Cancer Treatment Flashcards
Therapy Classifications
- Curative: Definitive chemotherapy which cures the patient
- Palliative: Chemotherapy which will not cure but which will improve life span or quality of life
- Adjuvant: Chemotherapy given after therapy of the primary tumor has been given
- Neoadjuvant: Chemotherapy given before primary therapy to reduce tumor size improving the success of primary surgery or radiation
(Both adjuvant and neoadjuvant goal is to increase survival but at times they prevent complicated courses)
Systemic Therapy Effectiveness
Factors affecting response and failure:
- Host features: Performance status, nutritional status, co-morbidities, organ function
- Drug determinants: MOA, pharmacokinetics and dynamics
- Tumor features: Kinetics, biological and genetic factors
- Why systemic therapy fails: MDR genes, genetic induction and repair mechanisms
Toxicity vs. Cure
- Success of chemotherapy: 90% of the cures by chemotherapy occur in 10% of the cancers
- Most cures occur with:
- Hematological malignancy (i.e. Leukemia and lymphomas)
- Solid tumors (i.e., testicular and trophoblastic disease)
- Cure sometimes requires high dosing leading to severe toxicity
- Success depends upon tilting the balance in favor of survival
- More specific types of drug therapies may make more cures possible w/o risking great toxicity
Therapy Outcome
Factors
- Sensitivity of tumor to drugs/radiation
- Tumor burden
- Host performance status
- Tumor biology
Growth Fraction
- Indicates the percentage of cells that are actively dividing
- In solid tumors is about 20%
- It is much higher in hematological malignancies, such as leukemias
- The protein Ki-67 is a cellular marker for cellular proliferation
- It is expressed by cells in G1,S, G2 and M phases of the cell-cycle
- It is absent in resting or quiescent cells (G0 phase)
Tumor Stem Cells
Growth fraction containing self-renewing cells
Tumor Heterogeneity
Tumors may have several types of stem cells
Some are sensitive to chemo and other are not
(Analogy to bacterial heterogeneity in relation to abx sensitivity)
Logarithmic Growth
Mathematical description of cell number
Usual tumor burden for pt w/ symptomatic cancer exceeds 9 logs
Targeted Therapy
- Blocks the growth and spread of cancer by interfering with specific molecules (“molecular targets”) involved in the growth, progression, and spread of cancer
- The future of cancer management
Mitotoxicity
Cell-cycle specific (CCS)
- Drugs act on a specific phase of the cell cycle (CCS)
- More effective on tumors with high-growth fraction
- Schedule dependent (duration and timing)
Mitotoxicity
Cell-cycle non-specific (CCNS)
- Drugs act on all phases of the cell cycle
- Effective on tumors with high- and low-growth fraction
- Dose dependent
Cell-Cycle
Drugs
Toxicity of Anticancer Drugs
- Rapidly proliferating cells, such as bone marrow, mucosa of the GI tract, hair follicles and gonads are the most sensitive
- Bone marrow suppression is the most common dose limiting factor
- Dosage is titrated to avoid excessive neutropenia (granulocytes < 500/mm3) and thrombocytopenia (platelets <20,000/mm3)
Log Cell Kill
- The cytotoxic effects of antineoplastic drugs follow first-order kinetics:
- A given dose kills a constant percentage of cells (rather than a constant number)
- Therefore, the magnitude of tumor kill is a logarithmic function and a 3-log kill dose will reduce the cancer load from 109 to 106
- This concept mostly applies to hematological malignancies such as acute leukemias, high-grade lymphomas, less to solid tumors
Gompertzian Growth
- Curve describing the complex pattern of tumor growth
- Early, almost exponential growth rate
- Followed by slower growth rate
- Reaches a plateau as tumors grow larger in size
- Small tumors grow faster than larger ones
- The rate of cell-killing of many drugs is proportional to tumor growth rates
- Smaller tumors are more easily eradicated with drugs than larger tumors
Norton-Simon hypothesis
tumors given less time to regrow between treatments are more likely to be eradicated
Resistance to Chemotherapy
- Acquired resistance
- Multidrug resistance
- Primary resistance (cancer stem cells)
Drug Resistance
Mechanisms
- Resistance Mechanisms To Chemotherapy
- Properties that affect the mechanism of action of the drugs:
- increased nuclei acid repair mechanisms
- insensitivity to apoptosis [p53 and bcl-2 mutations]
- production of chemicals that inhibit the drugs o alterations in drug targets
- Properties That Affect The Intracellular Concentration Of The Drugs:
- Decreased production of prodrugs
- Increased inactivation of drugs
- Decreased accumulation
- Decreased transport
- Increased export
Rationale for Combination Chemotherapy
- Inclusion of compounds that:
- Act on different molecular targets
- Work in different phases of the cell cycle
- Have different dose-limiting toxicities
Intermittent Dosing
- Reduce toxicity [allowing bone marrow recovery]
- Pulling” some quiescent cells out of G0 phase and increase their susceptibility to cell-cycle specific drugs
- Take advantage of known synergies
MOPP
Drugs
Combination Regimens in Hodgkin’s Lymphoma
Mechlorethamine ⇒ alkylating agent (nitrogen mustard)
Oncovin (vincristine) ⇒ inhibitor of microtubules
Procarbazine ⇒ alkylating agent
Prednisone ⇒ apoptosis inducer
MOPP
Toxicity
- Bone marrow suppression
- Allergic reactions
- Infertility
- High risk of developing acute leukemia
- Methcloretamine thought being responsible of long-term effects
ABVD
Drugs
Combination Regimens in Hodgkin’s Lymphoma
One cycle over 4 weeks (day 1 and day 15) IV route. Outpatient setting
Adriamycin (doxorubicin) ⇒ topoisomerase inhibitor
Bleomicin ⇒ free radicals producer
Vinblastine ⇒ inhibitor of microtubules
Dacarbazine ⇒ alkylating agent
ABVD
Toxicity
- Hair loss
- Nausea and vomiting
- Myelosuppression
- Neuropathy
Tumor Lysis Syndrome
- A condition characterized by a series of metabolic complications observed shortly after chemotherapy (often combination) in pts with significant tumor burden.
- Observed most commonly in lymphomas and leukemias.
-
Hyperkalemia: intracellular ion released upon cell lysis
- Cardiac conduction anomalies
-
Hyperphosphatemia: intracellular ion released upon cell lysis
- Precipitates in the renal parenchyma
-
Hypocalcemia: formation of calcium/phosphate precipitates
- Precipitates in the renal parenchyma
- Tetany
- Myopathy
Hyper-uricemia/hyper-uricosuria
may lead to acute uric acid nephropathy (AUAN)
To prevent AUAN, pts affected by tumors with high-rate growth should receive prophylactic oral or IV, which is a xanthine oxidase inhibitor.
Delivery of Antineoplastic Drugs
-
Intravenous infusion
- The most common route. By de1inition makes 100% of the drug available in the blood.
- However, factors such as plasma protein binding, the extent of tumor perfusion and the compression on blood vessels must be taken into consideration.
-
Regional administration
- Intraperitoneal for ovarian tumors
- Intrapleural for lung tumors
- Intratechal administration for brain tumors and leukemia
-
Oral administration
- The most convenient and less expensive.
- However, problems with inconsistent drug availability, intestinal absorption, liver metabolism, etc.
Pharmacokinetic-Pharmacodynamic Relationships
- For most chemotherapeutic drugs there is a delay of days to weeks between measuring drug concentrations and clinical effect.
- The majority of chemotherapeutic drugs have a narrow therapeutic index.
- Therefore, most dosing strategies focus on minimizing toxicity rather than optimizing efficacy (reduction of tumor volume).
Cytotoxic Effects of Anticancer Drugs
