Tiêu đề 25. GENERAL INTRODUCTION TO CANCER CHEMOTHERAPEUTIC AGENTS.pdf ✅

PHARMD GURU Page 1 OBJECTIVES OF CHEMOTHERAPY: 1. For cancers like leukemias and lymphomas, several phases of chemotherapy are necessary. A cure may be sought with aggressive therapy for a prolonged period to eradicate all disease. For leukemias, this curative approach may consist of the following components: a. Remission induction: therapy given with the intent of maximizing cell kill. b. Consolidation (also known as intensification or post-remission therapy): therapy to eradicate any clinically undetectable disease and to lower the tumor cell burden below 103 , at which level host immunological defenses may keep the cells in control. c. Maintenance: therapy given in lower doses with the aim of maintaining or prolonging a remission. 2. For solid tumors, one or more approaches to chemotherapy may be used when seeking a cure based on the known utility of chemotherapy in line with other modalities, such as surgery or radiation. a. Adjuvant chemotherapy is given after more definitive therapy, such as surgery, to eliminate any remaining disease or undetected micrometastasis. b. Neoadjuvant chemotherapy is given to decrease the tumor burden before definitive therapy, such as surgery or radiation. 3. Palliative therapy is usually given when complete eradication of the tumor is considered unlikely or the patient refuses aggressive therapy. Palliative chemotherapy may be given to decrease the tumor size, control growth, and reduce symptoms. 4. Salvage chemotherapy is given as an attempt to get a patient into remission, after previous therapies have failed. GENERAL INTRODUCTION TO CANCER CHEMOTHERAPEUTIC AGENTS
PHARMD GURU Page 2 CHEMOTHERAPY DOSING: Chemotherapy dosing may be based on body weight, body surface area (BSA), or area under the concentration versus time curve (AUC). BSA is most frequently used because it provides an accurate comparison of activity and toxicity across species, making it easier to translate preclinical dosing into clinical trials and practice in humans. In addition, BSA correlates with cardiac output, which determines renal and hepatic blood flow and thus affects drug elimination. In very young or very small patients (e.g., infants less than a year of age or less than 10 to 12 kg of body weight), the BSA is not a good measure for calculating the dose as it can overestimate the patient’s size and lead to overdosing of chemotherapeutic agents, resulting in excessive toxicities. In this patient population, dosing chemotherapy based on body weight (in kilograms) is often a more frequently employed technique. DOSING ADJUSTMENTS: Dosing adjustments may be required for kidney or liver dysfunction to prevent toxicity. For some agents, dose adjustments are also made based on hematologic or non-hematologic toxicities. Very little is known about dosing chemotherapy in the obese population. COMBINATION CHEMOTHERAPY: Combination chemotherapy is usually more effective than single-agent therapy. 1. When combining chemotherapy agents, factors to consider include a. Antitumor activity b. Different mechanisms of action c. Minimally overlapping toxicities 2. The reasons for administering combination chemotherapy include a. Overcoming or preventing resistance b. Cytotoxicity to resting and dividing cells c. Biochemical enhancement of effect d. Rescue of normal cells 3. Dosing and scheduling of combination regimens are important because they are designed to allow recovery of normal cells. These regimens generally are given as short courses of therapy in cycles.
PHARMD GURU Page 3 4. Acronyms often are used to designate chemotherapy regimens. For example, CMF refers to a combination of cyclophosphamide, methotrexate, and fluorouracil used in the treatment of breast cancer. ADMINISTRATION: 1. Routes of administration vary depending on the agent and the disease state. Although intravenous (IV) administration is most commonly employed, oral administration of chemotherapy is becoming increasingly more common. 2. Other administration techniques include oral, subcutaneous, intrathecal, intra- arterial, intraperitoneal, intravesical, continuous IV infusion, bolus IV infusion, and hepatic artery infusion. 3. Drugs that may be given intrathecally include methotrexate, cytarabine, and hydrocortisone. Drugs should not be administered by the intrathecal route without specific information supporting intrathecal administration. Inadvertent administration of vinca alkaloids (e.g., vincristine) by the intrathecal route results in ascending paralysis and death. Th e U.S. Food and Drug Administration (FDA) requires that specific wording alerting the provider to this error must be included on the packaging of each dose of vincristine. They also recommend that safety measures are employed in the preparation and delivery of vinca alkaloids. 4. Products with different formulations, including liposomal or pegylated agents (e.g., liposomal doxorubicin, pegfilgrastim), are being used to decrease frequency of administration and/or reduce toxicities. RESPONSE TO CHEMOTHERAPY: Response to chemotherapy is defined in several ways and does not always correlate with patient survival. 1. Complete response (CR) indicates disappearance of all clinical, gross, and microscopic disease. 2. PR indicates a greater than 50% reduction in tumor size, lasting a reasonable period. Some evidence of disease remains after therapy. 3. Response rate (RR) is defined as CR + PR. 4. SD indicates tumor that neither grows nor shrinks significantly (less than 25% change in size).
PHARMD GURU Page 4 5. PD or no response after therapy is defined by a greater than 25% increase in tumor size or the appearance of new lesions. FACTORS AFFECTING RESPONSE TO CHEMOTHERAPY: 1. Tumor cell heterogeneity: Large tumors have completed multiple cell divisions, resulting in several mutations and genetically diverse cells. 2. Drug resistance: The Goldie-Coldman hypothesis states that genetic changes are associated with drug resistance, and the probability of resistance increases as tumor size increases. The hypothesis assumes that at the time of diagnosis, most tumors possess resistant clones. A well-studied mechanism of resistance involves the multidrug resistance (mdr) gene, which codes for membrane- bound P-glycoprotein. P-glycoprotein serves as a channel through which cellular toxins (i.e., chemotherapeutic agents) may be excreted from the cell. 3. Dose intensity is defined as a specific dose delivered over a specific period. Occasionally, the full dose cannot be given or a cycle is delayed owing to complications or toxicities. Suboptimal doses have resulted in reduced response rates and survival. Dose density involves shortening the usual interval between doses to maximize the drug effects on the tumor growth kinetics. 4. Patient-specific factors such as poor functional status, impaired organ function, or concomitant diseases may compromise how a chemotherapy regimen is given and affect how the patient responds to treatment. CLASSIFICATION OF CHEMOTHERAPEUTIC AGENTS A. Alkylating agents were the first group of antineoplastic agents. The prototype of this class is mechlorethamine, or nitrogen mustard, which was researched as a chemical warfare agent. Alkylating agents cause cross-linking and abnormal base pairing of DNA strands, which inhibit replication of the DNA. This mechanism is known as alkylation. These are phase-nonspecific agents. B. Most of the antitumor antibiotics are obtained from organisms of the Streptomyces genus. These agents may act by either alkylation (mitomycin) or intercalation. Intercalation is the process by which the drug slides between DNA base pairs and inhibits DNA synthesis. These are phase- nonspecific agents.