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Cytotoxic and Biotherapies Credentialing Programme ‐ Module 2 1. The Cell Cycle 2. Cancer Therapies 3. Adjunctive Therapies On completion of this module the RN will • State the difference between a normal cell cycle and a cancer cell cycle. • Understand why cytotoxic therapy causes toxicity. • Discuss the mechanism of action of cytotoxic and biotherapies • Discuss the differences between cytotoxic therapy and biotherapies. • Describe the role of adjuvant therapies in cancer therapy. REFERENCES Gulatte, M. M. (Ed.). (2007). Clinical Guide to Antineoplastic Therapy: A Chemotherapy Handbook (Second ed.). Pittsburgh: Oncology Nusing Society. Polovich, M., White, J., Kelleher, L. (Eds.). (2005). Chemotherapy and Biotherapy Guidelines and Recommendations for Practice. Pittsburgh: Oncology Nursing Society. The Cell Cycle ___________________________________________________
The cell cycle is the process by which cell division occurs. It consists of five stages that lead to cell replication. It is a vital process by which a single‐celled fertilized egg develops into a mature organism, as well as the process by which hair, skin, blood cells, and organs are renewed. Normal cell division is regulated. It occurs in an orderly manner resulting in functional cells. It is regulated by genes within the cell. The genes that tell the cell to begin the cycle are called proto‐onco genes. When there is enough of that cell the tumour suppressor genes turn the process off. Stages Go – Gap O (resting) G1 – Gap 1 S ‐ Synthesis G2 – Gap 2 M ‐ Mitosis The cell would enter
GO stage here
Description The cell exits the cell cycle at G1 and enters G0 (resting). The cell maintains its specialised functions but does not divide. Cells increase in size in Gap 1. The G1 control mechanism ensures that everything is ready for DNA synthesis. DNA replication occurs during this phase. During the gap between DNA synthesis and mitosis, the cell will continue to grow. The G2 control mechanism ensures that everything is ready to enter the M (mitosis) phase and divide. Cell growth stops at this stage and cellular energy is focused on the orderly division into two daughter cells. A control in the middle of mitosis (Metaphase Checkpoint) ensures that the cell is ready to complete cell division. Cell Cycle and Cancer Cancer is process where there is a loss in the control of cell growth. The process becomes unregulated. These cells have the ability to self renew with no programmed cell death (apoptosis). They remain immature and do not differentiate into functioning cells. This occurs when there is a genetic mutation of the cell that promotes cell division. This can occur at more than one stage of the cell cycle. Diagram of the Effects of Proto‐onco Genes and Tumour Suppressor Genes on the Cell Normal Cell Activity Proto‐onco Genes
Regulated cell proliferation and apoptosis Tumour Suppressor Genes
Cell
Cancer Cell Activity Genetic damage to the cell
Excessive Proto‐onco Genes
Excess cell proliferation and failure of apoptosis Tumour Suppressor Genes
Cell
The underlying principle of cancer growth is that permanent damage to cellular DNA contained within the nucleus promotes immature proliferation and inhibits normal cell death. This can be caused by a combination of factors including carcinogens, viruses and life style. Cancer Therapies ________________________________________________________ This section has been divided into two areas. One is cytotoxic therapies and the other is bio therapies. Both can be used either separately or in combination to treat cancers. Cytotoxic therapies ____________________________________________________ Chemotherapy is the use of systemic cytotoxic drugs in the treatment of cancer. They can be used as a single agent or in combination with other drugs or modalities. Their use is limited by the toxic effects that they can have on normal body tissues. The goal of cancer therapy is either to provide a cure (absence of detectable disease over a period of time; 5‐10 years), control the disease (extends life when cure unattainable), or palliation (provides symptom management when cure or control not possible). To achieve these goals cytotoxic therapy can be used in a variety of ways. Adjuvant therapy This is when cytotoxic therapy follows another treatment modality such as surgery or radiation. The goal of adjuvant therapy is to target any residual disease. Neo‐adjuvant The use of chemotherapy to decrease the size of a tumour or control local disease before it is removed surgically. The aim is to improve the chances of tumour removal and decrease the risk of micro‐metastases or of local recurrence. Myelo‐ablation Cytotoxic therapy is used with or without total body irradiation to obliterate the bone marrow in preparation for a stem cell transplant. Combination therapy This is when the administration of two or more cytotoxic drugs are given to treat cancer. Often a combination of agents target different stages of the cell cycle to maximise tumour kill/disease response. It also reduces the risk of drug resistance. Single agent therapy This is treatment with a single cytotoxic drug to treat cancer. This may be used in either first line or subsequent treatments. Mechanism of action of cytotoxic agents All cytotoxic therapy affects rapidly dividing cells. Each drug targets the cell cycle with the aim of reducing the number of malignant cells. This treatment does not differentiate between malignant and healthy cells therefore all rapidly dividing cells are affected. Their use is limited by the toxic effects they can have on healthy cells. Cytotoxic drug classification Cytotoxic drugs are classified according to the effect that they have on the cell cycle. Cell cycle specific These are drugs that exert their greatest effect at a specific stage of the cell cycle. They have the greatest tumour kill when given in divided but frequent doses or as a continuous infusion with a short cycle time. This allows the maximum number of cells to be exposed at a specific stage to the drug. These drugs are effective in the treatment of high growth fraction cancers. Drugs included in this classification are • Antimetabolites –folate analogs, purine analogs, pyramidine analogs • Plant alkaloids – vinca’s, taxanes, epipodo‐phyllotoxins • Bleomycin peptide antibiotics Cell cycle non specific These are drugs that exert their effect in all phases of the cell cycle including the Go phase. These drugs are effective in treating both high and low growth fraction cancers. These drugs may be given intermittently to limit toxicities. Drugs included in this classification are • Alkylating agents –platins, phosphamides, • Anti‐tumour antibiotics – anthracyclines, mycins • Hormonal therapies • Nitrosoureas Factors affecting response to treatment There are many factors that affect treatment response. They include • Age • Co‐morbidities • The type of genetic mutation present • Stage of the disease at diagnosis Measuring treatment response Treatment is monitored in terms of the response of the disease to the treatment. The response may be described as • Complete response (CR) – Absence of all signs and symptoms of cancer for at least one month using objective criteria. • Partial response (PR) – At least a 50% reduction in tumour mass for one month without the development of new tumours. • Stable disease (SD) – There is neither a 50% decrease nor a 25% increase in tumour size • Progressive disease (PD) – There is an increase of tumour size of 25% or more or the development of new tumours. • Relapse – After CR a new tumour is diagnosed or the original cancer returns. Long term effects of cytotoxic therapy Many cytotoxic drugs can cause delayed effects. For some people these effects do not
become evident for months or years. Therefore it is optimal to provide long term follow up for
people who have had chemotherapy.
Long term effects include
• Liver dysfunction
• Renal dysfunction
• Cardiomyopathy
• Pulmonary fibrosis
• Secondary cancers
• Sexual dysfunction
• Psychosocial issues
• Ongoing fatigue
Biotherapies ___________________________________________________
Research over recent years has increased the knowledge and understanding of tumour biology which has led to the identification of several new therapeutic agents for cancer treatment. Biological drugs have been developed that specifically target the cancer cell. They are known as targeted therapies or bio‐therapies. The goals of biotherapies are • To provide a cure when used as primary or adjuvant therapy. • To improve the overall response to the disease or improve survival when used in conjunction with conventional therapies. • To maintain and enhance a patients quality of life. Mechanism of action Biotherapies target specific cellular or metabolic pathways on which cancer cells depend for growth, proliferation, metastasis and angiogenesis. They are used to • Enhance the patients own immune response to increase tumour kill • Alter the action in which cancer cells grow by modifying the actions of the normal cells in the area of the tumour • Alter the pathway of transformation of normal cells to cancer cells • Prevent metastatic cells from developing • Enhance the repair of normal cells that have been damaged by conventional chemotherapy • Change cells that have been damaged by treatment to behave like normal cells Biotherapy classification used in cancer therapy • Monoclonal antibodies • Small molecule inhibitors • Haematopoietic growth factors Monoclonal antibodies (mAB’s) These antibodies have been engineered to target cancer cells. They bind to specific antigens within the cell and also use the patients own immune system to maximise tumour kill. The table describes the types of monoclonal antibodies that are available and where they are derived from. Monoclonal antibodies are not considered carcinogenic however there is a risk that health workers who are exposed to the drugs can become sensitised therefore the use of personal protective equipment is advised. Monoclonal antibodies can be categorised by their ending. The ending indicates where the antibody has been derived from. See table below Ending ‐umab ‐momab ‐ximab ‐zumab Derived from Human Murine ‐ mouse Chimeric – mouse and human antibodies Humanised ‐ mouse fused with human antibodies
Small molecule Inhibitors These inhibitors target specific metabolic pathways found within the cytoplasm of the cell. Haematopoietic growth factors They promote the proliferation and differentiation of neutrophils and enhances functional properties of mature neutrophils. Management Bio‐therapies cause less toxicity than conventional chemotherapy because they target a specific cell pathway but there is a greater risk of hypersensitivity. Pre medications are routinely prescribed prior to the administration of monoclonal antibodies. Detailed information regarding hypersensitivity can be found in module 7. Novel ways of delivering monoclonal antibodies Traditionally, these therapies have been given intravenously but are now being given via sub cut injection and into a ventricular reservoir in the brain. Now complete the work book section on cancer therapies Chemoprotectant Agents ____________________________________________________ A number of supportive drugs are used to prevent or decrease specific toxicities that may occur in the following body systems: heart, kidney, bladder, bone marrow. These drugs protect normal tissue from the cytotoxic effects of drugs while preserving their anti‐tumour effects. Common chemoprotectant agents • Mesna – Protects the bladder from the effects of the metabolites of cyclophosphamide and ifosfamide. • Mannitol – Prevents haemorrhagic cystitis • Allopurinol – Minimises the risk of crystallisation of electrolytes that form kidney stones therefore preventing renal failure. • Folinic acid – Used as an antidote for folic acid antagonist drugs like methotrexate. It is given to reduce the toxicities to normal cells therefore minimising the degree of mucositis and bone marrow suppression while still having the oncological effect of the methotreaxate. – Used in combination with fluorouracil to enhance the effect of the fluorouracil •
Dexrazoxane – Protects the heart from cardio‐toxic therapies. Now complete the work book section on adjuvant therapies