Chemotherapy

Chemotherapy By Dr Dambo

Introduction • Chemotherapy:- the treatment of disease or infection with chemicals or drugs • Effective chemotherapy for gynaecological cancers exploits xteristic differences b/w tumour cells and normal cells to selectively kill malignant cells without producing serious, irreversible harm to vital organs and tissues.

• Research in molecular biology and cell kinetics, has improved knowledge on the scientific basis of cancer chemotherapy, which is serving in the development of new drugs, establishment of more rational protocol basic for the design of protocols, the optimal use of the presently available drugs. • Long-lasting remissions and occasional cures for several types of cancer have been achieved with antitumour drugs. E.g up to 90% of patients with metastatic choriocarcinoma achieve a normal life expectancy, and almost 100% of those without metastases are cured now.

• The effect of the drugs may be monitored by the level of Beta-hCG which provide a reliable index of tumour growth. • The use of cytotoxic drugs for Ca of the Cx vagina and vulva is still on clinical trial basis, since this tumours usually grow more slowly, and cytotoxic drug treatment has been palliative but not curative;. these types of cancer are better controlled by surgery and radiation therapy, and chemotherapy should be considered only when these standard methods have proved ineffective

• Among the uncommon gynaecological Ca that may require chemotherapy are germ cell tumours of the ovary, uterine, vaginal or vulvar sarcomas. Because these tumours are rare, little is known about there sensitivity to antitumour drugs.

Normal cell cycle • • • • •

Go: resting phase (cell not committed to division) G1 enzyme produced necessary for DNA production (18 hours) S: DNA synthesis (20hours) G2: specialized protein and RNA synthesis (3hours) M: mitosis (1hour)

Cell Kinetics • Cell kinetics is helpful in understanding the dynamics of tumour cells, in which some cells divide more slowly than others some cells enter or leave a nondividing state, and some are lost from the tumour population entirely. • The MITOTIC INDEX (MI) is the fraction of cells in mitosis in a steady-state.

• GROWTH FRACTION (GF) is the overall proportion of proliferating cells in a given tumour • CELL CYCLE TIME denotes the amount of time needed by a proliferating cell to progress through the cell cycle and produce a new daughter cell. • DOUBLING TIME is the time required for the tumour cell population to double.

Effects on chemotherapy on the cell cycle • The effects of various classes of anticancer agents on tumours depend on the basic events occurring in the 4 main phases of the cell cycle and the pharmacologic mechanisms of the drug action, and these cytotoxic effects influence the design of rational drug regimens. • Two basic classes of antineoplastic drugs are recognised: -Cell cycle(phase) specific agents -Cell cycle(phase) non-specific agents.

• CELL CYCLE SPECIFIC drugs: lethal to cells

only during a reproductive phase.

• More effective in tumours in which a large proportion of cells are actively dividing , as occurs when the cell mass is low. • They produce a greater kill, if given in multiple, repeated fractions rather than as a large single dose. • Drugs include: -methotrexate/fluorouracil: s phase -corticosteroids/asparaginase: G1 phase -bleomycin: G2 phase -vinca alkaloids: M phase

• CELL CYCLE NON SPECIFIC drugs:- are able

to sabotage the cells no matter what phase they are in.

• Are effective in large tumours in which the growth fraction LI and MI are low. • Drugs in this group are dose dependent, since a single bolus injection generally kills the same number of cells as do repeated doses totaling the same amount ie, the degree of cell kill is directly proportional to the absolute dose given • Drugs include: -Alkylating agents -Nitrosoureas -Antibiotics

Nitrosoureas Carmustine

Cellular differentiation Of clones

Go Resting Stem cell (Recruitment)

1. Vinca alkalloids (vincristine, vinblastine) 2.Taxanes (paclitaxel) 3. Podophyllotoxins (etoposides)

1. 2. 3.

steroids? Asparaginase diglycoaldehyde

Cell cycle(phase)-non specific agents

18hrs G1

•

Alkylating agents (cyclophosphamide, busulfan, chlorambucil)

Stem cell

•

Anthracycline antibiotics (doxorubicin, dactinomycin)

•

Miscellaneous (cisplatin, carboplatin)

•

Nitrosoureas (also Go)

1 hr

3 hrs

G2

S

Bleomycin 20 hours

Antimetabolites 2. Methotrexate 3. 5-fluorouracil 4. Mercaptopurine 5. Hydroxyurea 6. Cisplatin, carboplatin

G1 – Enzymes produced necessary for DNAProduction. S – DNA synthesis M – Mitosis Go – Resting phase (cells not committed to division)

Cancer chemotherapy agents • Classified into six general categories on the basis of their mechanism of action: -Alkylating agents -Antimetabolites -Plant alkaloids -Hormonal agents -immunotherapeutic agents -Miscellaneous

• Can also be classified based on their biochemistry into:-Alkylating agents -Antimetabolites -Vinca Alkaloids -Antibiotics -Miscellaneous

Alkylating agents • They bind to DNA therefore interferes with correct base pairing and produce single and double stranded breaks. DNA replication in S phase is consequently inhibited. • They also inhibit cellular glycolysis, respiration and synthesis of various enzymes, proteins and nucleic acids. • Eg Cyclophosphamide -Chlorambucil -Ifosfamide .

• Side effects of alkylating agents include:-Nausea -Vomiting -Myelosuppression -Nephrotoxicity -Ototoxicity -Haemorrhagic cystitis (Cyclophosphamide) -Alopecia -Decreased sperm production -Cessation of menstruation -Infertility -Can cause secondary cancers although not all agents are equal in their carcinogenic potential. The most common secondary cancer is a leukemia (Acute Myeloid Leukemia) that can occur years after therapy.

Antimetabolites • They interfere with normal synthesis of nucleic acids by substituting different compounds for the normal purines and pyrimidines in metabolic pathways • Exert their major activity during the S phase • Eg Methotrexate (folate antagonist) -Mercaptopurine (purine antagonist) -Fluorouracil (pyrimidine antagonist)

• Methotrexate is a folic acid antagonist. • It inhibits the enzyme dihydrofolate reductase, which reduces dihydrofolate to tetrahydrofolate, the precursor of coenzymes essential for the formation of purines and pyrimidines.

• Side effects of Antimetabolites:-Nausea -Vomiting -Mucositis -Stomatitis -Hepatitis -Myelosuppression -Nephrotoxicity -Alopecia -Dermatitis -Hepatocellular damage

Plant alkaloids • They cause the arrest of metaphase of mitosis by crystallization (through toxicity) of the microtubules of the mitotic spindle. • Eg -Vinca alkaloids:-Vincristine -Vinblastine -Podophyllotoxins:Etoposide -Taxanes;Paclitaxel

• Side effects of plant alkaloids:-Nausea -Vomiting -Constipation -Alopesia -Myelosuppression -Paralytic ileus -Neurotoxicity (convulsions) -Peripheral neuropathy -Bladder atony N. B. Vincristine is one of the very few chemotherapeutic drugs that is not myelotoxic.

Antibiotics • They interfere with nucleic acid synthesis and block DNA-directed RNA and DNA transcription. • Eg Doxorubicin (Adriamycin) Bleomycin Actinomycin D

• Side effects of Antibiotics :-Nausea -Vomiting -Alopecia -Diarrhoea -Mucositis -Cardiomyopathy -Myelosuppression -Pulmunary fibrosis (Bleomycin) .Bleomycin is also not myelotoxic.

Miscellaneous • Platinum Agents:-They act in a similar way like the alkylating agents but are given intraveinously. -Eg Cisplatin Carboplatin Side effects include :-Severe nausea and vomiting -myelosuppression -ototoxicity (high tone deafness) -nephrotoxicity -neurotoxicity (dose-dependent peripheral neuropathy)

Miscellaneous contd • Hormones:Do not possess cytotoxic action but can cause tumour regression by altering the hormonal millieu. They are primarily effective against tumours that arise from hormone responsive tissues e.g endometrial and breast cancer. This treatment are not curative but may provide excellent palliation of symptoms in selected patients. They include MEDROXYPROGESTERONE, PREDNISOLONE and TAMOXIFEN Side effects: - Fluid retension CVD due to prolonged use.

Route of administration • Oral -Alkylating agents -May be given on daily basis but usually intermittent • Intravenous -Drugs are normally given at intervals of 1-4 weeks. -This allows bone marrow to recover. • Intramuscular • Intrapleural Bleomycin given for recurrent pleural effussions but forms adhesions. • Intraperitoneal -Cisplatin -Given high concentration of drug into the peritoneal which acts as a reservoir.

• Drugs can be used alone or in combination. • Combination is more effective than single chemotherapy. • Advantages of combination chemotherapy theoretically:-Drugs combine to give synergistic effect -Reduced resistance to the drugs -The cumulative toxic effects of each individual drug is avoided by combination. • Sequential therapy:- this is an alternative mechanism in preventing the development of drug resistance by giving different drugs in turn. This also allows for a shorter treatment time. Effective for germ cell tumours and GTD but not epithelial tumours.

Ovarian cancer • Chemotherapy is the standard in most ovarian cancers after initial surgery. • Of all gynaecological malignancies, ovarian cancer responds best to chemotherapy regimens • Drugs used include: -Cisplatin -Carboplatin -Cyclophosphamide -Paclitaxel

Endometrial Cancer • Mainly confine to patients with recurrent metastatic or advanced disease • Agents -Doxorubicin -Paclitaxel -Medoxyprogesteron

Cervical carcinoma • As in endometrial carcinoma • Agents -Platinum compounds - Cisplatin -Carboplatin

Conclusion • The role of chemotherapy in gynaecological cancer is limited. Only the rare trophoblastic and germ cell tumours are cured by drugs. Its use in solid tumours is adjunctive to surgery and radiotherapy, and will remain so unless new drugs with greater activity and tolerable toxicity become available. • Probably the most important contribution from chemotherapy is improved quality and duration of survival.