Chemotherapy Flashcards
How do they discover chemotherapy?
Chance
Screening of compounds
Chemical engineering
Experiments
How do you know when to give chemotherapy?
The fractional cell kill hypothesis which states that 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, you give it when bone marrow has increased but cancer cells haven’t re-grown by as much.
What tumours are highly sensitive to chemotherapy?
Lymphomas Germ cell tumours Small cell lung Neuroblastoma Wilm's tumour
What cancers are moderately sensitive to chemotherapy?
Breast Colorectal Bladder Ovary Cervix Lung
What cancers have a low sensitive to chemotherapy?
Prostate
Renal cell
Brain tumour
Endometrial
How can different chemo therapies work?
Antimetabolites (on DNA synthesis)
Alkylation agents (on DNA)
Intercalating agents (on DNA transcription and duplication
Spindle poisons (on mitosis)
How do alkalating agents work?
Damage DNA to prevent replication
How are platinum compounds formed?
They are formed from platinated inter and intrastrand adducts leading to inhibition of DNA synthesis.
MOA of methotrexate or 5-fluorouracil (anti-metabolites)
They both interfere with the folate cycle
Inhibit Thymidylate Synthase - 5FU
Inhibit dihydrofolate reductive to prevent tetrahydrofolate formation - methotrexate
Describe the MOA of spindle poisons
Once chromosome are aligned at metaphase, spindle microtubules depolymerise, moving sister chromatids towards opposite poles.
The nuclear membrane then re-forms and the cytoplasm divides.
Spindle poisons disrupt this.
How do microtubule binding agents work?
Micro-tubule binding agents affect microtubules by:
- Inhibiting polymerisation
- Stimulating polymerisation and preventing depolymerisation
Describe, on a cellular level, the MOA of specific spindle poisons
Taxoids - promote spindle microtubule assembly and prevent disassembly.
Vinca alkaloids - Prevent spindle formation
How do alkylation agents become resistant?
- Decreased entry or increased exit of agent
- Inactivation of agent in cel
- Enhanced repair of DNA lesions produced by alkylation
What are the clinical indications of chemotherapy?
Cancer!
But, aim is different in different malignancies.
Performance score (how active)
Clinical stage
Prognostic factors or score
Molecular or cytogenetic markers
Basically, look at side effects vs the anticipated or best outcome.
How do you normally give chemotherapy?
IV - most common - bolus, infusional bag, continuous pump infusion. (PICC or Hickman line)
PO - convenient but depends on oral bioavailability
SC - convenient in a community setting
Into a body cavity - Bladder, pleural effusion
Intralesional - directly to cancerous area - consider pH
Intrathecal - into CSF - by lumbar puncture or omaya reservoir
Topical - onto the skin
IM - rarely
What are the common side effects of chemotherapy?
Alopecia Mucositis Pulmonary fibrosis Nausea / vomiting Diarrhoea Cardiotoxicity Local reaction Cystitis Sterility Renal failure Myalgia Myelosuppession Phlebitis Neuropathy
What effects of chemo can occur as a result of tumour dying?
Acute renal failure - hyperuricaemia caused by rapid tumour lysis leads to precipitation of urate crystals in renal tubules
GI perforation at site of tumour - reported in lymphoma
Disseminated Intravascular Coagulopathy - occurs in AML
Describe the vomiting that occurs as a result of chemotherapy
Multifactoral but includes direct action of chemotherapy drugs on the CTZ.
Patterns of emesis:
Acute phase - 4-12hours
Delayed onset - 2-5days later
Chronic phase - may persist, up to 14 days.
Describe how alopecia occurs as a result of chemotherapy
Hair thins at 2-3 weeks
May be total
May re-grow during therapy
Marked with doxorubicin, vinca alkaloids, cyclophosphamide
Minimal with platinums
Help sometimes with scalp cooling (could just become patchy)
Describe skin toxicity occurring with chemotherapy
Local:
- irritation and thrombophlebitis of veins
- Extravasaion
General:
- Bleomycin; hyperkeratosis, hyperpigmentation, ulcerated pressure sores
- Busulphan, doxorubicin, cyclophosphamide, actinomycin D - Hyperpigmentation.
Describe mucositis occurring with chemotherapy
GI tract epithelial damage
May be profound and involve the whole tract
Most commonly worse in oropharynx
Presents as:
Sore mouth / throat
Diarrhoea
GI bleeding
Describe cardio toxicity occurring with chemotherapy
Cardio-myopathy - worse with doxorubicin and high dose cyclophosphamide. Mortality is approximately 50%.
Arrhythmias:
Cyclophosphamide
Etoposide
Describe lung toxicity occurring with chemotherapy
Bleomycin - pulmonary fibrosis
Mitomycin C, cyclophosphamide, melphalan, chlorambucil - pulmonary fibrosis
Describe haematological toxicity occurring with chemotherapy
Most frequent dose limiting toxicity
Most frequent cause of death from toxicity
Different agents cause variable effects on degree and lineages:
- Neutrophils (neutropenia)
- Platelets
The dose of chemotherapy needs to be altered depends on the individual patient, what is the dose based on?
SA and/ or BMI
Drug handling ability (liver function, renal function)
General wellbeing (performance status and comorbidity)
What are some important DDIs with chemotherapy?
Drugs may increase plasma levels of the chemotherapy drugs:
Vincristine and itraconazome leads to more neuropathy
Capecitabine (aral 5FU0 and warfarin
Methotrexate - penecillin and NSAIDs
Capecitabine and St Johns Wart, Grapefruit juice
How do you monitor chemotherapy during treatment?
Response of cancer
- Radiological imaging
- Tumour marker blood tests
- Bone marrow / cytogenetics
Drug levels
-E.g. methotrexate drug assays taken on serial days to ensure clearance from the blood after folinic acid rescue
Check for organ damage
- Creatinine clearance
- Echocardiogram
How do drugs drugs get from bench to bedside?
- Chemical engineering
- Pre-clinical studies e.g. animals
- Clinical trials program (phase I,II,III)
- Licensed by FDA
- Clinics and Nice
What things need to be taken into account when deciding the treatment phasing?
Growth fraction
The ‘cell kill’ of each cycle of the chemotherapy regiment
Marrow and GI recovery before next cycle
How tolerable it is.
What causes variability in the amount of drug that ends up in the blood?
Abnormalities in absorption - N&V, compliance, gut problems
Abnormalities in distribution - weight loss, reduced body fat, ascites
Abnormalities in elimination - liver & renal dysfunction, other meds
Abnormalities in protein binding - low albumin, other drugs
