Principles of Treatment of Pediatric Oncology Flashcards
What does a low therapeutic index mean?
The ratio between efficacious dose and toxic dose is very small, so small errors in dosing can have big consequences
Phase I Trial?
Toxicity and determine maximum tolerated dose
Phase II Trial?
Toxicity and response rate
Phase III Trial?
Efficacy vs. standard
Phase IV Trial?
Efficacy, safety, long-term effects after approval
Most common type of Phase I trial? Goal? How to determine if dose level is tolerable? Downside?
- 3+3 design: enrol 3 patients in clinical trial, give drug, and assess for toxicity
- Goal: less than 33% of patients have “unacceptable toxicity” - previously defined, known as “dose limiting toxicity”
- If no patients have dose limiting toxicity, then go up to next dose level
- If one patient has toxicity, enrol another 3 patients. If one more patient does have toxicity, then dose level is considered intolerable, and dose is de-escalated. If only the 1/6 or none, go up to next level and repeat same.
- Downside is have to pause trial while await toxicity assessment, so can become quite lengthy for patients who are waiting
Rolling 6 design of phase I trial? How to escalate dose?
- Allows you to enrol 6 patients at a time
- Can escalate as long as you know that 3/3, 4/4, 5/5, 6/6 patients do not actually have toxicity
- But if more than one has toxicity, have to slow down or de-escalate
- Useful for multicentre trial with patients waiting
What is the final dose level called?
- Maximum tolerated dose: <33.3%
- Is the recommended Phase II dose
- Europe and US definitions different
What is a simon 2 stage design for phase II trial?
-usually pick a response rate of about 30%
If 1 patient or <1 in first 10 who does not have a response, then will never reach 30% and will close the trial
-But if >3 patients respond then know will reach endpoint and don’t have to go on to second stage
-If have 2-3 who respond, want to expand
What is the utility of the principle of multi-drug therapy?
To overcome drug resistance to individual agents
What is the Goldie-Coldman hypothesis?
- Mathematical model
- Hypothesis is that cancer cells within a tumour mutate to a resistant phenotype at a rate that is intrinsic to the genetic instability of the particular tumour
- Will predict that if you use different chemo agents with different mechanisms of action, different toxicities or no overlapping toxicities in setting of MRD, then would increase likelihood of cure in those particular patients
- This may be less relevant with biologic therapy, but for chemo, forms basis of therapy
- Other tenant of hypothesis is that don’t give same drugs over again - “trick” cancer by alternating strategies - e.g. alternating cycles
Principle of dose intensity?
- Theory that maximize dose to kill the most cells, but don’t want to give at cost to patient
- Why supportive care is important and has contributed to improved outcomes
For drug disposition in the body - what is ADME? What things affect it?
- Absorption
- Distribution
- Metabolism
- Excretion
- Clearance, half-life, AUC, volume of distribution, bioavailability and biotransformation
- Age, organ function, drug interactions
Examples of common pro-drugs?
Cyclophosphamide
Ifosphamide
Irinotecan
Significance of pharmacodynamics?
-Effects of drug on the body, relationship between drug concentration and effect
What is pharmacogenomics referring to?
Genetic variations effect on spectrum of drug action
e.g. UGT1A1 deficiency
Phases of cell cycle?
G0 - resting phase, cell has left the cell cycle
G1 - cells increase in size, ready for DNA synthesis
S - DNA replication
G2 - cells increase in size, ready for mitosis
M - mitosis
What cell cycle phase do alkylating agents work at?
G0
What cell cycle phase do antitumor antibiotics work at?
Cell cycle non-specific
What cell cycle phase do antimetabolites work at?
S
