General Principles of Antineoplastics - Fitz Flashcards
What is the goal of antineoplastic therapies?
Eradicate cancer cells without affecting normal tissues.
What is the reality of antineoplastic therapies (in relationship to the goal)?
All cytotoxic drugs affect normal tissues as well as malignancies → aim for a favourable therapeutic index.
(No treatment addresses the fundamental cause.)
What are five distinguishing features of cancer?
- cancer alters DNA
- rapidly dividing cells that don’t die
- caused by upregulation of oncogenes or downregulation of tumour suppressor genes (p53 affected in 50% of cancers)
- in solid tumours, angiogenesis is required to supply blood to the growing tissue
- derived from normal tissue
- cancer cells are not recognized by the immune system as foreign
- may express different proteins (or different amounts of a protein) compared to normal cells
- loss of differentiation (reverting to more developmental forms)
- cancer stem cells (colony forming ability) → metastasis to other tissues
What is differential sensitivity?
Something that affects the cancer cell MORE than normal tissue.
What is meant by “cancer type” in non-evidence based medicine?
- when determining chemotherapeutic treatment success, the generic term “cancer” is meaningless - certain cancers respond to certain drugs, and others do not
- breast cancer survival in 1950’s 5-15%, now 85% survival rate
- lung cancer survival rates 15%
- New treatments make survival rate numbers irrelevant
What was the typical definition of a “cure”?
5 years of disease-free survival
What is the definition of “cure” in the cancer world?
- Should not use the word “cure”, but, instead, refer to “no evidence of disease”.
- Palliative goal for better/longer life
- Control cancer OR convert into chronic disease (CML)
What is meant by “survival rate” in non-evidence based medicine?
- Percent success is irrelevant to individual patients.
- 95% alive in 5 years? → NO, alive/dead
- all or nothing
Why is antineoplastic therapy “extremely conservative”?
- for an individual patient, survival isn’t a percentage
- there are no placebo groups - new therapies are tried in comparison to conventional approaches
- new therapies are often first tried on patients where all else has failed
- there may not be an opportunity to try something else
What are the six processes targeted by antineoplastic drugs?
- Rapid cell growth (cytotoxic drugs)
- Angiogenesis/metastasis
- Lack of differentiation
- Lack of immune response
- Cell surface markers
- Defective gene products
(from least specific → most specific)
What cells are affected by cytotoxic drugs?
- Cancer Cells
- Bone marrow
- GI mucosa (nausea and vomiting)
- Hair follicles (alopecia)
- Taste buds (resulting in dysgeusia)
- “Radiation recall reaction” - erythema and desquamation of the skin at sites of prior (or simultaneous) radiation therapy (RUBICINS)
- Fetus (absolute contraindication in pregnancy)
What is the most common dose-limiting complication in administration of cytotoxic drugs?
Bone marrow suppression
What types of drugs are cell cycle specific (CCS)?
- Plant alkaloids (G2/M phase)
- DNA synthesis inhibitors/Antimetabolites (S phase)
- only proliferating cells killed (high growth factor tumors preferentially eliminated)
What types of drugs are less effective in slow growing cancers?
Cell-cycle Specific Antineoplastics
Why is it is common to follow CCNS drug treatment with a CCS drug?
So that cancer cells are recruited into the cell cycle, where CCS drugs can be more effective.
What types of drugs are cell cycle non-specific?
- Cross-linking/alkylating agents
- kill cells in any phase, including G0, although final toxicity may be manifested during a specific phase
- Anthracycline antibiotics
What kind of cells do Cell Cycle Non-Specific antineoplastics kill?
both proliferating and non-proliferating cells killed (attack both high and low growth factor tumours)
What type of drugs are schedule dependent?
Cell Cycle Specific
(duration and timing matter in addition to dose)
What type of drugs are dose dependent?
Cell Cycle Non-Specific
(total dose matters more than schedule)
What is the Cell Kill Hypothesis?
Proposes that actions of CCS drugs follow first order kinetics:
a given dose kills a constant PROPORTION of a tumor cell population (rather than a constant NUMBER of cells).
***Most applicable to leukemias.
What two components determine the dosing frequency in terms of the Cell Kill Hypothesis?
- Tumor burden
- Kinetics of division
What are the four curves on the Cell Kill Hypothesis Graph and what do they stand for?
- Exponential growth of cancer cells without treatment
- Low frequency treatment prolongs life (kill rate < growth rate)
- High frequency treatment results in successful “cure” (kill rate > growth rate)
- Decreased treatment time if surgery first, then high frequency treatment (decreased tumor burden)
- Magnitude of the kill is LOGARITHMIC
- e.g. 3log kill = 1012 → 109 or 109→ 106
What are three critical points about treatment according to the Cell Kill Hypothesis?
- Early start to the treatment is (obviously!) helpful
- Treatment must continue past the time when cancer cells can be detected using conventional techniques
- Appropriate scheduling of treatment courses and care to ensure that a sufficient log-kill is obtained are also crucial factors that enable success
What factors on the cancer side directly determine the effectiveness of antineoplastic therapy?
- growth fraction determines efficacy of CCS drugs
- doubling time affects course scheduling
- type and stage can determine cure vs. palliation
- resistance can limit treatment and/or force a switch in medication
