment. The frequency and severity of most adverse effects increase with increasing dose. Sterility and secondary malignancies have been reported with prolonged use of alkylating agents.

Anthracyclines

Anthracyclines are cytotoxic (cell killing) antibiotics that are also non-cell-cycle specific chemotherapy agents. They are probably amoung the most commonly used cytotoxic drugs. Many antracyclines also have immunosuppressant activity.
Doxorubicin (adriamycin) is an example of an anthracycline medication which is used in a variety of cancers including affecting the breast, endometrium (lining of the womb), ovary, testicle, thyroid, stomach, bladder, liver and lung, soft tissues and several childhood cancers. Epirubicin and mitozantrone are other examples of anthracycline medications.

Side effects of anthracyclines
Side effects of anthracycline use include:

• Myelosuppression (bone marrow suppression) especially of white blood cells, but also of red blood cells and platelets. These side effects of chemotherapy can be minimised with red blood cell and platelet transfusions. In addition if you develop fever during treatment (febrile neutropenia) you must see a doctor for careful management;
• Increased risk of infection and bleeding;
• Toxicity to the heart which may lead to arrhythmias. Damage may become permanent after approximately one month of treatment especially if you have been previously exposed to these drugs. It is for this reason that doctors are often reluctant to prescribe anthracyclines if you have been treated with them in the past;
• Severe local reactions, including tissue necrosis (death) or extravasation (leakage of drug outside the blood vessels);
• Secondary malignancies;
• Radiation recall: The recurrence of skin damage from previous radiotherapy;
• Alopecia (hair loss): This may be associated with significant effects on quality of life;
• Nausea and vomiting;
• Oral ulceration.

Taxanes

Taxanes are cytotoxic agents that work on a protein called tubulin found in the cytoplasm of cells. Tubulin is needed for the production of microtubules which are essential in cell division. Microtubules help separate chromosomes (agents carrying our DNA) when cells divide. Taxanes are generally used when other chemotherapy regimens have failed. They tend to be effective against ovarian, breast and lung cancers.
Taxanes currently available in Australia include:

• Paclitaxel (Anzatax, Taxol);
• Nanoparticle albumin-bound paclitaxel (Abraxane); and
• Docetaxal (Taxotere).

Paclitaxel has been shown to have activity in a broad range of solid tumours.
Docetaxal is very similar to paclitaxel in terms of mechanism of action, metabolism, and elimination. It is currently approved as second line therapy for advanced breast cancer and non-small cell lung cancer (NSCLC).
Nanoparticle albumin-bound paclitaxel is used for metastatic breast cancers. It binds the active component (paclitaxel) to a protein (Albumin) normally found in the blood. This increases the drug’s solubility and avoids the use of other additives, associated with side effects, that normally act to increase the water solubility of the drug.

Side effects of taxanes
Taxanes cause bone marrow suppression like many other chemotherapeutic agents. The most common effect is neutropaenia, which increases the chance of infection. Other side effects include:

• Nausea and vomiting: A variety of anti-emetic (anti-nausea) agents are available for patients receiving chemotherapy to help control and even eliminate symptoms of nausea. Particularly useful agents are a class of drugs called 5-HT3 antagonists such as ondansetron (Ondaz, Zofran) and granisetron (Kytril injections and tablets) combined with dexamethasone (steroid). Other anti-emetics include metoclopramide (Maxalon) and domperidone (Motilium);
• Diarrhoea;
• Mouth sores;
• Joint and muscle aches;
• Alopecia (hair loss);
• Paraesthesia (abnormal sensation);
• Mild allergic reactions (flushing, shortness of breath, urticaria (hives), rash);
• Anaphylactic reactions;
• Injection site reactions.

Due to these side effects, your doctor may treat you with steroids and/or anti-histamine drugs prior to commencement of treatment with paclitaxel or taxotere. This helps to reduce some of the side effects and minimise any hypersensitivity reactions.

Vinca alkaloids

Vinca alkaloids act on a specific phase of the cell cycle called metaphase (M phase). They are another class of anti-tubulin agents (along with the taxanes) and work by binding tubulin and inhibiting the production of microtubules. This halts cell division and leads to cell death. Vinca alkaloids are used to treat both haematological (diseases of blood cells such as leukaemias) and non-haematological (solid organ) malignancies.
There are four vinca alkaloids currently available namely vinblastine, vincristine, vindesine and vinorelbine (Navelbine).

Side effects of vinca alkaloids
Vinca alkaloids cause a number of the common side effects seen with chemotherapy such as:

• Nausea and vomiting;
• Hair loss;
• Mouth sores;
• Headache;
• Constipation.

Vinblastine also causes bone marrow suppression like many other agents, resulting in increased bleeding, infection and anaemia risk. In addition, vinca alkaloids can damage nerves. For example, vincristine may cause numbness, sensory impairment, blurred or double vision and/or general weakness.

Anti-metabolites

Anti-metabolites are molecules that have very similar structures to true proteins within cells. They are therefore taken up by cells which cannot distinguish the drug from the real protein. Once inside the cell, anti-metabolites interact with DNA and RNA like the normal protein would but due to slight variations in their properties prevent the cell processes from continuing. Anti-metabolites therefore prevent normal proteins from binding in the cell and halt normal function and division. In other words, they mimic and interfere with the binding of real proteins. Once again this leads to programmed cell death (apoptosis).
The molecules mimicked by anti-metabolites include folate, purine and pyrimidine. These agents seem to be particularly important in DNA synthesis and cellular metabolism in cancer cells.

Folate antagonists
These agents mimic folate and enter the cell. They inhibit an enzyme called dihydrofolate reductase which is needed in the production of amino acids and purine nucleotides, the building blocks of DNA, RNA and key cellular proteins.
Methotrexate is the main folate antagonist. It may be used in a variety of solid tumours and haematological malignancies. In addition its immunosuppressant properties may be utilised in the treatment of non-malignant conditions such as rheumatoid arthritis and psoriasis.

Side effects of folate antagonists
Methotrexate is very toxic at high doses, particularly to bone marrow and the digestive tract lining. Symptoms of toxicity include:

• Bone marrow suppression, including bleeding, anaemia and increased risk of infection;
• Nausea;
• Anorexia;
• Diarrhoea raging from mild to severe ulceration and bleeding.

Methotrexate is often administered with leucovorin, which is an agent designed to reduce the anaemia and toxicity to normal cells that often accompanies methotrexate therapy.

Purine antagonists
Purine antagonists mimic the purines adenine and guanine, two of the bases that make up DNA. By mimicking these molecules, purine antagonists block DNA synthesis and prevent cell division. Examples of purine antagonists include 6-mercaptopurine (Puri-Nethol), 6-thioguanine, dacarbazine and fludurabine. Purine antagonists are used for the treatment of acute leukaemias.

Side effects of purine antagonists
The side effects of 6-mercaptopurine are listed below which are similar to those seen with many other chemotherapeutic agents. They are rare in children.

• Bone marrow suppression, resulting in increased bleeding and infection risk;
• Mouth sores;
• Skin rash/acne;
• Mild nausea;
• Abnormal liver function;
• Hair loss.

Anorexia, fever, fatigue/weakness and facial flushing can also occur with other purine antagonists than 6-mercaptopurine.

Pyrimidine antagonists
Pyrimidine antagonists mimic the pyrimidines cytosine and thymine, the other two bases making up nucleotides and DNA. By mimicking these molecules, pyrimidine antagonists block DNA synthesis and prevent cell division in a similar mechanism to purine antagonists.
The pyrimidine antagonists include 5-fluorouracil (Efudix), cytarabine, capecitabine (Xeloda) and gemcitabine (Gemzar). 5-Flurouracil has a major role in the treatment of gastrointestinal cancers. Capecitabine is an oral version of 5-fluorouracil and is used in the treatment of metastatic colon cancer and metastatic or resistant breast cancer. Cytarabine is used to treat leukaemias, and gemcitabine is used in solid cancers such as ovarian or in combination with cisplatin to treat non-small cell lung cancer.

Side effects of pyrimidine antagonists
As 5-fluorouracil is active against dividing cells, it also kills healthy cells, which contributes to the following side effects:

• Tiredness
• Nausea and diarrhoea
• Bone marrow depression that may lead to anaemia
• Increased tendency to bruise
• Mouth sores
• Altered pigmentation of the skin

The side effects of capecitabine are similar, as it is converted to 5-fluorouracil once inside the body. Cytarabine may also cause anorexia, fever and rash.

More information

	For information on breast cancer, types of breast cancer and its investigations and treatments, as well as some useful videos, see Breast Cancer.
	For information on prostate cancer, including diagnoses, types of treatments, and some useful tools, videos and animations, see Prostate Cancer.

References

1. Chu E, Sartorelli A, ‘Cancer Chemotherapy’ Katzung, Bertram G. Basic & Clinical Pharmacology, 10th Edition, McGraw-Hill, 2007.
2. Kumar P, Clark M. Clinical Medicine. WB Saunders, Company, 2002.
3. Longmore, Wilkinson, Rajagopalan. Oxford Handbook of Clinical Medicine, 6th Edition, Oxford University Press, 2004.
4. The Cancer Council Australia, Understanding Chemotherapy Fact Sheet, 2007. Available from: [PDF File]
5. Gradishar WJ, Tjulandin S, Davidson N, Shaw H, Desai N Bhar P, Hawkins M, O’Shaughnessy J. Superior efficacy of albumin-bound paclitaxel, ABI-007, compared with polyethylated castor-oil-based paclitaxel in women with metastatic breast cancer: results of a phase III trial. J Clin Oncol 2005; 23: 7794-7803.
6. Harries M, Ellis P, Harper P. Nanoparticle albumin-bound paclitaxel for metastatic breast cancer. J Clin Oncol 2005; 23: 7768-7771.