S7) Cancer Chemotherapy Flashcards
What is the aim of chemotherapy?
The aim of chemotherapy is to kill/prevent replication of tumour cells at a greater rate than normal healthy tissue
What is the role of chemotherapy?
- Curative
OR
- Palliative
When is chemotherapy usually given?
- Given as an adjunct to surgery/radiotherapy
OR
- Given in isolation
What are the factors leading to increased tumour growth?
- Increased growth fraction
- Decreased duration of cell cycle
- Decreased rate of cell loss
How can one classify tumours according to chemosensitivity?
- High sensitivity
- Modest sensitivity
- Low sensitivity
Identify five types of high sensitivity tumours
- Lymphomas
- Germ cell tumours
- Small cell lung tumours
- Neuroblastoma
- Wilm’s tumour
Identify five types of modest sensitivity tumours
- Breast tumours
- Colorectal tumours
- Bladder tumours
- Ovary tumours
- Cervix tumours
Identify four types of low sensitivity tumours
- Prostate tumours
- Renal cell tumours
- Brain tumours
- Endometrial tumours
Identify the four groups of chemotherapy
- Antimetabolites
- Antibiotics
- Alkylating/Platinating agents
- Mitotic spindle inhibitors
Provide two examples of alkylating/platinating agents
- Platinating – Cisplatin
- Alkylating – nitrogen mustards e.g. Chlorambucil
Describe the mechanism of action of alkylating/platinating agents
- Target DNA synthesis in G1/S phase
- Forms covalent bonds with DNA nucleosides disrupting structure and preventing replication
Identify some specific ADRs of alkylating/platinating agents
- Peripheral, sensory and motor neuropathy
- High frequency ototoxicity
Describe the three possible mechanisms of resistance to alkylating agents
- Decreased entry or increased exit of agent
- Inactivation of agent in cell
- Enhanced repair of DNA lesions produced by alkylation
Provide some examples of microtubule poisons
- Vinca Alkaloids
- Taxanes
Describe the mechanism of action of microtubule poisons
- Target tubulin proteins in the mitotic phase
- Chromosomes can’t align and separate into two daughter cells in synchrony
How do microtubule-binding agents affect microtubule dynamics?
- Inhibit polymerisation
- Stimulate polymerisation and prevent depolymerisation
Identify the specific ADR of microtubule poisons
Neurotoxicity: glove and stocking peripheral neuropathy
Provide an example of a glycopeptide antibiotic
Bleomycin
Describe the mechanism of action of glycopeptide antibiotics
Most effective in G2 stage:
- Forms free radicals when chelated with Fe2+ which attack phosphodiester bonds in DNA
- Results in cutting (scission) of DNA strands
Identify the specific ADR of glycopeptide antibiotics
Pulmonary Fibrosis (10%)
Provide an example of an anthracycline antibiotic
Doxorubicin
Describe the mechanism of action of anthracycline antibiotics
Targets DNA synthesis in “S” phase:
- Intercalate between the base pairs in DNA which interferes with transcription/replication
- Topoisomerase II inhibition
- Generate free radicals – damage DNA
Identify the specific ADR of anthracycline antibiotics
Cardiotoxic
Provide two examples of antimetabolites
- Methotrexate
- 5-Fluorouracil
What is the mechanism of action of methotrexate?
Methotrexate inhibits dihydrofolate reductase, preventing DNA synthesis
What is Tamoxifen?
Tamoxifen is a SERM (selective oestrogen receptor modulator) and acts as antagonist of the oestrogen receptor in breast tissue
Describe the metabolism of Tamoxifen
Tamoxifen is a prodrug and is metabolised by liver to its active form which can competitively bind to oestrogen receptors
Describe the mechanism of action of Tamoxifen
Tamoxifen causes cells to remain in the G0 and G1 phase of the cell cycle
When can Tamoxifen therapy be used?
To be eligible for therapy those with breast cancer must be ER (oestrogen receptor) positive
Identify some common side effects of Tamoxifen treatment
- Hot flushes/sweats
- Increased DVT/PE risk
- Weight gain
- Increased risk of endometrial cancer
What is the predicted response to chemotherapy dependent on?
- Performance score
- Clinical stage
- Prognostic factors/score
- Molecular / cytogenetic markers
What are the different routes of administration for chemotherapy?
- IV
- PO
- SC (community setting)
- Into a body cavity (bladder, pleural effusion)
- Intralesional
- Intrathecal (lumbar puncture / omaya reservoir – directly into ventricles)
- Topical
- IM (rarely)
Identify some common side effects of chemotherapy
Explain how acute renal failure occurs as a side effect of chemotherapy
Acute renal failure – hyperuricaemia caused by rapid tumour lysis leads to precipitation of urate crystals in renal tubules
Vomiting is multifactorial but includes direct action of chemotherapy drugs on the central chemoreceptor trigger zone.
What are the different patterns of emesis?
- Acute phase (4 - 12 hours)
- Delayed onset (2 - 5 days later)
- Chronic phase (persist up to 14 days)
Mucositis is due to GI tract epithelial damage.
Where does it commonly occur?
- May be profound and involve whole tract
- Commonly worst in oropharynx
Mucositis is due to GI tract epithelial damage.
How does this present?
- Sore mouth/throat
- Diarrhoea
- G.I. bleed
What causes variability in the pharmacokinetics of chemotherapy?
- Abnormalities in absorption
- Abnormalities in distribution
- Abnormalities in elimination
- Abnormalities in protein binding
What is the result of the abnormalities in absorption?
- Nausea
- Vomiting
- Compliance
- Gut problems
What is the result of the abnormalities in distribution?
- Weight loss
- Reduced body fat
- Ascites
What is the result of the abnormalities in elimination?
- Liver dysfunction
- Renal dysfunction
- Other medication
What is the result of the abnormalities in protein binding?
- Low albumin
- Other drugs
Other drugs may increase plasma levels of the chemotherapy drug.
What are the important drug reactions that should be considered during chemotherapy?
- Vincristine and itraconazole (common antifungal)
- Capecitabine (oral 5FU) and warfarin
- Methotrexate and penicillin, NSAIDs
- Capecitabine and grapefruit juice
Which three factors should be monitored during chemotherapy treatment
- Response of cancer – radiological imaging, tumour marker blood tests, bone marrow/cytogenetics
- Drug levels
- Organ damage – creatinine clearance, echocardiogram
What principles can one learn from the fractional kill hypothesis?
- Bone marrow cells recover quicker than tumour cells
- Hence a new dose of chemotherapy is given after bone marrow regeneration has occurred
Provide two examples of vinca alkaloids
- Vincristine
- Vinblastine
