18 - Chemotherapy Flashcards
How does imatinib work as a chemotherapy drug?
BCR-ABL tyrosine kinase inhibitor
What factors contribute to tumour growth?
- Growth fraction: The growth fraction is the proportion of cells in a tumor that are actively dividing at any given time. A high growth fraction means that a large number of cells are actively dividing, which can lead to rapid tumor growth. In contrast, a low growth fraction means that only a small percentage of cells are actively dividing, which can slow down tumor growth.
- Duration of cell cycle: The duration of the cell cycle refers to the time it takes for a cell to divide and create two new daughter cells. Tumor cells may have a shorter cell cycle duration than normal cells, allowing them to divide more quickly and contribute to tumor growth.
- Rate of cell loss: The rate of cell loss refers to the rate at which cells in a tumor die or are destroyed.
What is the fractional cell kill hypothesis?
A defined chemotherapy concentration, applied for a defined time period, will kill a constant fraction of the cells in a population, independent of the absolute number of cells so…
- Fraction of cells killed not number of cells killed
- Given in doses to allow bone marrow to recover (this recovers faster than cancer cells)
How are tumours classfied based on their chemo-sensitivity and give some examples of tumours in each category?
- High will only need chemo
- Low may not respond to chemo at all so need surgery
What are the different groups of chemotherapy drugs based on their mechanisms of action?
- Molecular targeting approaches
Imatinib - Alkylating agents
Carmustine - Platinum compounds
Cisplatin and Oxalplatin - Antimetabolites
Methotrexate, 5-Fluorouracil - Spindle poisons
Taxanes (paclitaxel)
What is the mechanism of action of alkylating agents/platinating agents and what are some examples of these drugs?
- Target DNA synthesis in G1/S phase
- Forms covalent bonds with DNA nucleosides disrupting structure and preventing replication
- Stops DNA replication
What are some specific ADRs of alkylating/platinating agents?
- Peripheral, sensory and motor neuropathy
- High frequency ototoxicity
What are some possible mechanisms of resistance to alkylating agents?
- Decreased entry or increased exit of agent
- Inactivation of agent in cell: Cancer cells can produce enzymes that can inactivate the alkylating agents, which can reduce their ability to damage the DNA.
- Enhanced repair of DNA lesions produced by alkylation: Some cancer cells can increase their ability to repair DNA damage caused by alkylating agents. This can reduce the effectiveness of the drugs by repairing the DNA damage that the drugs are meant to cause.
What are some examples of antimetabolites and what are their mechanism of action?
- Methotrexate: in malignancy works as dihydrofolate reductase inhibitor stopping DNA synthesis
- 5-Fluorouracil: Inhibits thymidylate synthase which is needed to make pyrimidines for DNA synthesis
Some cancer cells can increase their ability to repair DNA damage caused by alkylating agents. This can reduce the effectiveness of the drugs by repairing the DNA damage that the drugs are meant to cause.
Azathioprine
What are some examples of microtubule/spindle poisons and what is their mechanism of action?
- Vinca Alkaloids: Vincristine which is a microtubule assembly inhibitor
- Taxanes: - microeconomics, money relation to help you remember.
Paclitaxel which is a microtubule depolymerisation inhibitor
- Cells cannot undergo prometaphase and anaphase as tubulin proteins affected. Cell cannot divide properly so cell undergoes apoptosis
What is an adverse drug reaction associated with spindle poisons?
Neurotoxicity: glove and stocking peripheral neuropathy
When is chemotherapy used and why is there different responses with the same chemotherapy on the same cancer?
CANCER: different schedules used to balance side effects and best anticipated outcome
Predicted response depends on each patients:
- performance score
- clinical score
- prognostic factors
- molecular or cytogenetic markers
What are the different routes of administration for chemotherapy?
What are the two different types of IV pump that can be used in chemotherapy?
- With Hickman it goes into SVC and patient can wear a pump of chemo
- Both methods the patient can go home
What are the common side effects of chemotherapy?
Most common
- Hair loss
- Mucositis
- Nausea and vomiting
- Diarrhoea or constipation
- Neuropathy
Why can acute renal failure occur during chemotherapy?
Tumor lysis syndrome: Some chemotherapy drugs can cause rapid destruction of cancer cells, which can lead to the release of large amounts of waste products into the bloodstream, including potassium and uric acid. These waste products can overload the kidneys and cause AKI.
Hyperuricaemia caused by rapid tumour lysis leads to precipitation of urate crystals in renal tubules so need to monitor for this
What are some other serious acute side effects with chemotherapy apart from acute renal failure that can cause a patient to die?
- GI perforation: at site of tumour such as a lymphoma in the stomach that melts away with chemo. Can cause peritonitis. If at risk then artificially feed in hospital
- DIC: onset a few hours after starting treament for acute myeloid leukaemia
Raynaud’s phenomenon is a condition in which the blood vessels in the fingers, toes, ears, and nose become narrow, leading to reduced blood flow to these areas.
Why do people vomit after chemotherapy and what are the different patterns of emesis?
Multifactorial but direct action of chemotherapy drugs on central chemoreceptor trigger zone
Acute phase: 4-12 hours
Delayed onset: 2-5 days later
Chronic phase: persistance up to 14 days
Give anti-emetics
What happens to body hair when undergoing chemotherapy treatment and how can we minimise the effects of this?
- Hair thins after 2-3 weeks and often total body
- Can regrow during therapy and be marked with chemo drugs like doxorubicin but warn patient this doesn’t mean tumour is coming back
- Minimal hair loss with platinums
What are some toxic skin effects that can occur when a patient is undergoing chemotherapy?
- Thrombophlebitis of veins and extravasation
Bleomycin
- Hyperkeratosis, and ulcerated pressure sores
Hyperpigmentation when using doxorubicin and cyclophosphamide
- Beau’s lines
Mucositis is a side effect of chemotherapy, how does this present?
- Can involve whole tract but worse in oropharynx
- Secondary infections can occur e.g thrush
- Presents as sore throat, GI bleed and diarrhoea
What are the cardiotoxic and lung toxic effects of chemotherapy?
Cardio: cardiomyopathy (bleomycin) and arrhythmias (cyclophosphamide)
Lung: pulmonary fibrosis (bleomycin and lots of others). Need to be careful giving concurrent radiotherapy and oxygen as they can make the fibrosis worse even after treatment years later, carry card!!
What is the most common cause of cancer therapy death?
Haematological toxicity!! e.g neutropenia and low platelets
Prescribing chemotherapy is a highly specialised field, why is this and what factors are taken into consideration when prescribing?
- Narrow TI and large side effect profile
- Dose depends on patient surface area/BMI, drug handling ability (e.g liver function) and general wellbeing (e.g performance status and comorbities)
What causes variability in the pharmacokinetics of chemotherapy?
What are some important drug reactions that need to be considered during chemotherapy?
- Vincristine and itraconazole (common antifungal) can cause more neuropathy
- Capecitabine (oral 5FU) and warfarin
- Methotrexate and penicillin, NSAIDs
- Capecitabine and grapefruit juice/St John’s Wort
THESE DRUGS CAN INCREASE AMOUNT OF CHEMO DRUG IN PLASMA SO MORE SIDE EFFECTS
What monitoring do we need to be doing during chemotherapy treatment?
- Response of cancer: imaging, tumour marker tests, cytogenetics
- Drug levels: e.g methotrexate drug assays to ensure clearance from the blood
- Check for organ damage: echocardiograms, creatinine clearance
How do clinical trials inform new chemotherapy therapies?
- There is a shift to more targeted therapies e.g monoclonal antibosies
- Overall survival is the ultimate measure
What is the first line treatment for temporal arteritis?
High dose (40-60mg) of prednisolone as sight threatening and can cause PMR!!
- If visual or neurological symptoms give them the highest dose
Why are NSAIDs used as adjuncts in management of rheumatoid arthritis?
Can use lower doses of steroids so less side effects
What do you need to warn young females about when prescribing methotrexate?
- If planning to have a baby may have fertility issues and high risk of baby having spina bifida
Why shouldn’t you give azathioprine to patients with low TPMT levels?
You need TPMT to metabolise Azathioprine. This can lead to the accumulation of the metabolites in the body which can lead to toxicity.
Why is there an increased risk of malignancy when taking TNFa inhibitors?
TNF-α plays a role in the immune response against cancer cells, and its inhibition may impair this response, allowing cancer cells to grow and spread
Why do you need to stop aspirin and NSAIDs when administering chemotherapy?
- Chemo can cause you to be thrombocytopenic and these drugs lower platelets so high risk of bleeding
