Cancer chemotherapy Flashcards
Why is the cell cycle important to consider when giving chemotherapy?
- Chemo agents will only work if the cell is actively going through the cell cycle
- Cancer drugs won’t work if cell is in the dormant phase
- Can give drugs to move cells out of dormant phase and into cell cycle - then use chemo drugs
What is the growth fraction of a tumour?
- Proportion of cells dividing at any given time
- Useful indicator of sensitivity to chemotherapeutic agents
- Tumours with large growth fractions are more responsive to treatment
Why are multiple cycles of chemotherapy required to eradicate tumours?
- Tumours are heterogenous
- Different cells in tumours are at different stages of the cell cycle
- Some cells are proliferating, others are dying or lying dormant
- Repeated cycles are required to eradicate remaining and regrowing cells
Outline the fractional cell kill hypothesis
- A given dose of chemotherapy kills a constant proportion of a tumour cell
- Repeated doses are required
- Frequency and duration of treatment limited by toxicities
Why is chemotherapy given in pulses?
- Allows normal cells to recover in between doses
- Normal cells recover faster than cancerous cells
What affects the growth fraction of a tumour?
- Dependant on tumour size
- In early stages when tumour volume is low, growth fraction is high
- The bigger the tumour, the smaller the growth fraction
What does a small growth fraction mean?
- Less actively dividing cells to be targeted by the chemotherapy
Give some example of highly chemo-sensitive tumours
- Lymphomas
- Germ cell tumours
- Small cell lung
- Neuroblastoma
Give some examples of moderately chemo-sensitive tumours
- Breast cancer
- Colorectal
- Bladder
- Ovary
Give some examples of low chemo-sensitive tumours
- Prostate
- Renal cell
- Brain tumours
- Endometrial cancer
Give some different types of chemo drugs
- Antimetabolites - work on DNA synthesis
- Alkylating agents - work directly on DNA
- Intercalating agents - work on DNA transcription
- Spindle poisons - work on mitosis
Outline the mechanism of action of alkylating agents
- Form inter-strand cross-links between coils of DNA
- Defective DNA replication
- Cell death
How do platinum compounds act as anti-cancer drugs?
- Formation of platinated inter and intra-strand adducts - - Leading to inhibition of DNA synthesis
- DACH platinum adducts are bulky so better DNA synthesis inhibitors
Give an example of an alkylating agent
- Oxaliplatin
Give some examples of antimetabolites
- Methotrexate
- 5-fluorouracil
What is the mechanism of action of 5-fluorouracil
- Inhibits thymidylate synthase (TS)
- Pyrimidines can’t be incorporated into final DNA
- DNA can’t be produced
What is the mechanism of action of methotrexate?
- Inhibits dihydrofolate reductase
- Prevents purine formation
- DNA can’t be produced
What is the mechanism of action of spindle poisons?
- Inhibit polymerisation of spindle microtubules
- Or prevent depolymerisation of microtubule spindles
What are some examples of spindle poisons?
- Taxoids
- Vinca alkaloids
What is the mechanism of action of taxoids?
- Promote assembly of microtubule spindles
- Prevent disassembly
What is the mechanism of action of vinca alkaloids?
- Prevent spindle formation
What is the mechanism of resistance of cancer cells against alkylating agents?
- Decreased entry or increased exit of an agent via a glycoprotein pump that recognises noxious substances
- Inactivation of agent in cell by scavenger molecules
- Enhanced repair of DNA lesions produced by alkylation
What are some side effects of chemotherapy?
- Nausea/vomiting
- Mucositis
- Alopecia
- Skin toxicity
- Cardio toxicity
- Lung toxicity
- Haematological toxcity
Why does cancer result in vomiting?
- Multifactorial but includes direct action of chemotherapy drugs on the central chemoreceptor trigger zone
Outline the pattern of emesis resulting from chemotherapy
- Acute phase 4-12 hours
- Delayed onset 2-5 days later
- Chronic phase may persist up to 14 days
Outline alopecia resulting from chemotherapy
- Hair thins at 2-3 weeks
- May be total loss
- May regrow during therapy (does not mean that cancer is back)
- Marked with doxorubicin, vinca alkaloids, cyclophosphamide
- Minimal with platinums
Outline the local skin toxicity caused by chemotherapy
- Irritation and thrombophlebitis of veins
- Extravasation
- If a vein gets punctured, drug can enter local tissue
Outline the general skin toxicity caused by chemotherapy
- Bleomycin causes hyperkeratosis, hyperpigmentation and ulcerated pressure sores
- Bulsuphan, doxorubicin, cyclophosphamide, and actinomycin D cause hyperpigmentation
Outline mucositis caused by chemotherapy
- GI tract epithelial damage
- May be profound and involve whole tract
- Most commonly worst in oropharynx
- Presents as sore mouth/throat, diarrhoea, GI bleed
Which cancer drugs cause cardio-toxicity?
- Cardiomyopathy is caused by doxorubicin and high dose cyclophosphamide
- Arrhythmias caused by cyclophosphamide and etoposide
Which cancer drugs cause lung toxicity?
- Bleomycin
- Mitomycin C
- Cyclophosphamide
- All cause pulmonary fibrosis
Outline the haematological toxicity of cancer therapy
- Most frequent dose-limiting toxicity
- Most frequent cause of death from toxicity
- Different ages cause variable effects on degree and lineages
- Neutrophils, platelets, erythrocytes
What chemotoxicities are caused by cisplatin and carboplatin?
- Ototoxicity
- Nephrotoxicity
What chemotoxicities are caused by bleomycin?
- Pulmonary fibrosis
What chemotoxicities are caused by cyclophosphamide?
- Haemorrhagic cystitis
What chemotoxicities are caused by methotrexate?
- Myelosuppression
What are the clinical indications of chemotherapy?
- Cancer
- Different aim in different malignancies
- Predicted response is also different within the same cancer
- Balance side effects with anticipated or best outcome
What are the routes of chemotherapy administration?
- IV - most common
- PO - convenient but depends on oral bioavailability
- SC - convenient in a community setting
- Intralesional - directly into cancerous area
- Intrathecal - into CSF by lumbar puncture
- Topical
Through what methods is chemotherapy given to patients IV?
- Bolus
- Infusional bag
- Continuous pump infusion e.g. PICC line, Hickman line
What causes variability in pharmacokinetics and chemotherapy?
- Abnormalities in absorption
- Abnormalities in distribution
- Abnormalities in elimination
- Abnormalities in protein binding
What causes abnormalities in absorption of chemotherapy drugs?
- Nausea and vomiting
- Compliance
- Gut problems
What causes abnormalities in distribution of chemotherapy drugs?
- Weight loss
- Reduced body fat
Ascites
What causes abnormalities in elimination of chemotherapy drugs?
- Liver and renal dysfunction
- Other meds
What causes abnormalities in protein binding of chemotherapy drugs?
- Low albumin
- Other drugs
What are the important drug interactions of chemotherapy drugs?
- Other drugs may increase plasma levels of the chemotherapy drug
- Vincristine and itraconazole (antifungals) lead to more neuropathy
- Warfarin
- Methotrexate - caution with prescribing penicillin, NSAIDs
- Capecitabine, St Johns Wort, grapefruit juice
What are the adverse effects of chemotherapy (due to the effect of treatment on the tumour)?
- Acute renal failure - hyperuricaemia caused by rapid tumour lysis leads to precipitation of urate crystals in renal tubules
- GI perforation at site of tumour
- Disseminated intravascular coagulopathy
What needs to be monitored during chemotherapy?
- Response of the cancer (radiological imaging, tumour marker blood tests, bone marrow/cytogenetics)
- Drug levels
- Checks for organ damage (creatinine clearance, echocardiogram)
