Antineoplastic Drugs - General Principles Of Use
The following discussion reviews several general considerations surrounding the use of antineoplastic drugs: myelosuppression, kinetics and therapeutic drug monitoring, and drug interactions. These topics are presented independently from one another and are intended to provide an introduction to various practical aspects of antineoplastic drug use.
1. Discuss the common patterns of myelosuppression and common patterns of timing of antineoplastic drug regimens.
2. List those antineoplastic drugs which are not myelosuppressive.
3. Discuss the current role of therapeutic drug monitoring in oncology patients.
4. Be able to recognize and prevent undesirable clinically significant drug interactions with antineoplastic drugs.
Balmer C, Valley AW. Basic principles of cancer treatment and cancer chemotherapy. In: DiPiro JT, Talbert RT, Yee GC, Matzke, GR, Wells BG, Posey LM, editors. Pharmacotherapy: A Pathophysiologic Approach. Stamford: Appleton & Lange. 1997:2403-2465.
Lieschke GJ, Burgess AW. Granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor. N Engl J Med 1992;237:28-35, 99-106.
ANTINEOPLASTIC DRUGS - GENERAL PRINCIPLES OF USE
MYELOSUPPRESSION = depression of bone marrow elements
Myelosuppression occurs with many chemotherapeutic agents because cells in the bone marrow are continually proliferating. It is of importance for obvious reasons: suppression of white blood cells can lead to INFECTION; suppression of platelets can lead to BLEEDING; suppression of red blood cells can lead to ANEMIA.
The severity of depression of the different cell lines and the rapidity with which that depression is seen are a function of the circulating life of the different cells. Thus, effects on granulocytes and platelets are more severe, and occur earlier than effects on red blood cells.
PATTERNS OF MYELOSUPPRESSION: NADIR = low point. On the average, the nadir white blood cell count is reached about 10 days following a single dose of most alkylators, antimetabolites or antibiotic chemotherapeutic agents. Recovery of peripheral counts follows. This pattern becomes somewhat obscured when multiple doses or multiple drugs are given. Drugs are commonly given in cycles (eg. every 3 or 4 weeks), allowing time for recovery of normal cells like those of the bone marrow. PLURIPOTENT STEM CELLS in the bone marrow (earlier precursors) have a low rate of cell proliferation and are thus less likely to be affected by many drugs. But granulocyte precursors (later, committed, precursors), as well as platelet and red blood cell precursors, in the bone marrow are depleted by chemotherapy. More mature, nonproliferating (even later) precursors continue to differentiate into mature cells within the first several days after chemotherapy. When these cells live out their lifespan, the precursor supply is depleted and peripheral counts fall to a low point, the nadir. Counts then recover within three to four weeks, after feedback stimulates the stem cells in the marrow to increase proliferation. Chemotherapy given at the time pluripotent stem cells increase their proliferation could cause permanent bone marrow damage. Not infrequently, drugs are given on days 1 and 8 of a 28 day cycle. The second dose of chemotherapy, one week after the first, is tolerated because the pluripotent stem cells have not yet increased their proliferation (ie. the second treatment is given BEFORE the peripheral count has reached its nadir)
Some drugs (BUSULFAN, NITROSOUREAS, MITOMYCIN-C) can cause more DELAYED and PROLONGED myelosuppression. They appear to be less selective, and may damage the slowly proliferating stem cells. Commonly, the intervals between doses or courses of these drugs are longer than those discussed above.
Some drugs are NONMYELOSUPPRESSIVE. These include BLEOMYCIN, VINCRISTINE, ASPARAGINASE, CISPLATIN and STEROIDS.
Colony stimulating factors (granulocyte colony stimulating factor [GCSF] and granulocyte-macrophage colony stimulating factor [GMCSF]) are being used to prevent (and sometimes to treat) chemotherapy-induced granulocytopenia. The drugs are given parenterally, either subcutaneously or intravenously. The high cost of these factors would seem to support their use in specified circumstances (eg. patients who have had neutropenia and fever after previous cycles of the same chemotherapy, patients who have had chemotherapy delayed because of neutropenia, mobilization prior to and to facilitate marrow recovery after bone marrow/stem cell transplantation). Commercially available colony stimulating factors don't ameliorate thrombocytopenia, although megakaryocyte growth and development factor is under investigation.
GENERAL KINETIC CONSIDERATIONS FOR CHEMOTHERAPEUTIC AGENTS
In general, monitoring of drug concentrations does not currently accompany the clinical use of most chemotherapeutic agents. Historically, ASSAY DEVELOPMENT was a major LIMITING FACTOR. There is a PAUCITY of data documenting BLOOD LEVEL - EFFICACY or BLOOD LEVEL - TOXICITY relationships, although research in this area is increasing. An EXCEPTION to this is METHOTREXATE. Methotrexate toxicity is clearly related to blood levels and duration for which that blood level is maintained. Methotrexate levels are usually obtained in conjunction with HIGH DOSE METHOTREXATE and LEUCOVORIN RESCUE. Post high dose methotrexate levels are used to adjust leucovorin doses (ie. prolong the duration and/or increase the dose). Occasionally, methotrexate levels are used to characterize methotrexate kinetics in individual patients, with subsequent adjustment in methotrexate doses.
Several guidelines have been proposed for dosage adjustment of CARBOPLATIN. These guidelines take in to account RENAL FUNCTION, and PREVIOUS MYELOSUPPRESSIVE TREATMENT. They were derived using an endpoint of toxicity (thrombocytopenia). Increasingly, carboplatin is dosed using an endpoint of desired AUC (Dose = AUC[CrCl + 25]. To date, there is a better correlation between carboplatin AUC and toxicity than between AUC and therapeutic effect.
AUC dosing is being studied for other cytotoxic drugs, although carboplatin is the drug most frequently dosed based on AUC in "routine" practice.
Achievement of "therapeutic" blood levels extrapolated from animal data is also being used increasingly as a goal in dosage escalation in Phase I studies of antineoplastic drugs. (ie. instead of escalating by a predetermined percentage)
DRUG INTERACTIONS WITH CHEMOTHERAPEUTIC AGENTS
Interactions with METHOTREXATE - Several cases of methotrexate toxicity, including some with fatal outcomes, have been attributed to drug interactions. Drugs reported have included: ASPIRIN, COTRIMOXAZOLE, PENICILLIN, NSAIDS (INDOMETHACIN, KETOPROFEN). Although several different mechanisms have been suggested, one mechanism that might be common to all of these drugs is inhibition of tubular secretion of methotrexate. This would result in prolonged excretion of methotrexate and enhanced toxicity. If a person on methotrexate is to receive a drug that potentially inhibits tubular secretion (eg. weak acids), or is reported to interact by another mechanism, the drug could be added 12-24 hours after methotrexate. (In some cases patients are started on both drugs concurrently. It is obviously difficult to estimate how much methotrexate toxicity might be due to a drug interaction when we haven't observed the degree of toxicity due to methotrexate alone. In such cases, patients should be monitored keeping in mind that adverse effects might be more severe than generally expected from a given dose of methotrexate.) Patients receiving methotrexate should be questioned about concurrent medications and adjustments made as necessary (eg. change aspirin to acetaminophen, if possible; delay a dose until 12-24 hours after methotrexate, if possible; etc.)
A different interaction involving methotrexate and NITROUS OXIDE was reported to be responsible for severe toxicity observed during the first year of a perioperative adjuvant breast cancer trial. Nitrous oxide inhibits homocysteine methyltransferase which inhibits formation of one of the reduced folate precursors. In other words, nitrous oxide exerts an additive effect with methotrexate on folate metabolism. This interaction might be clinically significant in patients who are receiving methotrexate at the time they get nitrous oxide anesthesia.
Interactions with PROCARBAZINE - Three types of interactions with procarbazine have been described. First procarbazine is a MONOAMINE OXIDASE (MAO) INHIBITOR. There is documentation in animals that procarbazine does indeed inhibit MAO. The clinical significance of procarbazine MAO inhibition in humans is not known. Reported reactions that have been attributed to MAO inhibition include an "intensely itchy skin eruption" and a "manic reaction". The classic MAO inhibitor interaction that we would be concerned about, of course, is hypertensive crisis precipitated by foods with high tyramine content. There are no reports of this reaction (where procarbazine is the MAO inhibitor). It is
generally recommended to avoid those foods containing high amounts of tyramine, keeping in mind that this effect is poorly documented. Examples of such foods include some cheeses and some wines, fermented sausages, pickled herring, caviar and yeast extracts. Note that baked goods do not contain very much tyramine and are unlikely to cause a problem.
Second, procarbazine is reported to cause an ALCOHOL "flush" or "Antabuse-like" reaction. The documentation for this interaction comes from early reports of the use of procarbazine. Several patients were reported to have facial flushing when they drank alcohol. Most of these patients were taking continuous daily procarbazine. This is not how procarbazine is usually given today. From these reports, we can't tell how many patients didn't get a flush, or how many might have facial flushing from alcohol without procarbazine. At any rate, there doesn't appear to be evidence of a more severe "Antabuse reaction".
Lastly, procarbazine can cause CNS DEPRESSION and this is said to be additive with other CNS depressants. Many patients receiving procarbazine receive other CNS depressants (eg. analgesics, antiemetics). Patients should be monitored for sedation. Use of the two drugs together is not contraindicated.
Interactions with 6-MERCAPTOPURINE - The interaction of 6-mercaptopurine (6-MP) or azathioprine with ALLOPURINOL is probably the most well known of interactions with antineoplastic agents. 6-MP (or azathioprine) toxicity (thrombocytopenia, granulocytopenia) is enhanced and may be fatal. The dose of 6-MP or azathioprine should be decreased to one-third to one-fourth the normal amount when allopurinol is used concurrently. Several kinetic analyses have failed to document the interaction although there are multiple case reports of clinical toxicity presumably due to the combination. These analyses utilized IV 6-MP. More recently, the mechanism of the interaction has been further delineated and it has been shown to be important with oral, and not IV, 6-MP. (6-MP is generally given orally.) Allopurinol inhibits the first-pass metabolism of orally administered 6-MP: After oral 6-MP, the entire dose travels via the portal circulation to the liver where a large portion is metabolized by xanthine oxidase before reaching the systemic circulation. Thus, bioavailability is low. Allopurinol inhibits xanthine oxidase, thereby increasing the plasma concentration of 6-MP. (As IV 6-MP is rapidly distributed, only a fraction of it is metabolized initially by hepatic xanthine oxidase. Thus changes in xanthine oxidase won't be as important when 6-MP is administered by this route.)
Interactions with PHENYTOIN - Several reports describe patients on phenytoin whose phenytoin concentrations dropped shortly after receiving various chemotherapeutic agents. Doses were increased in some cases, and within several weeks after chemotherapy, patients developed phenytoin toxicity. The mechanism of the initial decrease in phenytoin concentration is not clear (both a decrease in absorption and an increase in metabolism have been proposed). But the pattern is the same in many reported cases, providing support for the occurrence of a drug interaction. Patients on phenytoin should have blood concentrations measured 24-72 hours after receiving chemotherapy. If concentrations are low and dose increases are clinically indicated, follow-up levels should be obtained after chemotherapy to allow for downward adjustment and prevent toxicity.
Interactions with LEVAMISOLE - Levamisole is reported to interact with alcohol. The documentation for this interaction is scanty. In the large trial of 5-FU and levamisole for adjuvant therapy in Dukes Stage C colon cancer, adverse consequences from alcohol intake were not discussed.
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