Chemotherapy Flashcards
What is the function of imatinib?
Inhibits a tyrosine kinase present in the Philadelphia chromosome (causes CML)
What is the fractional cell kill hypothesis?
Pulsed episodes of chemotherapy are given to allow bone marrow to replenish and repair DNA damage
Bone marrow repairs faster than cancer cells
note: still causes gradual decline in the rate of bone marrow repair
note: this does not apply to haematological malignancies (in this case the aim is to eradicate bone marrow and replace it with stem cells)
Contrast tumours with differing degrees of sensitivity to chemotherapy. What are the aims of chemotherapy in the different groups?
Highly sensitive:
- lymphomas
- germ cell tumours
- small cell lung cancer
- neuroblastoma
Modest sensitivity (chemotherapy used to shrink tumours and reduce the chance of metastasis before surgery):
- breast cancer
- colorectal cancer
- bladder cancer
- ovarian cancer
- cervical cancer
Low sensitivity (chemotherapy used to shrink tumours and reduce the chance of metastasis before surgery):
- prostate cancer
- renal cancer
- brain cancer
- endometrial cancer
How do cancer cells develop mechanism of resistance to cytotoxic agents?
Decreased entry/increased exit of agent (P-glycoproteins involved - multidrug resistance protein which removes charged xenobiotics)
Inactivation of agent e.g. via glutathione conjugation
Enhanced repair of DNA lesions caused by alkylation
Outline the mechanism of action of the different chemotherapy agents.
Antimetabolites:
- affect DNA synthesis
- e.g. 5-fluorouracil (inhibits pyrimidine synthesis)
- e.g. methotrexate (inhibits purine synthesis)
Alkylating agents:
- form inter- and intra-strand adducts which impair DNA replication
- e.g. platins
Intercalating agents:
- form inter- and intra-strand adducts which impair DNA repair
- e.g. doxorubicin affects topoisomerase II which is needed to enable breaking, rotation, and re-ligation of DNA strands
DNA scissors:
- cut phosphodiester bonds
- e.g. bleomycin
Spindle poisons:
- interfere with mitosis
- vinca alkaloids inhibit microtubule polymerisation
- taxanes and epothilones stimulate microtubule polymerisation and prevent depolymerisation
What are some of the clinical indications for chemotherapy?
Cancer
Rheumatoid arthritis (methotrexate)
note: aim differs depending on the type of malignancy and level of toxicity deemed acceptable e.g. curative v.s. palliative
How does the predicted response to chemotherapy differ?
How well the patient is able to function (affected by co-morbidities)
Clinical stage of cancer
Prognostic factors
Molecular/cytogenic markers
How is the ability of patient receiving chemotherapy to function assessed?
Performance score =
1 = able to function, work affected
2 = increased time spent in bed
3 = 50%+ time spent in bed
4 = bed-bound
5 = dead
What are some of the different routes of administration of chemotherapy?
IV:
- bolus
- infusional bag
- continuous pump infusion (allows community treatment; well tolerated) e.g. peripherally inserted central catheter (PICC), Hickman line
- enables fine control of delivery and quick cessation of treatment in case of emergency
PO
- rare; toxicity damages GI tract
- variable bioavailability
- N&V likely
SC
Into body cavity e.g. bladder, pleural effusion
Intralesional (directly into cancerous area) if tumour is localised
Intrathecal (CSF or into ventricles) for CNS tumours
Topical
IM (rare)
Give some examples of ADRs associated with chemotherapy.
- alopecia (all over body; not always present)
- mucositis (GI tract epithelial damage)
- N&V (acute, delayed, or chronic)
- diarrhoea
- cystitis
- sterility
- GI perforation
- DIC
- skin toxicity = general (e.g. bleomycin, indicated for testicular cancer, causes hyperkeratosis, hyperpigmentation, ulcerated pressure sores, and pulmonary fibrosis which is worsened by high flow O2) or local (irritation/thrombophlebitis of veins or necrosis when drugs enter subcutaneous tissue instead of veins)
- myalgia
- neuropathy
- pulmonary fibrosis
- cardiotoxicity
- local reaction
- renal failure
- myelosuppression —> neutropenia
- phlebitis
- lethargy (universal symptom)
- arrhythmias
- tumour lysis syndrome
note: more pronounced in cancers highly sensitive to chemotherapy
What is the most frequent dose-limiting ADR associated with chemotherapy?
Haemotoxicity
What is tumour lysis syndrome?
Tumour lysis —> DNA released —> purines in circulation —> purines metabolised to urate —> hyperuricaemia
EMERGENCY!
What are some considerations when calculating the appropriate dose of chemotherapy?
Surface area/BMI
Liver function
Renal function
Performance status
Co-morbidities
What may cause abnormalities in absorption, distribution, elimination, and protein-binding of chemotherapy agents?
ABSORPTION:
- N&V
- compliance
- GI disturbances
- GI cancer
DISTRIBUTION:
- weight loss
- reduced body fat
- ascites (due to ovarian cancer)
ELIMINATION:
- liver dysfunction
- renal dysfunction
- bladder cancer
- drug interactions
PROTEIN-BINDING: low albumin
What are some of the different goals of chemotherapy?
NEOADJUVANT = given before surgery/radiotherapy for primary cancer
ADJUVANT = given after surgery to excise primary cancer to reduce risk of relapse
PALLIATIVE = treat current/anticipated symptoms without curative intent
PRIMARY = first line treatment of cancer
SALVAGE = for relapsed disease
