Welcome to the 2nd part of the discussion about chemotherapy drugs for childhood cancer. See here for the first part.
Chemotherapy drugs are an essential part and parcel for the treatment of childhood cancer. Here is a list of common childhood cancers and tumors. There are many clinical trials going on to improve the therapy outcome and reduce toxicity to chemotherapy drugs. Development of a new drug and regimen takes many years. Sometimes you may hear or read on the internet that this drug is on Phase 2 trial; you cannot take it. What does it mean?
Clinical Trials of Chemotherapeutic Drugs
During development and before registration, drugs progress through a number of different phases of trial to establish a safe dose for administration, their efficacy, and their side effect profile.
Phase I: safety assessment and dose finding (maximum tolerated dose or recommended phase II dose). Small number of individuals, usually incorporating pharmacokinetic studies.
Phase II: efficacy assessment and further safety assessment. Small studies, but larger than in phase I. Subsequent phases of testing are increasingly expensive. Therefore, many drugs do not progress beyond the initial phase I and II stages.
Phase III: Randomized controlled trials in large patient groups comparing the new treatment or regimen to the current standard practice. These usually involve hundreds or thousands of patients and are the gold standard for proof of the efficacy of the new intervention. They are expensive and complex to coordinate, often involving many centers across many countries. Standardisation of trial design, analysis and reporting through the CONSORT guidelines (Begg et al. 1996) has improved the quality of clinical trial research
Trial Endpoints
Various endpoints can be used to determine the advantage of one drug or regimen compared to another. These include:
Overall survival (OS): denotes the percentage of individuals in the group who are likely to be alive after a particular duration of time. It takes into account death due to any cause – both related and unrelated to cancer. It is the most robust endpoint and the gold standard outcome measure for regulatory authorities such as the Food and Drug Administration (FDA).
Progression free survival (PFS): measures the proportion of people among those treated for a cancer whose disease will remain stable (without signs of progression) at a specified time after treatment.
Disease-free survival (DFS): the proportion of people among those treated for a cancer who will remain free of disease at a specified time after treatment.
Time to recurrence (TTR): the proportion of individuals who have a recurrence of tumour at a defined time point.
Relapse free survival (RFS): the time to the first relapse or death from any cause, and not including second primaries or other cancers.
Time to progression (TTP): a measure of time after a disease is diagnosed (or treated) until the disease starts to get worse.
Defining Outcomes to Treatment
In 2000, international standardized criteria for measuring tumor response, called the Response Evaluation Criteria in Solid Tumors (RECIST), were published (Therasse et al. 2000). Here is details about Recist criteria
Download full RECIST Guideline PDF
Normal cell cycle
Inherent to cytokinetic principles is the concept of the cell cycle. Daughter cells formed as a result of mitosis consist of three subpopulations: (1) cells that are nondividing and terminally differentiated, (2) cells that are continually proliferating, and (3) cells that are resting but may be recruited into the cell cycle (i.e., stem cells). All three populations exist simultaneously in tumors.
Agents that are cell-cycle-phase nonspecific (e.g., alkylating agents) have a linear dose-response curve; that is, the greater the dose of drug, the greater is the fraction of cell kill. However, cell-cycle-phase-specific drugs have a plateau with respect to cell killing ability, and cell kill will not increase with further increases in drug dosage.
The life cycle of eukaryotic cells comprises numerous phases. Chemotherapeutic drugs can be classified as either phase-specific or non-phase-specific drugs. A phase-specific agent is only effective during a specific phase of the cell life cycle, whereas a non-phase-specific agent is effective during all phases.
Go phase: gap/resting state where cell is not dividing.
G1 phase: Gap1/interphase: Phase for the production of specialized proteins, RNA, and enzymes for DNA synthesis.
S phase: DNA synthesis. Phase for doubling cellular DNA
G2 phase: production of cellular components for mitosis: DNA, RNA, microtubular precursors of mitotic spindles.
M phase: Mitotic phase, cells divide: RNA production followed by cell duplication.
Log-kill hypothesis of chemotherapy drugs
Cell killed by first-order kinetics.
A constant fraction of cells is killed by a given drug dose, not a constant number.
A constant percentage of the total number of cancer cells present in the tumor will be killed with each course of chemotherapy. Hence, repeated doses of chemotherapy must be used for total cell killing.
Growth fraction
Growth fraction is the percentage of actively dividing cells at any given point in time.
- High growth fraction tumour: more sensitive to cycle-specific drugs.
e.g. 1. leukemia and lymphoma
- Normal with tissues with high growth fractions like bone marrow, hair follicles, and intestinal.
- Low growth fraction tumors (solid tumors, e.g., carcinomas of the colon, lung cancer) are less responsive to cycle-specific drugs.
Tumour burden
The tumor burden is the size of the tumor as determined by the number of cells present.
Small tumor burden → more responsive
Higher the tumor burden → probability of drug resistance.
Cancer cells usually follows Gompertzian growth pattern
No more today. See you on next part.
