L. Bressler November, 1997 Antineoplastic Drugs - General Principles Of Use I. Antineoplastic drugs - general principles of use II.

General inetic considerations for Chemothearapeutic Agents III. Drug interaction with Chemotherapeutic Agents INTRODUCTION The following discussion reviews several general considerations surrounding the use of antineoplastic drugs: myelosuppression, inetics and therapeutic drug mon itoring, and drug interactions. These topics are presented independently from on e another and are intended to provide an introduction to various practical aspec ts of antineoplastic drug use. OBJECTIVES 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 inte ractions with antineoplastic drugs. REQUIRED READING NONE SUGGESTED READING Balmer C, Valley AW. Basic principles of cancer treatment and cancer chemotherap y. In: DiPiro JT, Talbert RT, Yee GC, Matz e, GR, Wells BG, Posey LM, editors. P harmacotherapy: A Pathophysiologic Approach. Stamford: Appleton & Lange. 1997:24 03-2465. Liesch e GJ, Burgess AW. Granulocyte colony-stimulating factor and granulocyte-m acrophage 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 b one marrow are continually proliferating. It is of importance for obvious reason s: suppression of white blood cells can lead to INFECTION; suppression of platel ets 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 whi ch that depression is seen are a function of the circulating life of the differe nt 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 al yl ators, antimetabolites or antibiotic chemotherapeutic agents. Recovery of periph eral 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 wee s), allowing time for recovery of normal cells li e those of the bone marr ow. PLURIPOTENT STEM CELLS in the bone marrow (earlier precursors) have a low ra te of cell proliferation and are thus less li ely to be affected by many drugs. But granulocyte precursors (later, committed, precursors), as well as platelet a nd red blood cell precursors, in the bone marrow are depleted by chemotherapy. M ore mature, nonproliferating (even later) precursors continue to differentiate i nto mature cells within the first several days after chemotherapy. When these ce lls live out their lifespan, the precursor supply is depleted and peripheral cou nts fall to a low point, the nadir. Counts then recover within three to four wee s, after feedbac stimulates the stem cells in the marrow to increase prolifera

tion. Chemotherapy given at the time pluripotent stem cells increase their proli feration could cause permanent bone marrow damage. Not infrequently, drugs are g iven on days 1 and 8 of a 28 day cycle. The second dose of chemotherapy, one wee after the first, is tolerated because the pluripotent stem cells have not yet increased their proliferation (ie. the second treatment is given BEFORE the peri pheral count has reached its nadir) Some drugs (BUSULFAN, NITROSOUREAS, MITOMYCIN-C) can cause more DELAYED and PROL ONGED myelosuppression. They appear to be less selective, and may damage the slo wly proliferating stem cells. Commonly, the intervals between doses or courses o f these drugs are longer than those discussed above. Some drugs are NONMYELOSUPPRESSIVE. These include BLEOMYCIN, VINCRISTINE, ASPARA GINASE, CISPLATIN and STEROIDS. Colony stimulating factors (granulocyte colony stimulating factor [GCSF] and gra nulocyte-macrophage colony stimulating factor [GMCSF]) are being used to prevent (and sometimes to treat) chemotherapy-induced granulocytopenia. The drugs are g iven parenterally, either subcutaneously or intravenously. The high cost of thes e factors would seem to support their use in specified circumstances (eg. patien ts who have had neutropenia and fever after previous cycles of the same chemothe rapy, patients who have had chemotherapy delayed because of neutropenia, mobiliz ation prior to and to facilitate marrow recovery after bone marrow/stem cell tra nsplantation). Commercially available colony stimulating factors don't ameliorat e thrombocytopenia, although mega aryocyte growth and development factor is unde r investigation. GENERAL KINETIC CONSIDERATIONS FOR CHEMOTHERAPEUTIC AGENTS In general, monitoring of drug concentrations does not currently accompany the c linical use of most chemotherapeutic agents. Historically, ASSAY DEVELOPMENT was a major LIMITING FACTOR. There is a PAUCITY of data documenting BLOOD LEVEL - E FFICACY or BLOOD LEVEL - TOXICITY relationships, although research in this area is increasing. An EXCEPTION to this is METHOTREXATE. Methotrexate toxicity is cl early related to blood levels and duration for which that blood level is maintai ned. Methotrexate levels are usually obtained in conjunction with HIGH DOSE METH OTREXATE and LEUCOVORIN RESCUE. Post high dose methotrexate levels are used to a djust leucovorin doses (ie. prolong the duration and/or increase the dose). Occa sionally, methotrexate levels are used to characterize methotrexate inetics in individual patients, with subsequent adjustment in methotrexate doses. Several guidelines have been proposed for dosage adjustment of CARBOPLATIN. Thes e guidelines ta e in to account RENAL FUNCTION, and PREVIOUS MYELOSUPPRESSIVE TR EATMENT. They were derived using an endpoint of toxicity (thrombocytopenia). Inc reasingly, carboplatin is dosed using an endpoint of desired AUC (Dose = AUC[CrC l + 25]. To date, there is a better correlation between carboplatin AUC and toxi city than between AUC and therapeutic effect. AUC dosing is being studied for other cytotoxic drugs, although carboplatin is t he 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 ant ineoplastic drugs. (ie. instead of escalating by a predetermined percentage) DRUG INTERACTIONS WITH CHEMOTHERAPEUTIC AGENTS Interactions with METHOTREXATE - Several cases of methotrexate toxicity, includi ng some with fatal outcomes, have been attributed to drug interactions. Drugs re ported have included: ASPIRIN, COTRIMOXAZOLE, PENICILLIN, NSAIDS (INDOMETHACIN, KETOPROFEN). Although several different mechanisms have been suggested, one mech anism that might be common to all of these drugs is inhibition of tubular secret ion of methotrexate. This would result in prolonged excretion of methotrexate an d enhanced toxicity. If a person on methotrexate is to receive a drug that poten tially inhibits tubular secretion (eg. wea acids), or is reported to interact b y 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 dif ficult to estimate how much methotrexate toxicity might be due to a drug interac tion when we haven't observed the degree of toxicity due to methotrexate alone. In such cases, patients should be monitored eeping 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 medicati ons and adjustments made as necessary (eg. change aspirin to acetaminophen, if p ossible; 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 perioper ative adjuvant breast cancer trial. Nitrous oxide inhibits homocysteine methyltr ansferase which inhibits formation of one of the reduced folate precursors. In o ther 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 h ave been described. First procarbazine is a MONOAMINE OXIDASE (MAO) INHIBITOR. T here is documentation in animals that procarbazine does indeed inhibit MAO. The clinical significance of procarbazine MAO inhibition in humans is not nown. Rep orted reactions that have been attributed to MAO inhibition include an "intensel y itchy s in eruption" and a "manic reaction". The classic MAO inhibitor interac tion that we would be concerned about, of course, is hypertensive crisis precipi tated 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, eeping in mind that this effect is poorly documented. Examples of such foods in clude some cheeses and some wines, fermented sausages, pic led herring, caviar a nd yeast extracts. Note that ba ed goods do not contain very much tyramine and a re unli ely to cause a problem. Second, procarbazine is reported to cause an ALCOHOL "flush" or "Antabuse-li e" reaction. The documentation for this interaction comes from early reports of the use of procarbazine. Several patients were reported to have facial flushing whe n they dran alcohol. Most of these patients were ta ing continuous daily procar bazine. 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 faci al 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 wi th other CNS depressants. Many patients receiving procarbazine receive other CNS depressants (eg. analgesics, antiemetics). Patients should be monitored for sed ation. 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 nown 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 allopurin ol is used concurrently. Several inetic analyses have failed to document the in teraction although there are multiple case reports of clinical toxicity presumab ly due to the combination. These analyses utilized IV 6-MP. More recently, the m echanism 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.) All opurinol inhibits the first-pass metabolism of orally administered 6-MP: After o ral 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 di stributed, only a fraction of it is metabolized initially by hepatic xanthine ox idase. Thus changes in xanthine oxidase won't be as important when 6-MP is admin istered by this route.) Interactions with PHENYTOIN - Several reports describe patients on phenytoin who se phenytoin concentrations dropped shortly after receiving various chemotherape utic agents. Doses were increased in some cases, and within several wee s after chemotherapy, patients developed phenytoin toxicity. The mechanism of the initia l decrease in phenytoin concentration is not clear (both a decrease in absorptio

n 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 interact ion. 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 Du es Stage C colon cancer, adverse conseque nces from alcohol inta e were not discussed. ________________________________________ Previous Next SyllabusThe College of Pharmacy UICPHARM@uic.eduThe University of Illinois at Chicago Last modified: Dec 19, 1997

Pain Management in Cancer Patients L. Bressler November, 1997 I. Subjective nature of pain II. Opioid analgesics III. Special considerations IV. Side effects of opioid analgesics V. Other drugs VI. Tolerance and dependence with opioid analgesics ________________________________________ OBJECTIVES 1. Discuss factors influencing pain in cancer patients. 2. Discuss the subjective nature of pain. 3. Discuss the possible sites of action of opioid analgesics. 4. Be able to choose an opioid analgesic regimen based upon specific patient con cerns (eg. renal function, age). 5. Be able to adjust an analgesic regimen based upon therapeutic response and/or side effects. 6. Discuss common side effects associated with opioid analgesics, and ways to mi nimize or prevent them. 7. Discuss the role(s) of other, non-opioid drugs in the management of pain in c ancer patients. REQUIRED READING 1. Levy MH: Pharmacologic treatment of cancer pain; N Engl J Med 335:1124-1132, 1996 SUGGESTED READING 1. Reisine T, Pasterna G: Opioid Analgesics and Antagonists, in The Pharmacolog ical Basis of Therapeutics (eds. Hardman, Limbird, Molinoff, Ruddon, Gilman), Mc Graw Hill, 1996, p.521-555 ________________________________________ PAIN MANAGEMENT IN CANCER PATIENTS I. SUBJECTIVE NATURE OF PAIN A. Basically, there are two components of pain. The first component is the senso ry input to the central nervous system (CNS) that results in recognition of the

sensation of pain. Under controlled laboratory conditions, the amount of stimulu s required to produce such a sensation (ie. PAIN THRESHOLD) would be very simila r in all subjects. However, this sensation, produced outside of a pathological s etting, is not "pain". By definition, pain is subjective. It is defined as a sensory and emotional expe rience. The second component is the REACTIVE, SUBJECTIVE COMPONENT. It is the re action to the first component - the meaning or the interpretation of the pain. I t is influenced by the setting in which the pain occurs (eg. more fear might be evo ed by "crushing" chest pain than by the same quality and intensity of pain i n another part of the body) and by the experiences, attitudes and beliefs of the patient. The reactive component varies widely from person to person and it woul d seem, then, that it is the reactive component that we are dealing with when pa tients complain of pain, and when we treat pain. B. ACUTE versus CHRONIC PAIN Acute pain serves as a warning to patients to see medical attention. Frequently , acute pain can be "understood", in that one nows the cause. A healing period can anticipated. Such is not the case with chronic pain, especially that due to cancer. It serves no useful purpose and its presence cannot be "rationalized" or "understood". The subjective component is obviously very important in chronic p ain due to cancer. Twycross describes this quite well: "Chronic pain differs fro m acute pain in that it is a situation rather than an event, it is impossible to predict when it will end, it usually gets worse rather than better, it appears to be entirely meaningless and frequently expands to occupy the patient's whole attention, isolating him from the world around. Consequently, there is a greater li elihood of a negative pain-potentiating psychological component in chronic p ain than in acute pain. Depression, anxiety, fear, mental isolation, other unrel ieved symptoms, and pain itself will all tend to exacerbate the total experience of pain. To relieve the pain, all these factors must be considered." There are few or no OBJECTIVE SIGNS of chronic pain. PAIN IS WHAT THE PATIENT SA YS HURTS. ________________________________________ II. OPIOID ANALGESICS are the mainstay for treatment of chronic pain due to canc er A. MECHANISM - opioid analgesics exert their effects by binding to opiate recept ors. 1. Transmission of pain impulses to the brain may be altered following opioid bi nding at the receptor. 2. The reactive component of pain may be altered following opioid binding at the receptor. Some areas of the brain rich in opiate receptors are those relating t o mood and behavior. B. GUIDELINES FOR USE 1. For patients with persistent, severe pain, medication on a SCHEDULED BASIS ra ther than PRN is generally preferred. It is easier to prevent pain from recurrin g than to treat it once it has recurred. The anxiety component increases as the last dose is wearing off and pain must be experienced before the next dose is gi ven. This exacerbates the pain and ma es it more difficult to eradicate with sub sequent doses. 2. PO:PARENTERAL RATIO - Due to a first-pass effect, all of the opioids are more effective when given parenterally than when given orally. The ratio of oral to parenteral effectiveness of morphine is reported to be 1:6 (ie. six times the pa renteral dose is required to achieve the same effect orally). This and other est imates are based on single dose studies. Chronic oral use seems instead to resul t in a ratio closer to 1:2 or 1:3. A helpful "rule of thumb" is to use 1:2 or 1: 3 as the PO:PARENTERAL RATIO for all opioids, as a starting point. Thus, when sw itching a patient from oral to parenteral, doses can be halved (or decreased to one-third), and when switching from parenteral to oral, doses can be doubled (or tripled). This "rule of thumb" also ma es calculating equianalgesic doses easie

r - if all of the drugs have a similar PO:PARENTERAL potency ratio, parenteral e quianalgesic doses (ie. equivalent to 10mg morphine SQ) can be applied, proporti onately, to oral opioids as well. C. EQUIANALGESIC DOSES DRUG ROUTES OF ADMINISTRATION APPROXIMATE EQUIANALGESIC DOSES* APPROXIMATE DURATION codeine PO, parenteral 120mg 4-6 hours hydromorphone PO, parenteral PR 2mg 2-5 hours levorphanol PO, parenteral 2mg 4-6 hours meperidine PO, parenteral 100mg 2-4 hours methadone PO, parenteral 10mg 6-12 hours morphine PO, parenteral PR 10mg 3-4 hours oxycodone PO 15mg 4-6 hours * parenteral doses equianalgesic to morphine sulfate 10mg SQ Again, the same equianalgesic doses would apply to oral opioids, if one uses the PO:PARENTERAL potency ratio of 1:2 or 1:3 for all opioids, as mentioned previou sly. The table of equianalgesic doses provides GUIDELINES for switching from one opioid to another. Determination of equianalgesic doses was not done in patient s with chronic pain due to cancer and the doses are approximate. D. STARTING DOSES Common starting doses for opioid-naive patients are shown in the table. These do ses are not necessarily equianalgesic. They are determined by experience of the prescriber, dosage forms and sizes available, and individual patient characteris tics (eg. patients 70 years or older may start with lower doses of opioid as the y may be more sensitive to the therapeutic effect, as well as to side effects). COMMON STARTING DOSES OPIOID-NAIVE PATIENTS codeine 30mg hydromorphone 2mg levorphanol 2mg meperidine 50mg methadone 5mg morphine 10mg oxycodone 5mg E. If an opioid is to be started in a patient who is not opioid-naive, the dose equ ianalgesic to the previous opioid should be estimated. This can be used as a sta rting point, eeping in mind that the dose might have to be increased (eg. maybe the previous opioid or dose was ineffective) or decreased (eg. maybe tolerance developed to the previous analgesic and there was not complete cross tolerance w ith the new opioid. See below) F. CHANGING DOSES Similarly, increments in opioid dose are conveniently made ta ing into account t he dosage forms and sizes available. Furthermore, the per cent increase is highe r when the doses are lower, and lower at higher doses. For example, consider a p atient being started on morphine sulfate solution, 2mg/ml. A common starting dos e would be 10mg (one teaspoonful). If 10mg didn't provide satisfactory relief, t he dose might be increased 100% - 20mg (two teaspoonsful). On the other hand, in a patient receiving 100mg of morphine, the dose might be increased to 120 or 14 0mg.

I. MONITORING PARAMETERS EFFICACY - What degree of pain relief is obtained? How long does the degree of r elief obtained last? (ie. duration of analgesia) If the degree of relief is inad equate, an increase in dose may be attempted. If the degree of relief is adequat e but the duration is shorter than the prescribed dosing interval, a decrease in interval may be attempted. Alternatively, the dose may be increased to prolong the duration of pain relief, as discussed above. How OFTEN should efficacy be ASSESSED? Daily might be ideal. In the case of seve re pain, efficacy should be assessed following one dose. More practical in an ou tpatient setting is assessment after several days on a regular dose. HOW should EFFICACY be ASSESSED? As the patient. Remember, pain is subjective. An observer cannot accurately measure pain (or pain relief). A numeric pain rati ng scale may be useful - either verbal or written. A patient may define an "8" o

G. MAXIMUM DOSE There is no absolute maximum dose of opioids for chronic pain due to cancer. Sin ce tolerance develops to respiratory depression (see below), doses can be increa sed gradually to maximize pain control. As long as patients are getting some rel ief, and side effects are at an acceptable level, opioid doses can be increased. When patients are getting no relief, or side effects are greater than analgesic effect, opioid doses should not be further increased. Instead, a new drug shoul d be instituted. Patients may display individual variation in analgesic response to the same drug. Such variation cannot be accurately predicted. H. DURATION OF ANALGESIC ACTION Approximate durations of analgesic action are shown in the table above. Duration of pain relief can vary among individuals, and does not appear to correlate wel l with half-life. In general, the only "long acting" opioid is methadone, which may provide pain relief for six or eight or even twelve hours. It is not unusual for patients ta ing "short acting" opioids (ie. everything other than methadone or perhaps, levorphanol) to report that pain relief lasts for only three or two or even one hour. SUSTAINED RELEASE morphine preparations (MS Contin?, Oramorph SR?) and oxycodone (Oxycontin?) have recommended dosing intervals of eight or twelve hours. Kadian ? is a sustained release morphine capsule that is indicated for Q 24 hour dosing . These preparations have demonstrated bioavailability equivalent to immediate r elease products. Since evidence of a blood level-response relationship for morph ine in chronic pain is equivocal, it is not clear that this bioavailability trul y predicts duration of pain relief. The manufacturers recommend that the dose be increased (rather than the interval be shortened) in the event that the duratio n of pain relief is inadequate. Clinically, this does prolong the duration, alth ough the total daily dose may be greater than the previous, immediate release, t otal daily dose. The long acting morphine capsule reportedly can be opened and t he contents placed in food or a feeding tube without destroying the sustained re lease mechanism. The duration of respiratory depression (as well as miosis) from METHADONE is con siderably longer than the duration of analgesia. The potential exists then, for frequent, repeated dosing with resultant cumulative toxicity. If methadone does not provide pain relief for at least six hours, its use should be re-evaluated s ince it is not "long acting" in this case. It should not be given any more frequ ently than every six hours. Transdermal FENTANYL is mar eted for the treatment of chronic pain, with a recom mended dosing interval of 72 hours. Clinical observations seem to indicate that the manufacturer's conversion guidelines from other opioids are rather conservat ive, and that the duration of pain relief may be shorter than 72 hours. Although the place of this preparation in cancer pain therapy is still not clearly defin ed, it would seem to be useful in select populations (eg. patients who can't ta e solid oral dosage forms, patients with feeding tubes). Twycross, reporting on pain management in hundreds of terminally ill cancer pati ents, also recommends increasing the dose of immediate release morphine when eff ective analgesia is maintained for less than four hours.

ut of 10 as unbearable pain. A decrease to a "3" or "4" may be quite acceptable. Other similar pain assessment scales may also be utilized. OVERALL ASSESSMENTS or GLOBAL ASSESSMENTS made by patients li ely ta e in to account other than just analgesic efficacy. A drug may wor very well but if the patient considers the side effects unacceptable, their overall assessment may be negative. SIDE EFFECTS - As the patient about common side effects: CONSTIPATION; SEDATION - Sedation occurs early on and usually improves within several days. New onset of sedation in a patient previously stable on an opioid is unli ely due to the o pioid (unless the patient has acutely deteriorated); CONFUSION - Confusion also occurs early on and should improve. Confusion is seen more often with methadone and more often in the elderly. ________________________________________ III. SPECIAL CONSIDERATIONS A. COMBINATIONS Remember ASPIRIN and ACETAMINOPHEN in Percodan?, Percocet?/Tylox?, Vicodin? and others. Patients ta ing acetaminophen 1gm every four hours and not getting adequ ate pain relief could be switched to another drug so as not to increase acetamin ophen. Hepatotoxicity has been reported with chronic regular use of therapeutic doses of acetaminophen. B. CONTINUOUS INFUSIONS of opioid (morphine, hydromorphone) - Morphine doses report ed have ranged from 1mg to several grams per hour. As is the case with intermitt ent administration, there is no absolute maximum dose. Continuous infusions bene fit patients requiring frequent dosing or patients who can't ta e medication ora lly. They have been administered intravenously or subcutaneously. Infusion rates should be controlled by infusion control devices. Several guidelines are availa ble for dosing continuous opioid infusions: 2.5mg morphine IV push every 10 minutes until relief. Then start continuous infu sion at an hourly rate equal to the cumulative IV push dose. Alternatively, start at 1mg morphine/hour with subsequent adjustment based on de gree of pain relief and side effects. Or, for patients on high opioid doses, calculate the 24 hour opioid dose, conver t this dose to parenteral (morphine) and then divide by 24 to determine the hour ly dose. C. Avoid METHADONE in the elderly, in patients with severe liver dysfunction (ie. p atients thought to have decreased liver metabolizing capacity) and in patients w ith compromised pulmonary function. In the latter two groups of patients, the po tential exists for cumulative toxicity with methadone. D. Avoid MEPERIDINE for chronic frequent use and in patients with renal dysfunction . Meperidine is metabolized to normeperidine which has CNS stimulatory activity and can cause seizures. Normeperidine accumulates in patients with renal dysfunc tion. However, there are also reports of neurotoxicity in very ill patients (but without renal failure) who received regular, frequent dosing with meperidine. T here is some suggestion that CNS toxicity might also occur with FENTANYL, which is structurally similar to meperidine, and is metabolized to norfentanyl. MORPHI NE-6-GLUCURONIDE may also accumulate in patients with renal dysfunction or on hi gh doses of morphine. It is thought to contribute the development of myoclonus. E. HEROIN Orally administered heroin is no different than morphine. Indeed, it is metaboli zed to morphine. Parenterally administered heroin has greater solubility than mo rphine, thus more drug can be delivered in a small volume. This is important in patients with little or no muscle mass receiving frequent intramuscular injectio ns. Dilaudid HP? offers a concentrated solution of parenteral opioid (10mg per m l), obviating the need for heroin. Newer, more concentrated strengths of morphin e are also available for parenteral use. F. PROPOXYPHENE -

Qualitatively, propoxyphene binds to opiate receptors, resulting in the same eff ects as other opioid analgesics. Quantitatively, however, propoxyphene is much l ess potent than other opioids and is commonly considered with non-opioid analges ics. There are some situations in which propoxyphene may be particularly useful: Propoxyphene WON'T MASK A FEVER. Other non-opioid analgesics (aspirin and nonst eroidal anti-inflammatory drugs, acetaminophen) have antipyretic activity. Propo xyphene DOESN'T INHIBIT PLATELET AGGREGATION. Inhibition of platelet aggregation occasionally limits the use of aspirin and many nonsteroidal anti-inflammatory drugs (but not acetaminophen). ________________________________________ IV. SIDE EFFECTS OF OPIOID ANALGESICS A. RESPIRATORY DEPRESSION In equianalgesic doses, ALL OPIOIDS DEPRESS RESPIRATION TO THE SAME DEGREE. Clin ically, respiratory depression may be seen as shallow and slow respirations. It has been reported that respiratory depression (decreased rate) was significant w hen it was accompanied by somnolence. Tolerance develops to respiratory depressi on, and usually, respiratory depression is not a problem when using opioids for chronic pain due to cancer. B. NAUSEA and VOMITING Opioids produce vomiting by stimulation of the chemoreceptor trigger zone (CTZ). There is also a VESTIBULAR component to GI symptoms, in that nausea and vomitin g are seen more in ambulatory than in supine patients. PHENOTHIAZINES may help m inimize nausea and vomiting (eg. prochlorperazine 10mg every 4 hours). ANTIHISTA MINES such as meclizine or dimenhydrinate can help minimize the vestibular compo nent. Tolerance also develops to the nausea and vomiting. Symptoms commonly impr ove within about a wee of regular opioid use. C. SEDATION Sedation may be seen with all of the opioids. It is more common in the elderly a nd with methadone. Tolerance also usually develops to opioid-induced sedation. D. CONSTIPATION Constipation occurs in a significant percentage of patients receiving opioids. T olerance does not appear to develop to constipation. Regular use of stool soften ers or bul laxatives may minimize constipation. However, stimulant laxatives ar e often required on a chronic basis. E. SWEATING/PRURITUS Sweating is due to vasodilation, probably mediated by histamine release. Pruritu s is also thought to be due to histamine release. Tolerance does not develop to sweating or pruritus. It is reported that fentanyl does not cause release of his tamine. F. SEIZURES see above discussion of MEPERIDINE. MYOCLONIC JERKS are sometimes seen with morp hine or other opioids, especially at high doses. They appear to be particularly discomforting for caregivers. Benzodiazepines have been used to treat myoclonic jer s. G. As is the case with analgesic response, there is UNPREDICTABLE INDIVIDUAL VARIAT ION IN TOXICITY. When one opioid produces unacceptable side effects, another opi oid may be tolerated. ________________________________________ V. OTHER DRUGS A. NONSTEROIDAL ANTI-INFLAMMATORY DRUGS These drugs are commonly used for pain due to BONE METASTASES. It is proposed th at PROSTAGLANDINS are involved in the development of bone metastases. Prostaglan dins increase the sensitivity of pain receptors (nociceptors) to painful stimuli . Nonsteroidal anti-inflammatory drugs are frequently used in addition to opioid s in the management of bone pain.

B. TRICYCLIC ANTIDEPRESSANTS In experimental systems, SEROTONIN and DOPAMINE enhance morphine analgesia, and NOREPINEPHRINE antagonizes morphine analgesia. These findings, although not prov en in pathologic pain, provide a rationale for the use of tricyclics. Clinically , tricyclics appear to be most effective in the management of PAINFUL NEUROPATHI ES (eg. postherpetic neuralgia, infiltration of nerve by tumor). C. PHENOTHIAZINES Based on the above information, theoretically, we might expect phenothiazines to be antianalgesic, as they bloc dopamine receptors. Probably, any "analgesic" e ffect is related to sedation, especially in anxious patients. A similar effect i s probably seen with ANTIHISTAMINES. BENZODIAZEPINES may serve the same purpose in anxious patients. D. STIMULANTS COCAINE was added to Bromptons mixtures (traditionally, morphine or heroin + coc aine in an alcohol vehicle) to counteract the sedation from the opioid. In recen t years, morphine sulfate solution has been found to have efficacy comparable to a Bromptons mixture. Further, with "standard" formulae, the ability to titrate the individual ingredients in Bromptons is diminished. Cocaine may be useful as a local anesthetic in patients with head and nec cancer, when absorbed through mucous membranes rather than swallowed. DEXTROAMPHETAMINE or METHYLPHENIDATE (5mg BID) may be useful in patients who hav e intolerable sedation but can't decrease the dose of opioid without compromisin g the analgesic effectiveness. E. ANTICONVULSANTS PHENYTOIN, CARBAMAZEPINE, and GABAPENTIN, as well as other anticonvulsants, are often used to treat neuropathic pain. They tend to decrease "shoots" in shooting , lancinating pain, not affecting underlying nociceptive pain. F. MEMBRANE STABILIZERS Li e the anticonvulsants, LIDOCAINE and MEXILITENE have been suggested to be use ful in neuropathic pain. G. NMDA antagonists (eg. dextromethorphan) are being studied for pain. Animal data suggests two beneficial effects: prevention of tolerance to the analgesic effect of opioids (see below) and relief of neuropathic pain. Their use is investigati onal at this time. ________________________________________ VI. TOLERANCE AND DEPENDENCE WITH OPIOID ANALGESICS TOLERANCE - This refers to an increased amount of opioid necessary to produce th e same effect previously seen with a smaller amount of opioid. Tolerance develop s to several opioid side effects - RESPIRATORY DEPRESSION, NAUSEA and VOMITING, SEDATION and CONFUSION. Twycross states that tolerance to the analgesic effect i s not a clinical problem when opioids are used in chronic pain in cancer patient s. When patients require more opioid, their disease can frequently be seen to be progressive. Foley notes that tolerance develops to the ANALGESIC EFFECT and th at cross tolerance between opioids is not complete. In either case, side effects permitting, opioid doses can be increased when previous doses are no longer as effective. When switching drugs, the possibility of incomplete cross tolerance m ay be considered, and a smaller than equianalgesic dose be started accordingly. PHYSICAL DEPENDENCE implies that a withdrawal syndrome can be seen upon abrupt w ithdrawal of an opioid or upon administration of an opioid antagonist. Physical dependence is a property of the drug, not the patient. It is generally not a con cern in chronic pain in cancer patients. Should the need for opioid be decreased or removed, a withdrawal syndrome can be avoided by tapering the opioid over se veral days. It has been noted that withdrawal reactions can be prevented if the dose of opioid is 25% of the previous day's dose. PSYCHOLOGICAL ADDICTION or PSYCHOLOGICAL DEPENDENCE results from a variety of pe rsonality, environmental, psychosocial, etc. factors. It does not result from si mply exposure to the opioid for a legitimate medical purpose. ADDICTION is NOT A

CONCERN AMONG CANCER PATIENTS WITH CHRONIC PAIN. ________________________________________ Previous Next SyllabusThe College of Pharmacy UICPHARM@uic.eduThe University of Illinois at Chicago Last modified: Dec 19, 1997

L. Bressler November, 1997 Cancer Associated Hypercalcemia I. Cancer associated Hypercalcemia II. Treatment ________________________________________ OBJECTIVES 1. Describe, in brief, the pathophysiologic changes associated with cancer assoc iated hypercalcemia. 2. Discuss the mechanism(s) of the various treatment modalities for cancer assoc iated hypercalcemia. 3. Be able to discuss relative advantages and disadvantages of the various treat ment modalities for cancer associated hypercalcemia, and to recommend treatment for specific patients. REQUIRED READING NONE SUGGESTED READING 1. Bilezi ian JP: Management of acute hypercalcemia; N Engl J Med 326:1196-1203, 1992 2. Hall TG, Schaiff RAB: Update on the medical treatment of hypercalcemia of mal ignancy; Clin Pharm 12:117-125, 1993 ________________________________________ CANCER ASSOCIATED HYPERCALCEMIA Hypercalcemia is reported to occur in 10-20% of patients with malignancies. Mali gnancy is one of the most common causes of hypercalcemia. Certain cancers are mo re li ely than others to cause hypercalcemia. The most common cancers that are a ssociated with the development of hypercalcemia are SQUAMOUS CELL LUNG CANCER, S QUAMOUS CELL HEAD AND NECK CANCERS, BREAST CANCER, MULTIPLE MYELOMA, T-CELL LYMP HOMAS, RENAL CELL CANCER, AND OVARIAN CANCER. Hypercalcemia may be associated with BONE METASTASES in patients with solid tumo rs eg. metastatic breast cancer. Increased BONE RESORPTION by OSTEOCLASTS leads to hypercalcemia. The increased bone resorption in this setting may be mediated by PROSTAGLANDINS or other factors. In addition, TUMOR CELLS may be able to RESO RB BONE DIRECTLY. Hypercalcemia is also associated with HEMATOLOGIC MALIGNANCIES li e multiple mye loma or T-cell lymphomas. Again, hypercalcemia in these cases results from incre ased BONE RESORPTION by OSTEOCLASTS, mediated by lympho ines. Most widely studied in recent years is hypercalcemia associated with SOLID TUMOR S WITHOUT BONE METASTASES eg. squamous cell lung or head and nec cancers. Hyper calcemia in these cases is due to a systemic humoral factor(s) that is produced by the tumor, the so-called HUMORAL HYPERCALCEMIA OF MALIGNANCY (HHM). Recent in vestigations have identified parathyroid hormone-related protein (PTH-rP) as a p robable mediator of HHM. PTH-rP may act in conjunction with other factors (eg. T RANSFORMING GROWTH FACTOR ALPHA, TUMOR NECROSIS FACTOR, INTERLEUKIN-1) to cause

the effects seen in humoral hypercalcemia. The proximal cause of hypercalcemia in all of these situations is increased bone resorption. However, the idneys help to maintain calcium homeostasis by increa sing urinary calcium excretion when bone resorption increases. Changes in renal handling of calcium, then, are important in precipitating hypercalcemia in patie nts with increased bone resorption. Normal calcium reabsorption in the proximal renal tubule is lin ed with sodium reabsorption and with volume status. Hypercal cemia is associated with a decreased effect of ADH on the renal tubules, leading to dehydration. Dehydration leads to a decrease in GFR, increasing sodium and t hus calcium reabsorption, and worsening the hypercalcemia. Other factors li e vo miting also may also contribute to precipitating or maintaining hypercalcemia. Normal total serum calcium is about 8.5-10.5mg/dl. About 40% is bound to protein s, mainly albumin. Fifteen percent is complexed to anions, and 45% is the free, ionized, active form. Formulae are available for correcting calcium concentratio ns for changes in albumin. These are supposed to estimate ionized, active calciu m, although the correlation with measured ionized calcium is questionable. Howev er, ionized calcium is usually not measured, and the formulae, based on albumin, are frequently used (eg. corrected serum calcium = [(4 - albumin) X 0.8] + meas ured serum calcium) Clinical manifestations of hypercalcemia include GI: nausea, vomiting, constipat ion; NEUROLOGIC: wea ness, lethargy, confusion, coma; RENAL: polyuria, thirst. S ymptoms may depend on the rate of rise of calcium eg. slow, gradual increases ma y be less symptomatic than abrupt increases. Progressive hypercalcemia can lead to death. Prompt treatment is initiated in patients who are symptomatic and/or w hose calcium is very high (eg. > 13mg/dl). Other patients are treated, but perha ps less urgently. Remember also, that certain drugs can contribute to hypercalce mia (eg. thiazides, lithium). TREATMENT: The first line of treatment for cancer associated hypercalcemia is HYDRATION wit h SALINE. Hydration repletes volume, and increases calcium excretion. Promotion of sodium diuresis leads to calciuresis as noted above. Hydration over 2 days (2 -8L/day, depending on hydration status, of 0.9% NaCl) can decrease serum calcium by approximately 2mg/dl. Note that unless other treatment is initiated, or the underlying malignancy treated, calcium will rise again. FUROSEMIDE may be used to prevent fluid overload from hydration eg. in patients with CHF. Furosemide also has a calciuric effect and has been suggested as a tre atment in addition to, or following, hydration. Reports of successful lowering o f calcium with furosemide involved very high doses along with large volumes of f luid, strict electrolyte monitoring and replacement, and intensive care monitori ng. Outside of this setting, dehydration from furosemide can offset any calciuri c benefit, and its use should probably be reserved for patients who can't tolera te hydration, as noted above. BISPHOSPHONATES - Today, bisphosphonates are probably the most frequently used c alcium-lowering agents. They (ETIDRONATE, PAMIDRONATE) prevent osteoclastic bone resorption, and they may directly inhibit osteoclasts. Etidronate can also impa ir bone formation. For prompt response, bisphosphonates are given IV. Pamidronat e is more potent than etidronate, and is probably used more often, although its clear superiority is not well documented. The recommended dose of pamidronate is 60-90mg IV. With either bisphosphonate, calcium decreases in about 48 hours and over the next 2 to 3 days, may fall to normal. Although commonly recommended fo r administration over 24 hours, pamidronate has been safely administered by shor t infusion (eg. 0.5-3 hours), ma ing it attractive for outpatient use. Bisphosph onates are relatively free of side effects. There are reports of elevations of s erum creatinine with etidronate in large doses. The clinical importance of mild reversible elevations is not clear. Because of the reports, the recommendations are to avoid etidronate in patients with serum creatinine greater than 5, and to decrease the dose when creatinine is > 2.5. Clinically, however, bisphosphonate s may be safe to use even before patients are completely rehydrated (eg. while t heir creatinine may still be elevated). Oral etidronate has been recommended for maintenance of normocalcemia. Its effic

acy is less well established than that of parenteral bisphosphonates. Doses up t o 20mg/ g/day have been used. Although inhibition of bone formation is a potenti al concern, many patients with cancer associated hypercalcemia have a limited su rvival, and will be unli ely to suffer long-term consequences. PLICAMYCIN (mithramycin) is commonly used to treat cancer associated hypercalcem ia after hydration. The dose is 25mcg/ g and should be reduced in patients with renal dysfunction (eg. by 50%). Plicamycin may be given as an IV bolus or infusi on. Most side effects of plicamycin are associated with higher or repeated doses (eg. 25-50mcg/ g/day x 5). These side effects include thrombocytopenia, coagulo pathy, hepatitis. The 25mcg/ g dose given once and perhaps repeated in 48 to 72 hours if necessary is well tolerated. Although calcium is lowered to normal leve ls in a majority of patients, the duration of normocalcemia is variable. When pl icamycin provides normocalcemia for 7 days or more, it can also be a useful agen t for maintaining lowered calcium. GALLIUM NITRATE is given as a continuous IV infusion (200mg/m2/day x 5 days). It appears to be effective in a large proportion of patients. In a comparative stu dy with etidronate, the median duration of normocalcemia was 8 days. Overall, ga llium was reported to be more effective than etidronate. Gallium should be used after rehydration. Higher doses have been associated with nephrotoxicity, and it is recommended that gallium not be used in patients with serum creatinine great er than 2.5. Its relative place in therapy is yet to be defined, eeping in mind factors such as cost, duration of effect and duration of treatment, potential f or nephrotoxicity, etc. CALCITONIN is also used to lower serum calcium. It wor s within several hours, a nd may be useful in lowering calcium acutely. Calcitonin may also be used in pat ients with renal insufficiency or before rehydration. Resistance develops quic l y to calcitonin, and although some investigators suggest that steroids prolong t he effectiveness, others have not found that to be the case. Calcitonin requires frequent parenteral administration (IV or SQ). These latter factors ma e calcit onin a less than optimal choice for maintenance of normocalcemia. Finally, CISPLATIN has been used to treat hypercalcemia associated with certain malignancies. It may provide several wee s of normocalcemia. However, it should not be used in patients with renal insufficiency. Cisplatin should only be given to patients who have been well hydrated. Maintenance of normocalcemia may be achieved with intermittent administration of some of the agents described above to lower calcium initially (eg. plicamycin, pamidronate). Maintenance with oral etidronate was discussed above. ORAL PHOSPHA TE is also used to maintain normocalcemia, provided patients are not hyperphosph atemic. Neutral phosphate capsules should be emptied and mixed with liquid. The starting dose of phosphate is about 1gm/day in divided doses. Diarrhea frequentl y impairs dose escalation and/or compliance, thus minimizing effectiveness. ________________________________________ Previous Next SyllabusThe College of Pharmacy UICPHARM@uic.eduThe University of Illinois at Chicago Last modified: Dec 19, 1997

Hormonal Treatment - Introduction L. Bressler November, 1997 Hormonal treatment Introduction Hormones in breast cancer Principles of use of hormone treatment in breast cancer

Hormones in prostate cancer ________________________________________ OBJECTIVES 1. Discuss the settings for use of different hormones and hormone-related treatm ents in oncology. 2. Discuss common side effects of hormonal therapy in cancer patients. REQUIRED READING NONE SUGGESTED READING NONE ________________________________________ HORMONAL TREATMENT - INTRODUCTION Hormonal therapy is used extensively in the treatment of breast cancer, prostate cancer and lymphoid malignancies, as well as in the management of several compl ications of cancer (eg. brain metastases). Occasionally, hormonal therapy is inc orporated into chemotherapeutic regimens for other solid tumors, on the basis th at the tumor may have some hormone dependency. Many steroid hormone effects are mediated through interaction with HORMONE RECEP TORS. The steroid binds to a specific receptor in the cytoplasm. The STEROID/REC EPTOR COMPLEX is then translocated to the nucleus of the cell where it alters ce ll function through interaction with RNA. Some effects of steroids are non-recep tor mediated (ie. direct steroid binding to nucleic acids). The significance of such effects is not completely understood, but may have implications especially as regards the role of glucocorticoids in leu emias, lymphomas and multiple myel oma. The following is a brief overview of the use of pharmacologic agents for hormona l treatment of breast cancer and prostate cancer. It is not to be interpreted as a review on the treatment of these cancers. ________________________________________ HORMONES IN BREAST CANCER About 30% of patients with breast cancer respond to various hormonal manipulatio ns. This figure almost doubles when patients are selected on the basis of positi ve ESTROGEN RECEPTORS. Positive PROGESTERONE RECEPTORS in addition to positive e strogen receptor status increases the response rate even further. (Hormone recep tor positivity is a quantitative measurement, not merely presence or absence.) P atients with higher estrogen receptor positivity tend to be OLDER and have SLOWE R GROWING tumors than receptor negative patients. Tumors that have estrogen (pro gesterone) receptor positivity may respond to various hormonal manipulations, ad ditive or ablative: TAMOXIFEN - Tamoxifen is an ANTIESTROGEN that binds to estrogen receptors. It is very well tolerated. Usual dose is 10mg BID. There is little evidence for a dos e-response relationship, although occasional patients will respond to higher dos es after progressing on a lower dose. Ocular toxicity has been reported, primari ly when high doses have been used. Menopausal symptoms may be seen, especially i n premenopausal women. DIETHYLSTILBESTROL (DES) - DES is as effective as tamoxifen in advanced breast c ancer, but with more side effects. Thus, tamoxifen is commonly the first line ho rmonal agent. The usual dose of DES in breast cancer is 5mg TID. This may be ass ociated with nausea/vomiting, so treatment can be initiated with a lower dose (5 mg/day) and gradually increased to full dose over 1-2 wee s. Other side effects include SODIUM and WATER RETENTION and THROMBOEMBOLIC complications. AMINOGLUTETHIMIDE (AG) - AG may be used as a second (occasionally first or third ) line hormonal agent in breast cancer. AG bloc s the conversion of cholesterol

to delta-9-pregnenolone, an early step in adrenal steroid synthesis. More import ant in breast cancer, AG bloc s the peripheral (eg. in fat, muscle) conversion o f androstenedione to estrogen. With continued use of AG, the former mechanism is overridden by a compensatory increase in ACTH, thus AG is used in conjunction w ith HYDROCORTISONE (HC) (to suppress the reflex increase in ACTH). The latter me chanism, however, continues. And this mechanism is probably more important in br east cancer. Most side effects of AG are seen within the first six wee s of trea tment. These include LETHARGY, DIZZINESS and RASH. In most cases, the drug need not be discontinued. A common dosing schedule is: AG 250mg BID + HC 100mg/day x 2 wee s, then, AG 250mg QID + HC 40mg/day. AG dose is increased, as the drug ind uces its own metabolism. Higher initial doses of HC may help minimize occurrence of the rash due to AG. Newer agents (eg. ANASTROZOLE) are selective aromatase inhibitors. They wor by the second mechanism noted above, and don't affect adrenal steroid synthesis. Th eir relative place in therapy remains to be determined. PROGESTINS (eg. MEGESTROL 40mg QID) and ANDROGENS (eg. FLUOXYMESTRONE) may be us ed as second or third line hormonal agents. Megestrol is usually very well toler ated, frequently causing subjective improvement (eg. patients feel better). The major side effects of megestrol are weight gain (which is often desirable) and s weating. (The occurrence of weight gain with megestrol has lead to its use in ca ncer and AIDS cachexia.) Androgens are more li ely to be associated with adverse side effects such as masculinization. ________________________________________ PRINCIPLES OF USE OF HORMONE TREATMENT IN BREAST CANCER Responsive tumors commonly respond to subsequent hormonal manipulations after re sponse, then progression, with a previous hormone therapy. Response to hormonal therapy is slow (ie. it can't be evaluated for about 6-8 we e s). Fast growing tumors and/or visceral involvement respond less well to hormones. All hormonal agents have the potential to cause a "FLARE" of the disease, an app arent worsening with increased bone pain, hypercalcemia, etc. This is not necess arily an indication to discontinue the drug, although manifestations (eg. hyperc alcemia) should be corrected. Flare reactions, when they occur, do so with in th e first few wee s of therapy. WITHDRAWAL RESPONSES (ie. response seen when hormo ne therapy is discontinued) may also be seen in hormonally responsive tumors. Most of the above applies to the use of hormones in advanced breast cancer. Tamo xifen is also used as adjuvant treatment (ie. to prevent recurrence after primar y breast cancer) in certain populations. ________________________________________ HORMONES IN PROSTATE CANCER Hormones (or orchiectomy) are generally used in symptomatic STAGE D PROSTATE CAN CER. DES - 1mg/day - This dose causes less cardiovascular toxicity (edema, thrombosis , phlebitis) and is as effective as higher doses that have been tested. Sometime s 3mg/day is used in an attempt to decrease testosterone to castrate levels. The CLINICAL BENEFIT of 3mg versus 1mg is not clear. IMPOTENCE and DECREASED LIBIDO are associated with DES. Other side effects include NAUSEA, HOT FLASHES, and GY NECOMASTIA. Gynecomastia can be prevented by local irradiation to the breasts pr ior to starting treatment. LEUPROLIDE - Leuprolide was reported to be as effective and have less toxicity t han 3mg/day of DES. Leuprolide is a long-acting analog of luteinizing hormone re leasing hormone (LHRH), which inhibits gonadotropin (and thus testosterone) secr etion with chronic use. Leuprolide is given by daily subcutaneous injection or m onthly (or longer) depot IM injections. Leuprolide is also associated with IMPOT ENCE. Another common side effect is HOT FLASHES. Some non-hormonal treatments us ed to treat menopausal hot flashes in women (eg. clonidine) may be useful. GOSERELIN - Goserelin is another LHRH analog. It is administered monthly as a su

bcutaneous implant into the upper abdominal wall. Side effects are similar to th ose seen with leuprolide. FLUTAMIDE - Flutamide is an ANTIANDROGEN that inhibits either androgen upta e in to cells or the binding of androgen in the nucleus of target cells. Flutamide th us bloc s the effects of both testicular and adrenal androgen. It may thus be us ed in combination with an LHRH agonist to achieve "TOTAL ANDROGEN BLOCKADE". Ini tial treatment with LHRH agonists results in an increase in gonadotropin secreti on. This can cause a "flare", which can be dangerous in patients with IMPENDING SPINAL CORD COMPRESSION or URINARY TRACT OBSTRUCTION. Flutamide is used to BLOCK this INITIAL FLARE. Flutamide may also be used ALONE as hormonal therapy in sym ptomatic Stage D prostate cancer. The dose of flutamide is 250mg TID. In contras t to other hormonal therapies, flutamide appears to PRESERVE LIBIDO and SEXUAL P OTENCY. (This benefit is not seen when flutamide is combined with an LHRH agonis t.) The only side effect reported to occur more often with flutamide in combinat ion with LHRH agonist than with LHRH agonist alone is DIARRHEA. Other antiandrog ens include NILUTAMIDE and BICALUTAMIDE. High doses of KETOCONAZOLE (ie. 400mg q 8 hours) have been used to treat prostat e cancer. This is based on the ability of etoconazole to bloc adrenal and test icular androgen synthesis. In contrast to breast cancer, responses to sequential hormonal therapies in pros tate cancer are less common. ________________________________________ Previous Next SyllabusThe College of Pharmacy UICPHARM@uic.eduThe University of Illinois at Chicago Last modified: Dec 19, 1997

Malignant Effusions L. Bressler November, 1997 I. Malignant Pleural Effusions II. Malignant Pericardial Effusions III. Malignant Peritoneal Effusions ________________________________________ OBJECTIVES 1. Discuss, briefly, the factors responsible for the development of malignant ef fusions. 2. Discuss the treatments used in the management of malignant effusions. REQUIRED READING NONE SUGGESTED READING NONE ________________________________________ I. MALIGNANT PLEURAL EFFUSIONS The pleural space normally contains about 5-20ml of fluid. Usually the concentra tion of protein in this fluid is <2gm/dl. Factors that promote increased collect ion of fluid in this space (ie. a pleural effusion) include: increased capillary permeability, increased hydrostatic pressure (eg. in CHF), increased negative i ntrapleural pressure (eg. atelectasis), decreased oncotic pressure (eg. hypoalbu minemia), or increased pleural fluid oncotic pressure (eg. with pleural tumor gr owth). Impaired pleural lymphatic drainage also leads to accumulation of pleural fluid.

The most important factors contributing to the development of MALIGNANT PLEURAL EFFUSIONS are INCREASED CAPILLARY PERMEABILITY (from inflammation or disruption of capillary endothelium) and IMPAIRED LYMPHATIC DRAINAGE due to obstruction by tumor. These factors most commonly result from direct invasion of the pleural sp ace by primary or metastatic tumor. The most common tumors causing malignant pleural effusions are: LUNG CANCER, BRE AST CANCER and LYMPHOMAS. SYMPTOMS associated with malignant pleural effusions include: DYSPNEA, COUGH and CHEST PAIN. Dyspnea is due to pleural compression. Cough is nonproductive. It i s caused by compression of the bronchial walls by fluid. Inflammation of the par ietal pleura results in pleuritic chest pain. The severity of symptoms is related to the rapidity with which the fluid accumul ates rather than to the amount of fluid. Most effusions have more than 500ml of fluid. THORACENTESIS, the removal of the pleural fluid through a chest tube, is both di agnostic and therapeutic. The fluid is sent for analysis: cytology (to loo for the presence of malignant cells), protein (>3gm/dl in malignant effusions), spec ific gravity (>1.025 in malignant effusions), pleural/serum LDH (>0.6 in maligna nt effusions). Symptoms will improve with thoracentesis, but fluid removal alone will not generally be successful in controlling the effusion (ie. the recurrenc e rate in people treated with thoracentesis alone and followed for one month is 97%, with the majority of recurrences seen in 1-3 days). SCLEROSIS - This procedure produces fibrosis and obliterates small pleural blood vessels. It is done after the space occupied by the effusion is obliterated by thoracentesis followed by suction drainage. The purpose of sclerosis is to PREVE NT REACCUMULATION. The following agents have been used for sclerotherapy: QUINACRINE TALC NITROGEN MUSTARD THIOTEPA BLEOMYCIN DOXORUBICIN 5-FLUOROURACIL MITOXANTRONE DOXYCYCLINE The cytotoxic drugs wor by producing fibrosis, NOT BY EXERTING AN ANTINEOPLASTI C EFFECT. Systemic side effects (bone marrow suppression) can be seen with the i ntrapleural administration of cytotoxic drugs. TETRACYCLINE was among the most commonly used agents for sclerotherapy until rec ently, when the only parenteral preparation was removed from the mar et by the m anufacturer. A variety of other agents have been recommended in its place. The f ollowing represents some general information about the intrapleural administrati on of some of these agents. Individual procedures should be reviewed for each dr ug if needed. Patients are premedicated with opioid analgesics about 1/2 hour before treatment Bleomycin 60 units in 50ml D5W or NaCl, or doxycycline 500mg in 30ml NaCl, or mi toxantrone 30mg in 50-100ml NaCl, or nitrogen mustard (mechlorethamine) 20mg in 50-150ml NaCl, or thiotepa 30-45mg in NaCl is instilled through the chest tube. Lidocaine 100-300mg has been added to solutions to provide local anesthesia. The patient changes positions every 15 minutes for several hours (eg. lying flat , right side up, etc.). The chest tube clamp is removed and fluid drains, with suction, for about 24 hou rs. The chest tube drains by gravity, and when drainage is decreased (ie. to 50-100m l/day) and the lung remains re-expanded, the chest tube is removed. Note: The above is intended as a general overview of the sequence of events comm only observed in the management of malignant effusions. It is not intended as a step-by-step guide. TALC for pleurodesis is enjoying a resurgence in use in various centers. The pro

cedure for insufflation is different than that described above, and is usually d one in an operating room setting. The goals of sclerosis are the same. ________________________________________ II. MALIGNANT PERICARDIAL EFFUSIONS Malignant pericardial effusions are most common in BREAST and LUNG CANCERS. Hear t or pericardial involvement is also seen in leu emia, Hodg ins or non-Hodg ins lymphomas, melanoma, gastrointestinal cancers and sarcomas. Fluid accumulates in the pericardial space as a result of OBSTRUCTION OF LYMPHAT IC and VENOUS DRAINAGE OF THE HEART. Symptoms of pericardial effusions include DYSPNEA, COUGH, CHEST PAIN, ORTHOPNEA, PALPITATIONS, WEAKNESS, FATIGUE and DIZZINESS. CARDIAC TAMPONADE is the most se vere form of presentation. The occurrence of symptoms depends on how fast the fl uid accumulates, how much fluid accumulates and underlying ventricular function. TREATMENT of malignant pericardial effusions may involve PERICARDIOCENTESIS and SCLEROTHERAPY (eg. doxycycline, bleomycin, etc., similar to that discussed above for pleural effusions), or SURGERY. ________________________________________ III. MALIGNANT PERITONEAL EFFUSIONS When drugs are used in the management of malignant peritoneal effusions, SCLEROT HERAPY may also be similar to that noted above. ________________________________________ Previous Next SyllabusThe College of Pharmacy UICPHARM@uic.eduThe University of Illinois at Chicago Last modified: Dec 19, 1997

Chemotherapy - Induced Cardiac Toxicity L. Bressler November, 1997 ________________________________________ OBJECTIVES 1. List the antineoplastic drugs implicated in causing cardiac toxicity. 2. Describe the clinical picture(s) of antineoplastic-induced cardiac toxicity ( including ris factors, onset, manifestations, treatment, course, etc.). REQUIRED READING NONE SUGGESTED READING 1. Speyer JL et al.: Protective effect of the bispiperazinedione ICRF-187 agains t doxorubicin-induced cardiac toxicity in women with advanced breast cancer; N E ngl J Med 319:745-752, 1988 ________________________________________ CHEMOTHERAPY-INDUCED CARDIAC TOXICITY I. The most well- nown cause of chemotherapy-induced cardiotoxicity is DOXORUBIC IN (ADRIAMYCIN). There are different manifestations of doxorubicin cardiotoxicity: ARRHYTHMIAS - Arrhythmias are reported to occur acutely -during or within 24 hou rs of doxorubicin administration. The most common electrocardiographic (ECG) abn ormalities reported are nonspecific ST-T wave changes, decreased QRS voltage, si

nus tachycardia, supraventricular tachyarrhythmias, premature ventricular and at rial contractions, T-wave abnormalities and QT interval prolongation. Rarely, su dden death and life-threatening ventricular arrhythmias have been reported. Arrh ythmias appear to be more common in patients with abnormalities on baseline ECG. Drug treatment is generally not required, and future treatment is usually not c ompromised. For our purposes, the important aspect is recognizing that arrhythmi as may be drug-induced. CHRONIC CARDIOMYOPATHY - This is the most severe form of doxorubicin cardiotoxic ity and has been the subject of many discussions/trials in the literature. Cardi omyopathy is DOSE-RELATED. Overall, the incidence is reported to be less than 1% at cumulative doses less than 550mg/m2, and up to 30% at cumulative doses 560-1 155mg/m2. Morphologic damage increases progressively with increasing doses, alth ough the progression is slower in some individuals and faster in others. CARDIAC FUNCTION, HOWEVER, MAY REMAIN RELATIVELY NORMAL UNTIL A FAIR AMOUNT OF MORPHOLO GIC DAMAGE HAS OCCURRED. Morphologic damage has been quantitated by pathologists from samples obtained by myocardial biopsy. The cellular lesions are nown as "myofibrillar dropout". My ofibrillar dropout consists of swelling of the sarcoplasmic reticulum and, with more advanced stages of damage, complete loss of myofibrils. The quantitation sy stem goes from 0 to 3 (increasing numbers implying more damage to a greater numb er of cells). Effects on clinical function may be seen at biopsy scores of 2.5. Since some patients may receive high doses of doxorubicin without ever developin g cardiomyopathy and some develop cardiomyopathy at relatively low doses (ie. le ss than 550mg/m2 total dose), it would be beneficial to predict the development in individual patients. RISK FACTORS for the development of cardiomyopathy include TOTAL DOSE 450mg/m2 o r more, MEDIASTINAL IRRADIATION, AGE greater than 70 years. Other ris factors m ay be pre-existing cardiac disease and treatment with cyclophosphamide. Myocardial biopsies can be done in high ris patients, before the development of clinical cardiomyopathy, to predict whether or not they can safely receive more drug. With biopsy scores less than 2.5, the chance of developing congestive hea rt failure (CHF) if 100mg/m2 more drug is given is less than 10%. This chance in creases to 10-25% with grade 2.5 and to more than 25% with grade 3. So if patien ts with grade 2 don't receive any more drug, there is little li elihood of their developing CHF. Myocardial biopsies are not routinely available in most institu tions. Ejection fraction (EF) determined by radionuclide scanning has been sugge sted as the best noninvasive monitoring tool. For example, baseline EF can be ob tained in patients with ris factors. Then subsequent determinations (eg. every other dose or every 100mg/m2) can lead to decision points: EF less than 45%, dec rease in EF of greater than 5% to less than 50%, failure of EF to increase by at least 5% with exercise. These points may be indications to stop the drug or obt ain a biopsy, if possible. Other guidelines are available that incorporate a bas eline EF in all patients (ie. not just high ris patients). It should be noted that frequently, these decisions may not even need to be made (ie. total dose for an entire course of therapy is <450mg/m2 in a patient with no other ris factors, the disease progresses before a total of 450mg/m2, etc.). The CLINICAL MANIFESTATIONS of doxorubicin cardiomyopathy are those of severe bi ventricular CHF. Because of the progressive morphologic changes and the persiste nce of changes for a long time, symptoms have been reported to occur any time up to months after stopping the drug. Although CHF has been reported to have a hig h mortality rate, successful treatment is possible. Therefore symptoms of CHF sh ould be managed as CHF due to other causes. The incidence of cardiotoxicity has been reported to be less when doxorubicin is given as a PROLONGED INFUSION (ie. 96 hours) or in LOW WEEKLY doses instead of higher doses every three wee s. Various attempts have also been made to prevent cardiotoxicity. The most promising method of preventing doxorubicin cardiomyopathy appears to be DEXRAZOXANE (ICRF-187). It is thought to bloc the formation of oxygen free rad icals by chelating complexes between doxorubicin and iron. Doxorubicin can be re

duced to a semiquinone free radical that can react with molecular oxygen to yiel d free radicals: superoxide, hydroxyl. Iron must be present for these reactions to result in significant damage. Doxorubicin binds to iron and the iron-doxorubi cin complex catalyzes the free radical reactions. Classical free radical scaveng ers (tocopherol, N-acetylcysteine) do not bloc the reactions but ICRF-187, whic h is an iron chelator, can. In a randomized study, patients receiving doxorubici n-containing chemotherapy plus ICRF-187 had no biopsy scores of 2 or greater and a lower incidence of clinical CHF than the group receiving chemotherapy alone. Because of concern for a possible decrease in the antitumor effect of the anthra cycline, dexrazoxane is indicated AFTER a total cumulative dose of 300mg/m2 doxo rubicin. II. DAUNOMYCIN causes much the same type of cardiomyopathy as doxorubicin. The i ncidence has been reported to be 1.5% at a total dose of 600mg/m2 and 12% at 100 0mg/m2. III. IDARUBICIN (IDAMYCIN) is associated with cardiac toxicity similar to that s een with doxorubicin or daunomycin. IV. MITOXANTRONE is associated with cardiomyopathy, especially in patients who h ave received previous doxorubicin, but the incidence is less than that seen with doxorubicin. Cumulative dose recommendations for minimizing the occurrence of c ardiomyopathy are 160mg/m2 in patients without prior doxorubicin and 100mg/m2 in patients with prior doxorubicin. These cutoffs are also viewed in light of the patients underlying disease and the need for continued drug. (approximate equiva lent doses are 60mg/m2 doxorubicin and 12mg/m2 mitoxantrone) Other anthracyclines currently under study may, in some cases, be less cardiotox ic than doxorubicin. Similarly, the LIPOSOMAL ANTHRACYCLINES may be less cardiot oxic. V. 5-FLUOROURACIL (5-FU) has been implicated as a cause of cardiotoxicity. The t oxicity manifests as ischemic pain within hours of a dose. Myocardial infarction has been reported. Electrocardiogram changes consistent with ischemia and respo nse/prevention with nitrates have been noted. The toxicity is not clearly dose r elated, although it has been suggested that the incidence is considerably higher when 5-FU is given as a continuous infusion rather than a bolus (10% versus abo ut 1%). Some patients have received further treatment safely, but the need for 5 -FU in the face of cardiotoxicity may obviously be re-evaluated. VI. CYCLOPHOSPHAMIDE has been reported to cause cardiac necrosis resulting in th e acute or subacute development of CHF. This has been seen in some patients afte r the use of very high does (120-140mg/ g) in preparation for bone marrow transp lant. CYCLOPHOSPHAMIDE as well as the VINCA ALKALOIDS have also been reported to cause ischemic cardiac toxicity. ________________________________________ Previous Next SyllabusThe College of Pharmacy UICPHARM@uic.eduThe University of Illinois at Chicago Last modified: Dec 19, 1997

GI Toxicity From Chemotherapy L. Bressler November, 1997 I. Explanation of terms II. Vomiting mechanisms

III. Consequences of inadequately treated nausea and vomiting IV. Emetic Mechanisms of chemotherapeutic agents V. Antiemetics VI. Conclusions/Guidelines VII. Suggestions VIII. Stomatitis IX. Other GI toxicities: Diarrhea ________________________________________ OBJECTIVES 1. Discuss the (potential) mechanisms of chemotherapy-induced nausea and vomitin g. 2. Discuss the mechanism(s) of antiemetic drugs. 3. Discuss the phenomena of anticipatory nausea and vomiting. 4. Select an antiemetic regimen, noting patient specific concerns (eg. type of c hemotherapy, patient preferences). 5. Discuss the side effects of antiemetic treatments, and be able to prevent or minimize them. 6. Discuss the mechanism of chemotherapy-induced stomatitis. 7. Suggest, in writing, a rational treatment for chemotherapy-induced stomatitis . 8. List those chemotherapeutic agents commonly associated with diarrhea. 9. Suggest, in writing, a rational treatment for chemotherapy-induced diarrhea. REQUIRED READING NONE SUGGESTED READING NONE ________________________________________ I. Explanation of terms A. NAUSEA - a psychic experience of human beings which may or may not be associa ted with vomiting. It is a subjective phenomenon difficult to identify in experi mental animals. B. VOMITING - EMESIS; the forceful expulsion of the gastro-intestinal contents t hrough the mouth. C. RETCHING - the labored rhythmic activity of respiratory musculature which usu ally precedes or accompanies vomiting. Retching is not ordinarily accompanied by opening of the mouth. ________________________________________ II. Vomiting mechanisms A. VOMITING CENTER (VC) - The VC coordinates the act of vomiting. It is located in the reticular formation in the medulla. The VC is anatomically close to other loci in the medulla, specifically, those concerned with salivation, spasmodic r espiratory movements (eg. retching), the inspiratory and expiratory centers, and the vasomotor center. Activities of all of these centers are involved in the mo tor expression of vomiting. Drugs don't usually stimulate the VC directly. Inste ad, the VC receives input from the chemoreceptor trigger zone (CTZ), from the so -called "periphery", from higher brain centers and from the vestibular apparatus . B. CTZ - The CTZ is located in the floor of the fourth ventricle in the medullar y surface. It is more superficially located than the VC. It is exposed to both b lood and CSF, and it is sensitive, as the name implies, to emetic chemicals. Man y drugs that cause nausea and vomiting, but by no means all, do so via stimulati on of the CTZ. The prototype for studying CTZ stimulation (eg. in animals) is ap omorphine. C. "PERIPHERY" - "Peripheral" input to the VC is through vagal and sympathetic a fferents, originating primarily in the pharynx and GI tract. Note that parentera

lly administered drugs can cause nausea and vomiting by this mechanism. The prot otype for studying peripheral stimulation of the VC (eg. in animals) is intragas tric copper sulfate. D. HIGHER BRAIN CENTERS - Higher brain centers can also provide input to the VC. This may be in response to such stimuli as taste and smell. Higher brain center s probably are involved in NAUSEA, as well as in the development of ANTICIPATORY NAUSEA and VOMITING. E. VESTIBULAR APPARATUS - The vestibular apparatus provides input to the VC, pro bably by way of the CTZ. It is important in motion sic ness, but is thought not to have a major role in chemotherapy-induced nausea and vomiting. A multitude of neurotransmitters and receptors may be involved in the transmissi on of impulses to the VC. Of recent interest is the role of SEROTONIN in chemoth erapy-induced nausea and vomiting. NAUSEA and VOMITING are SEPARATE phenomena. It may be that an emetic stimulus di vides, producing vomiting, as described above, and nausea, a central phenomenon. ________________________________________ III. Consequences of inadequately treated nausea and vomiting A. NONCOMPLIANCE with chemotherapy 1. Noncompliance due to nausea and vomiting has been estimated to occur in as ma ny as 25-50% of patients. 2. Noncompliance is of particular concern in patients with potentially curable d iseases (eg. Hodg ins, testicular cancer). B. PATIENT DISCOMFORT 1. Time off from wor or school, with resultant financial consequences. 2. Disruption of personal life. C. MEDICAL COMPLICATIONS 1. ESOPHAGEAL TEAR (Mallory-Weiss syndrome) or pathologic BONE FRACTURE from vio lent or repeated retching or vomiting. 2. DEHYDRATION 3. Prolonged ANOREXIA and MALNUTRITION may compromise the patient's ability to t olerate normal dosages of chemotherapy. 4. METABOLIC ABNORMALITIES from vomiting: metabolic al alosis, hypo alemia, hypo chloremia 5. ANTICIPATORY NAUSEA and/or VOMITING a. Anticipatory nausea and/or vomiting are nausea or vomiting that occur before administration of, and in anticipation of, chemotherapy. b. Anticipatory symptoms have been reported in as many as one-third of patients receiving chemotherapy. c. Anticipatory symptoms are a conditioned response. The best treatment for anti cipatory nausea/vomiting is prevention, by minimizing post chemotherapy nausea a nd vomiting in the first place. ________________________________________ IV. EMETIC MECHANISMS of chemotherapeutic agents A. Emetic mechanisms (from those mechanisms and neurotransmitters discussed abov e) are nown for only a few drugs. 1. NITROGEN MUSTARD emesis in dogs is mediated through the CTZ, and in cats, thr ough the periphery and higher brain centers. 2. CISPLATIN emesis is mediated through the periphery and appears to be related to serotonin. 3. For most other drugs, the mechanism of emetic effect is un nown. In some case s, emetic mechanism is inferred indirectly from results of antiemetic use. B. It is li ely that there are several mechanisms for chemotherapy-induced nause a and vomiting, perhaps even more than one mechanism for the same drug. This ma es it unli ely that any one antiemetic will be successful against all chemothera py-induced nausea and vomiting, and also supplies a rationale for combination an tiemetic therapy. ________________________________________

V. ANTIEMETICS A. PHENOTHIAZINES 1. Proposed antiemetic mechanism: bloc ade of dopamine receptors in the CTZ. 2. Piperazines (PROCHLORPERAZINE, THIETHYLPERAZINE, PERPHENAZINE) are the most p otent antiemetics (among the phenothiazines) but also have the greatest tendency to cause extrapyramidal side effects (EPS). 3. Piperidines (THIORIDAZINE) are poor antiemetics. 4. Aliphatics (CHLORPROMAZINE) are less potent than piperazines, but are associa ted with less EPS. Chlorpromazine is often preferred in children for this reason (less EPS). 5. GUIDELINES for use a. Phenothiazines are often successful in minimizing nausea and vomiting from dr ugs with LOW to MODERATE EMETOGENIC POTENTIAL (eg. METHOTREXATE, 5-FLUOROURACIL) . b. Use a variety of dosage forms: parenteral, oral, rectal suppositories (eg. in case patients can't eep down oral medications). c. Duration of antiemetic effect is three to four hours, less than the usual rec ommended dosing intervals. Antiemetics can often be given at these more frequent dosing intervals. d. Occasionally, doses higher than those usually recommended may be administered , and may be more effective (eg. prochlorperazine 30-40mg as a short IV infusion ). e. SIDE EFFECTS accompanying short-term use i. EPS - ACUTE DYSTONIC REACTIONS (spasms of the nec or bac , with torticollis or opisthotonos in severe cases; difficulty swallowing, trismus, protrusion of t he tongue or oculogyric crisis). ii. EPS - AKATHISIA - motor restlessness ranging from a feeling of inner disquie t to inability to sit or lie quietly (agitation, jitteriness) or to sleep. iii. EPS - TREATMENT - DIPHENHYDRAMINE 25-50mg PO or parenterally (ie. if swallo wing is difficult) or BENZTROPINE 2mg PO or parenterally. BENZODIAZEPINES may al so be useful for a athisia. iv. autonomic effects - hypotension, dry mouth, urinary retention v. SEDATION B. BUTYROPHENONES - DROPERIDOL and HALOPERIDOL 1. Proposed antiemetic mechanism: bloc ade of dopamine receptors in the CTZ. 2. Clinically, butyrophenones are used as more "potent" antiemetics than phenoth iazines. This is somewhat empiric. Higher doses of phenothiazines may be just as "potent". (see above) 3. SIDE EFFECTS are qualitatively similar to phenothiazines. The doses are less well defined. 4. Suggested STARTING DOSES: DROPERIDOL 1.25mg IV push or IM; HALOPERIDOL 2.5mg IV push or IM (these are not necessarily equipotent and are somewhat empirically derived; IV doses may also be given as short infusions). Doses may repeated at four hour intervals and increased or decreased based on efficacy and side effect s. Oral haloperidol might be used by patients at home, following parenteral dosi ng. C. METOCLOPRAMIDE 1. High doses are more effective than low (standard, eg. 10mg QID) doses for che motherapy-induced nausea and vomiting. High doses bloc serotonin receptors as w ell as dopamine receptors. 2. A commonly reported dose/schedule is 2mg/ g in 50ml D5W or 0.9% NaCl infused over 15-30 minutes. This dose is repeated at approximately two hour intervals fo r a total of five times. a. Oral metoclopramide is less convenient to use, being only available in 10mg t ablets. b. Lower and higher doses of IV metoclopramide (eg. 1-3mg/ g) have also been use d. Higher doses might be used for outpatients who can only receive one or two (a s opposed to five) doses. 3. EPS, similar to those seen with phenothiazines and butyrophenones, also occur

with metoclopramide, as metoclopramide also bloc s dopamine receptors in the CT Z. 4. In addition, metoclopramide has a PERIPHERAL EFFECT, enhancing forward motili ty of the GI tract (ie. the "opposite" of vomiting). This may also result in DIA RRHEA. 5. SEDATION is also reported with metoclopramide. D. STEROIDS 1. Steroids have been reported to have an antiemetic effect, although the mechan ism remains speculative. In addition, most literature supports the use of dexame thasone in combination with other agents for highly emetogenic chemotherapy. 2. Much of the literature documenting a beneficial effect of steroids describes patients who received chemotherapy that was not clearly highly emetogenic (eg. C YCLOPHOSPHAMIDE, METHOTREXATE, 5-FLUOROURACIL). 3. The steroids most commonly used are DEXAMETHASONE and METHYLPREDNISOLONE (one suggested dose of dexamethasone: 20mg IV then 10mg PO every six hours for 24 ho urs). 4. Short term use of steroids in this setting isn't accompanied by many side eff ects. PERINEAL BURNING has been reported with IV injection of steroids. This can be minimized by prolonging the rate of injection. E. CANNABINOIDS 1. THC (DRONABINOL) is mar eted for chemotherapy-induced nausea and vomiting unr esponsive to more "standard" treatment. It is also recommended for delayed or pr olonged nausea and vomiting (symptoms lasting longer than 24 hours, usually foll owing treatment with cisplatin). This latter use probably requires better docume ntation before it can be accepted as "standard". 2. The antiemetic mechanism is unclear; THC may act at higher brain centers that transmit impulses to the vomiting center. 3. Usual dose of THC is 5-10mg/m2 PO every three to four hours. Doses for delaye d or prolonged nausea or vomiting are generally lower (eg. 2.5-5mg twice a day). 4. The most common SIDE EFFECTS are DROWSINESS and a "HIGH". Dizziness and redde ning of the eyes are also seen. 5. The cost of THC can be prohibitive - thus, it remains a useful second or thir d choice antiemetic. F. BENZODIAZEPINES 1. Benzodiazepines are frequently used in combination, or sometimes alone, to tr eat chemotherapy-induced nausea and vomiting. a. Benzodiazepines provide an ANTIANXIETY effect, quite useful in nervous patien ts. b. Benzodiazepines produce ANTEROGRADE AMNESIA, leaving the patient with a "fuzz y" recollection of the time of chemotherapy and shortly thereafter. This may hel p to PREVENT ANTICIPATORY NAUSEA and VOMITING. c. Benzodiazepines have been reported to have a separate ANTIEMETIC effect. The mechanism of such an effect is unclear. Perhaps it is an antinausea effect, acti ng on the psychic component. 2. LORAZEPAM has been used in various doses and by various routes of administrat ion (eg. 0.05mg/ g IM, 3mg PO, 4mg IV). 3. ALPRAZOLAM has been reported to be useful in patients with anticipatory sympt oms, when given beginning the night before chemotherapy. G. SEROTONIN ANTAGONISTS 1. Recent literature has focused on serotonin as a mediator in chemotherapy-indu ced nausea and vomiting. 2. Selective antagonists of serotonin at the S3 (serotonin3) receptor (ondansetr on, granisetron) have become among the most widely used antiemetics. Dolasetron was very recently mar eted. a. Results with serotonin receptor antagonists are quite positive for nausea and vomiting due to cisplatin as well as other chemotherapeutic agents, although th ey are very expensive to use. b. Serotonin receptor antagonists have no antidopaminergic activity and therefor e do not cause EPS. They also ar not sedating. They are very well tolerated; the most common SIDE EFFECT reported is HEADACHE.

c. The recommended dose of ondansetron is 32mg IV as a single dose or 0.15mg/ g IV as a short infusion before chemotherapy and 4 and 8 hours after chemotherapy. Other, widely used, lower doses may be similarly effective although there is le ss literature support for them. Oral tablets are mar eted for cyclophosphamide-c ontaining chemotherapy regimens. The oral dosage form is also li ely to be used for "follow-up" after IV dosing in patients receiving other chemotherapeutic age nts (eg. cisplatin). d. The recommended dose of granisetron is 10mcg/ g over 5 minutes, as a single I V dose before chemotherapy. Oral granisetron is also recommended instead of a pa renteral serotonin antagonist. Whether such use is, indeed, as effective and les s costly than parenteral agents is still being debated. e. Ondansetron and granisetron appear to be equivalent in efficacy.(Dolasetron i s probably of similar effectiveness.) There is however, little comparative data using 10mcg/ g of granisetron and 32mg of ondansetron. Most of the supportive li terature for granisetron describes higher doses (3mg or 40mcg/ g). Cost to indiv idual institutions or buying groups may be the ultimate determinant in the choic e of serotonin receptor antagonist. I would not recommend either of these drugs for most mildly or moderately emetogenic chemotherapy regimens, specific patient concerns notwithstanding. ________________________________________ VI. CONCLUSIONS/GUIDELINES A. CISPLATIN is the most highly emetogenic drug, causing nausea and vomiting in 90% or more (but not 100%) of patients. B. Other HIGHLY EMETOGENIC drugs include DTIC, DOXORUBICIN, NITROGEN MUSTARD, and I FOSFAMIDE. C. DTIC is often given daily for five days. Nausea and vomiting commonly decrease o ver the five day period. D. BLEOMYCIN and VINCRISTINE cause almost no nausea or vomiting E. Nausea/vomiting that are not anticipatory do not occur immediately. The shortest "lag time" is about 30-60 minutes, and "lag time" may be six hours or longer (e g. after CYCLOPHOSPHAMIDE). It should be remembered, however, that anticipatory nausea and vomiting still cause much discomfort for patients and may still requi re treatment. F. Nausea/vomiting, when they do occur, commonly IMPROVE WITHIN 24 HOURS. G. The EXCEPTION to this is CISPLATIN, following which nausea, vomiting, or anorexi a may last for a wee or more. H. Nausea/vomiting from CISPLATIN are DECREASED by giving the drug as a PROLONGED I NFUSION (eg. 24 hours). I. Antiemetics should be started BEFORE chemotherapy administration - well before n ausea and vomiting might be expected to be seen. J. Many of the antiemetics discussed above are used acutely, before chemotherapy. A ttention should be paid to follow-up with oral or rectal medications, lower dose s, or even continued dosing with the same drug. This assures treatment throughou t the expected duration of nausea and vomiting, or in the event of delayed or pr olonged symptoms. Having said that, it is commonly believed that most antiemetic s display decreased effectiveness when given over multiple days (eg. with daily x five cisplatin). Consistent follow-up with appropriate adjustments is importan t. K.

The choice of antiemetic is OFTEN EMPIRIC. The literature supports the use of an y of a number of drugs, even if a pharmacologic rationale (ie. based on mechanis m of nausea and vomiting of the particular chemotherapeutic agent[s]) is absent. L. The subjective nature of nausea and the degree of patient discomfort often seen may justify this empiric approach. M. Nausea and vomiting are DISTINCT ENTITIES. They may occur together or separately . The presence of (and disappearance of) nausea must be evaluated separately fro m vomiting. N. ANTICIPATORY NAUSEA and VOMITING are very real phenomena. The way to prevent the m would appear to be to prevent post chemotherapy nausea and vomiting from occur ring in the first place. O. SIDE EFFECTS play an important role in the patient's overall assessment of antie metic effectiveness. Patients may prefer a drug that, objectively, has not helpe d that much, over a drug with side effects that they find intolerable. P. Consider the patient's needs - do they want to be awa e or asleep? Do they have a companion if they are at home, or with whom they can travel to and from an out patient facility? Are they at ris of aspiration? Ma e sure sleeping patients li ft their heads so as not to aspirate if they vomit. Q. DEXAMETHASONE/METOCLOPRAMIDE is the most widely used combination for DELAYED nau sea and vomiting. Low doses of metoclopramide are used in this setting. ________________________________________ VII. SUGGESTIONS (see K above) A. The following regimens can be used for highly emetogenic chemotherapy. Some o f these regimens (ie. haloperidol and lorazepam) can be very sedating. This may be beneficial, but certainly needs to be considered in view of the patients' des ires, responsibilities, etc.: metoclopramide haloperidol/lorazepam high dose prochlorperazine ondansetron or granisetron or dolasetron chlorpromazine/secobarbital* *secobarbital can provide effects qualitatively li e those of lorazepam B. For less highly emetogenic chemotherapy: droperidol prochlorperazine dexamethasone C. THC as second line treatment for either of the above categories D. DIPHENHYDRAMINE prophylactically with any of the above to prevent EPS and/or increase sedation. E. Dexamethasone in combination with those regimens listed in A above ________________________________________ VIII. STOMATITIS As is the case with myelosuppression and alopecia, stomatitis (oral mucositis) r esults from the effects of chemotherapy on rapidly proliferating tissues - in th is case, epithelium in the mouth. Although mucositis can involve the esophagus, ileum or colon, stomatitis is the most common. Stomatitis is PAINFUL, which may IMPAIR NUTRITIONAL INTAKE. In addition, mucosal brea s predispose to secondary INFECTIONS. Among the chemotherapeutic agents most li ely to cause stomatitis are 5-FLUOROUR

ACIL, METHOTREXATE, BLEOMYCIN and DOXORUBICIN. SYMPTOMS of stomatitis generally begin 3-4 days after chemotherapy. They include tingling, dryness, pain, burning, sensitivity of teeth and gums, dysphagia and impaired taste. Symptoms progress, becoming the most severe within a wee . Lesio ns appear as an ULCERATION with ERYTHEMATOUS BORDERS. The lips, tongue, gums, bu ccal mucosa, palate or floor of the mouth may be involved. The lesions slowly HE AL (barring infection) in 7-10 days. TREATMENT of stomatitis is SYMPTOMATIC - PAIN RELIEF and HYGIENE. Various agents , alone or in combination, have been used. None have been studied in a comparati ve fashion so superiority of one treatment over another cannot be stated. VISCOUS LIDOCAINE and DICLONINE 0.5% are used for LOCAL ANESTHESIA. A common com bination is DIPHENHYDRAMINE/KAOLIN-PECTIN in equal parts. Although diphenhydrami ne is reported to have local anesthetic properties, documentation of this effect with the concentrations used clinically is scanty. Kaolin-pectin "soothes" or " coats", and prolongs the contact time of other agents with the oral mucosa. Sometimes combinations may mas the unpleasant taste of viscous lidocaine. For e xample: VISCOUS LIDOCAINE/MAALOX/MOUTHWASH (alcohol free if possible). MAALOX pr obably wor s as the aolin-pectin above, and MOUTHWASH provides an ANTISEPTIC as well as a FLAVOR. Alcohol in mouthwashes may intensify burning or drying. Extemporaneously prepared suspensions of SUCRALFATE have been described for use in stomatitis. It is suggested that sucralfate may help heal oral lesions. This is similar to its effects in peptic ulcer disease. A suspension of ALLOPURINOL has been used to minimize stomatitis due to 5-fluoro uracil (5-FU). This is based on the premise that allopurinol results in inhibiti on of one of the activation pathways of 5-FU (ie. a form of biochemical modulati on). CHLORHEXIDINE GLUCONATE (Peridex?) may be used to decrease secondary infections in stomatitis. It has been reported to decrease plaque and gingivitis as well as decreasing mucositis and bacteria. The dose is 15cc three times a day (swish & spit). TANNIC ACID (Zilactin?) is available without a prescription and may provide reli ef for painful stomatitis. After an initial burning sensation, it forms a thin p rotective film that can often withstand eating and drin ing. Patient acceptability is obviously an important consideration in choosing a trea tment for symptomatic relief of stomatitis. Patients must also be cautioned so a s not to aspirate food, bite their tongue, etc., following the use of local anes thetics. It may be necessary to swallow the anesthetic (eg. lidocaine) in order to reach some painful lesions, requiring a greater volume than that which can be dabbed on a more easily accessible lesion. Systemic side effects (eg. seizures) have been reported following the use of viscous lidocaine. Patients should use the minimum amount necessary to provide relief. ________________________________________ IX. OTHER GI TOXICITIES: DIARRHEA Several chemotherapeutic agents are associated with the development of diarrhea. Although alterations in colonic mucosa are a li ely mechanism for such, there m ay be other contributing factors as well. Diarrhea can be severe, with resultant fluid and electrolyte disturbances, and even fatality. Two of the most common c auses of diarrhea include 5-FLUOROURACIL and IRINOTECAN. Management of 5-FU-induced diarrhea is usually nonspecific and includes opioids (loperamide, diphenoxylate), aolin-pectin, or, occasionally, octreotide. IRINOTECAN is associated with acute diarrhea (eg. during or shortly after drug a dministration) that is thought to be cholinergic mediated. It is recommended tha t such diarrhea be treated with atropine. "High dose" loperamide is recommended for late irinotecan-induced diarrhea (eg. 4mg at the onset of diarrhea, then 2mg every 2 hours until diarrhea-free for 12 hours). ________________________________________ Previous Next SyllabusThe College of Pharmacy

UICPHARM@uic.eduThe University of Illinois at Chicago Last modified: Dec 19, 1997

GU and Electrolyte Toxicities L. Bressler November, 1997 ________________________________________ I. TUMOR LYSIS SYNDROME Tumor lysis syndrome is characterized by hyperuricemia, hyper alemia, hyperphosphatemia and hypocalcemia. It is due to the rapid release of the intracellular contents of tumor cells. Tumor lysis syndrome is seen with large tumor burdens with high growth fractions that are very sensitive to chemotherapy . Examples include high-grade lymphomas and leu emias with high leu ocyte counts. Tumor lysis syndrome is seen less often with solid tumors. It can be tre ated/prevented with HYDRATION, ALLOPURINOL 300-900 mg/day, and URINARY ALKALINIZ ATION to pH > 7. (This can be achieved with 50-lOO mEq sodium bicarbonate per li ter of fluid, with subsequent adjustment based on urine pH.) Dialysis may be required. A. HYPERURICEMIA results from the action of xanthine oxidase on hypoxanthin e and xanthine. It can lead to URATE NEPHROPATHY with resultant renal failure. B. HYPERKALEMIA associated with tumor lysis syndrome can lead to ARRHYTHMIA S. It can be treated with KAYEXALATE. C. HYPERPHOSPHATEMIA can also lead to renal failure. D. HYPOCALCEMIA results from hyperphosphatemia. It can lead to MUSCLE CRAMP S, ARRHYTHMIAS, or TETANY. Hypocalcemia may be treated with CALCIUM GLUCONATE. ________________________________________ II. STERILE HEMORRHAGIC CYSTITIS It is seen with cyclophosphamide and ifosfamide. It is thought to be due to an a l ylating metabolite, acrolein. Hemorrhagic cystitis has been seen after single high doses or prolonged low dose s. Patients may be asymptomatic or they may present with symptoms of cystitis (e g. burning, frequency). Hematuria may be microscopic (detectable only on urinaly sis) or gross . The potential danger accompanying hemorrhagic cystitis is BLOOD LOSS. HYDRATION is commonly employed to prevent hemorrhagic cystitis from cyclop hosphamide. When possible, the drug should be given early in the day, followed b y hydration and FREQUENT VOIDING (eg. every few hours). MESNA is always given wi th ifosfamide (and it may be used with cyclophosphamide) to prevent hemorrhagic cystitis. MESNA provides a substrate for acrolein to al ylate. ________________________________________ III. HYPOMAGNESEMIA FROM CISPLATIN is a common electrolyte abnormality. Magnesium falls in many patients who receive cisplatin. Unless it is very low (e g.< 1) or accompanied by hypocalcemia, hypomagnesemia is usually asymptomatic. A lthough magnesium replacement is frequently underta en, it is of questionable va lue in the absence of other electrolyte abnormalities. Urinary magnesium loss is increased and frequently continues even after cisplatin therapy is stopped. Thu s administered magnesium may simply be lost in the urine. It has been suggested that treatment is only necessary in patients who have other electrolyte abnormal ities, or who are symptomatic. ________________________________________ IV. HYPONATREMIA FROM CYCLOPHOSPHAMIDE It has been seen following high doses (eg. usually after doses of > 50mg/ g). It is characterized by a decrease in urine output occurring 6 to 8 hours after dru g administration, weight gain, increase in urine osmoiality and decrease in seru

m osmolality. The syndrome, resembling SIADH, is generally self-limiting. Furose mide can be given to preserve urine output and prevent symptomatic hyponatremia; potassium would be required to prevent hypo alemia. (Note that the possibility of this syndrome does not preclude the hydration suggested above to prevent hemo rrhagic cystitis. The latter is much more common, and the former has been report ed primarily after high doses.) ________________________________________ V. CISPLATIN NEPHROTOXICITY In the past, nephrotoxicity secondary to tubular damage, was the dose-limiting t oxicity of cisplatin. Increases in BUN and creatinine, and decreases in CrCl may be seen shortly after cisplatin therapy. Usually, with doses < 100mg/m2 , nephr otoxicity is mild and reversible. It is no longer the dose-limiting toxicity, as it may be prevented or minimized by the use of hydration immediately before and following drug administration. Mannitol has also been used to ensure diuresis a nd prevent nephrotoxicity, as has furosemide. Caution should be ta en so as not to dehydrate patients if diuresis is greater than hydration. Hypertonic saline has been used to prevent nephrotoxicity from higher doses of c isplatin (eg. 40mg/m2/day x 5 days). DDTC (diethyldithiocarbamate), a heavy metal chelator, has also been used as an investigational agent to prevent cisplatin nephrotoxicity. Amifostine, a recently mar eted protectant, is reported to decrease the nephroto xicity (as well as some other toxicities) of cisplatin or other al ylators. Its exact place in therapy remains to be determined. Currently it is approved for us e with cisplatin in advanced ovarian or non-small cell lung cancer. Frequent mon itoring for hypotension is required and amifostine can worsen the nausea and vom iting seen with cisplatin. ________________________________________ VI. Nephrotoxicity It has been associated with HIGH DOSE METHOTREXATE. High dose usually refers to doses > 1 gm/m2 and is given in conjunction with leucovorin. Nephrotoxicity is t hought to be due to precipitation of the metabolite of methotrexate in an acidic urine, leading to renal tubular injury. Acute renal failure due to obstruction can result. Further, elimination of methotrexate will be inhibited, leading to s evere toxicity. Nephrotoxicity can be prevented with hydration (eg. 3L/m2 x 24 h ours) and urinary al alinization to maintain urine pH >= 6.5. ________________________________________ VII. MITOMYCIN It has been associated with renal failure due to a hemolytic-uremic syndrome. Th ere is no consistently effective treatment, although recovery has been seen afte r temporary dialysis. ________________________________________ VIII. STREPTOZOCIN It is a nitrosourea derivative, is also associated with renal failure. The earli est sign is hypophosphatemia, and the most frequent sign is proteinuria. Urinaly ses should precede each dose of streptozocin. If the drug is stopped early (ie. when mild proteinuria is the only abnormality), toxicity is reversible. If the d rug is continued, increases in BUN and creatinine can follow, and nephrotoxicity can be irreversible. ________________________________________ IX. Renal failure is associated with nitrosoureas (BCNU, CCNU). Azotemia and increas es in creatinine have been seen following prolonged use and high cumulative dose s (eg. 1200 mg/m2). Most reports are in children treated for brain tumors. ________________________________________ Previous Next SyllabusThe College of Pharmacy

UICPHARM@uic.eduThe University of Illinois at Chicago Last modified: Dec 19, 1997

The Pulmonary Toxicity of Antineoplastic Agents Terry L. Stonich, Pharm.D. (with modifications by L. Bressler) Spring , 1998 I. Introduction II. Mechanisms of pulmonary injury III. Ris factors IV. Clinical Syndromes V. Diagnosis VI. Example VII. Other Antineoplastic agents VIII. Conclusion ________________________________________ OBJECTIVES 1. List five proposed mechanisms of pulmonary injury induced by antineoplastic a gents. 2. List five ris factors for development of antineoplastic induced pulmonary to xicity. 3. Discuss three clinical syndromes of pulmonary toxicity identified with the an tineoplastic agents. 4. Discuss the incidence, ris factors, treatment and outcome of bleomycin induc ed pulmonary toxicity. 5. List the major categories of antineoplastic agents reported to cause pulmonar y injury. REQUIRED READING NONE SUGGESTED READING 1. Cooper J et al: Drug induced pulmonary disease - Part I: Cytotoxic drugs; Am Rev Resp Dis 133:321-340 (1986) 2. DeVita V et al (eds): Cancer - Principles and Practice of Oncology, 3rd Editi on, 2162-2219 (1989) 3. Ginsbery S et al: The pulmonary toxicity of antineoplastic agents; Sem Oncol 9(1):34-51 (1982) 4. Batist G, Andrews J: Pulmonary toxicity of antineoplastic drugs; J Am Med Ass oc 246(13):1449-1453 (1981) ________________________________________ I. INTRODUCTION Although antineoplastic agents play an invaluable role in the treatment of malig nancies, there are toxicities inherent to their use. A serious and sometimes dos e limiting toxicity is pulmonary injury. ________________________________________ II. MECHANISMS OF PULMONARY INJURY Pulmonary toxicity secondary to antineoplastic drugs may be due to a variety of mechanisms. There are five major postulates to explain the development of this t oxicity. Generally it is thought that antineoplastics induce pulmonary injury by disturbing homeostatic mechanisms (ie. causing an imbalance between inflammator y reactions that may cause pulmonary damage and protective detoxification reacti

ons) for the following systems: A. Oxidant/Antioxidant System Oxidant molecules (eg. O2, H2O2, OH, HOCl) that are formed within phagocytic cel ls such as monocytes, macrophages and neutrophils may participate in redox react ions resulting in fatty acid oxidation that can lead to membrane instability and perhaps autologous cytotoxicity. Similarly, it is thought that these oxidant sp ecies may initiate damaging inflammatory reactions. Normally, antioxidant defens e mechanisms (superoxide dismutase, glutathione peroxidase, alpha tocopherol) pr ovide the necessary balance to offset the oxidant effects. When antineoplastic d rugs are administered, there may be a disturbance of this homeostasis resulting in pulmonary injury. B. Immunologic System Even in the "healthy" state, pulmonary host cells can exaggerate toxic reactions caused by exposure to substances that initiate or activate the immunologic syst em. Pulmonary cells release mediators that activate and attract inflammatory cel l types li e eosinophils, monocytes, neutrophils, etc. To counterbalance the amp lified effects of the immunologic system that may result in pulmonary tissue dam age, other tolerant cells (eg. lymphocytes, alveolar macrophages) exist. It is p ostulated that when cytotoxic drugs are administered, there is a disturbance of this usual homeostasis of toxic reaction and tolerant suppressor cells, resultin g in pulmonary injury. C. Matrix Repair System Normally, proliferation of fibroblasts leading to collagen deposition is helpful in repairing or limiting cell injury. However, excessive deposition of collagen can result in structure impairment. It has been postulated that when antineopla stic drugs are administered, the homeostatic control of fibroblast proliferation and collagen deposition is disrupted. D. Proteolytic System Neutrophils, macrophages, and other inflammatory cells produce a number of prote olytic enzymes that are associated with a myriad of pulmonary disturbances. Prot eolytic enzymes are normally controlled or inactivated by protease inhibitors th at are mediated by oxidant molecules. It is thought that although antineoplastic drug parent molecules do not affect this homeostasis, their oxidant radicals ma y inactivate protease inhibitors, thereby allowing proteolytic enzymes to functi on unopposed. E. Central Nervous System The CNS is thought to provide some control over pulmonary capillary permeability . It has been postulated that cytotoxic drugs may affect the hypothalamus and me dulla in such a way that permeability is increased. ________________________________________ III. RISK FACTORS FOR DEVELOPMENT OF PULMONARY TOXICITY As has been discussed, antineoplastic drugs do induce pulmonary toxicity. Howeve r, it should be realized that not all patients receiving these agents experience this toxicity. To identify those patients at ris , five major predisposing fact ors for development of pulmonary toxicity should be noted. A. Cumulative Dose Cytotoxic agents that are directly toxic to the lungs generally exhibit increasi ng toxicity with increasing dose. This is believed to be a result of drug accumu lation in the lung itself. Two patterns of dose related pulmonary toxicity are u sually clinically observed: 1. A threshold effect wherein there is a mar ed increase beyond a specific amoun t of drug received. For example, when total lifetime dose of bleomycin exceeds 4 50-500 units, there is a definite increase in ris for development of pulmonary toxicity. Pulmonary toxicity secondary to busulfan, in the absence of other pred isposing factors, has only been noted with total doses >500mg. 2. A linear effect wherein there is a constantly increasing ris for the develop ment of pulmonary toxicity as more drug is administered (eg. carmustine). B. Age

A normal physiologic phenomenon that has been observed with aging is a decrease in the effectiveness of the antioxidant defense system. Therefore, as a patient ages, he/she would be expected to be more susceptible to pulmonary toxicity from certain cytotoxic drugs. To date, however, age has been shown to be a ris fact or only for the development of bleomycin-induced pulmonary disease. C. Radiation Radiation therapy results in the production of oxidant species that lead to pulm onary damage. When antineoplastic agents (eg. bleomycin, mitomycin, busulfan) th at also affect the oxidant/antioxidant homeostasis are administered, there may b e synergistic toxicity. D. Oxygen Therapy Reactive oxidant metabolites (eg. O2, H2O2, OH) are produced when high concentra tions of oxygen are administered. Synergistic toxicity may also be possible betw een high concentrations of O2 and drugs that can disrupt the normal oxidant/anti oxidant homeostasis. This appears to be the case with bleomycin, cyclophosphamid e and mitomycin. E. Multidrug Regimens Although not clearly defined, the incidence and severity of pulmonary toxicity m ay increase with multidrug regimens. Typically, these chemotherapy regimens incl ude bleomycin, mitomycin, cyclophos- phamide, methotrexate, or carmustine. It ha s not been determined whether any single drug is the causative agent or if the i nteraction of these antineoplastics results in enhanced toxicity. ________________________________________ IV. CLINICAL SYNDROMES IDENTIFIED Pulmonary toxicity induced by antineoplastic agents is manifested in three typic al clinical patterns. Although they will be described individually, there may be certain patients that present with symptoms from more than one pattern. A. Chronic Pneumonitis/Fibrosis This presentation is observed most frequently and has been reported with virtual ly all antineoplastic drugs associated with pulmonary toxicity. However, it shou ld be noted that it is not usually associated with antimetabolites. With this ma nifestation of pulmonary damage, the patient experiences slow, progressive (ie. wee s to months) dyspnea on exertion, a nonproductive cough and fatigue. Based o n clinical utility and assessment of severity, the antineoplastic drug may be di scontinued in an attempt to manage this toxicity. Steroids have been administere d to enhance resolution of this syndrome, but documentation of their efficacy is anecdotal. B. Hypersensitivity Reactions These reactions are commonly associated with bleomycin, methotrexate, and procar bazine, and are manifested as an acute syndrome (ie. hours to days) consisting o f dyspnea, fever, and nonproductive cough. Peripheral and/or pulmonary eosinophi lia with pulmonary infiltrates can be observed. Usual treatment of these hyperse nsitivity reactions includes drug discontinuation and steroid administration, re sulting in a good prognosis for the affected patient. C. Noncardiogenic Pulmonary Edema This pattern of pulmonary toxicity is a very rare and acute complication associa ted with the use of cytarabine, methotrexate, and cyclophosphamide. Prognosis in these instances is variable. ________________________________________ V. DIAGNOSIS The definitive diagnosis of cytotoxic drug induced pulmonary toxicity is difficu lt since a detailed history of drug administration in the absence of other situa tions that may lead to pulmonary damage is required. However, the following have been reported: A. Chest X-ray changes consistent with progressive pulmonary fibrosis; however, a patient may have a normal X-ray even when histologically demonstrated pulmonar y damage is present. B. Pulmonary histopathologic features including endothelial cell damage, fibrobl

ast proliferation, and epithelial abnormalities C. Arterial blood gases revealing hypoxia with hypocapnia D. Pulmonary function abnormalities: typically a restrictive process is seen, wi th a reduced diffusion capacity for carbon monoxide, decreased total lung capaci ty, and other ventilatory defects. ________________________________________ VI. EXAMPLE - BLEOMYCIN The model for antineoplastic-induced pulmonary damage, both interstitial pneumon itis/pulmonary fibrosis and hypersensitivity, is bleomycin, which will be used f or illustrative purposes. A. Incidence Literature reports of the incidence of bleomycin pulmonary toxicity vary from 240% of all patients receiving the drug. It is thought that these differences in occurrence may be due to differences in ris factors in the populations studied. It has been suggested that a realistic estimate of patients affected is near 10 % of those receiving bleomycin. Of this population, 10% will die due to pulmonar y toxicity, resulting in an overall fatality of 1% of patients treated. B. Ris Factors 1. Age - older patients (ie. >70) are more sensitive to bleomycin-induced pulmon ary toxicity. However, younger patients, especially those receiving high cumulat ive doses, are still at ris . 2. Cumulative Dose - at approximately 450-500 total units, the incidence of pulm onary toxicity sharply increases. It should be noted, however, that caution shou ld be exercised in all patients at even lower cumulative doses since contributin g ris factors may be present. 3. Radiotherapy - lowest effective doses of radiotherapy should be administered since there is a synergistic phenomenon that occurs. It should be noted that thi s synergism is seen regardless of sequence of therapy administration (ie. radiat ion followed by bleomycin or bleomycin followed by radiation). 4. Oxygen Therapy - only clinically necessary oxygen supplementation should be p rovided to patients who have received bleomycin since this contributes to the de velopment of pulmonary fibrosis. 5. Multidrug Regimens - close monitoring is warranted when bleomycin is administ ered as part of a multidrug regimen, especially those containing cyclophosphamid e. 6. Route of Administration - although further documentation is required, it is t hought that continuous infusion of bleomycin may decrease the incidence of pulmo nary toxicity. 7. Organ Failure - Delayed excretion of bleomycin is seen in patients with renal failure. This has been reported to lead to an increased sensitivity to pulmonar y toxicity. This relationship is inconclusive. C. Treatment No single or specific treatment is accepted as a standard in managing bleomycininduced pulmonary toxicity. For those patients experiencing chronic pneumonitis/ fibrosis, discontinuation of the drug should be considered when a rapid decline in pulmonary function (especially CO diffusion capacity) is observed. For those patients experiencing hypersensitivity reactions, bleomycin discontinuation with steroid therapy is usually recommended. ________________________________________ VII. OTHER ANTINEOPLASTIC AGENTS REPORTED TO INDUCE PULMONARY DAMAGE Several other antineoplastic drugs or drug classes have been reported in the lit erature to induce pulmonary damage. These include: MITOMYCIN, NITROSOUREAS (BCNU , CCNU), ALKYLATING AGENTS (BUSULFAN, CYCLOPHOSPHAMIDE, CHLORAMBUCIL, MELPHALAN) , ANTIMETABOLITES (METHOTREXATE, AZATHIOPRINE, 6-MERCAPTOPURINE, CYTARABINE), VI NCA ALKALOIDS, PROCARBAZINE, and FLUDARABINE. ________________________________________ VIII. CONCLUSION

The pulmonary toxicities associated with chemotherapy administration can pose si gnificant problems in the management of cancer patients. Methods to prevent pulm onary toxicity and standard, effective management of the toxicity once it occurs must still be developed. ________________________________________ Previous Next SyllabusThe College of Pharmacy UICPHARM@uic.eduThe University of Illinois at Chicago Last modified: Dec 19, 1997

Neurotoxicity From Chemotherapy L. Bressler November, 1997 ________________________________________ OBJECTIVES 1. Describe, briefly, the manifestations of neurotoxicity seen with several anti neoplastic drugs. 2. Discuss the implications (or lac thereof) for treatment of chemotherapy-indu ced neurotoxicity. REQUIRED READING NONE SUGGESTED READING 1. Weiss HD et al: Neurotoxicity of commonly used antineoplastic agents; N Engl J Med 291:75-81 (1974) and 291:127-133 (1974) 2. Kaplan RS, Wierni PH: Neurotoxicity of antineoplastic drugs; Sem Onc 9:103-1 30 (1982) ________________________________________ NEUROTOXICITY FROM CHEMOTHERAPY Several antineoplastic drugs can cause distinct neurologic side effects. Often t here is no drug treatment for these toxicities. The decision to discontinue trea tment because of toxicity may be subjective: How severe are the symptoms? How bo thersome are they to the patient? Is the patient responding to therapy? With thi s introduction, then, the discussion that follows serves to familiarize the read er with the neurotoxic side effects seen with different drugs. The reader should be able to answer questions regarding the li elihood of occurrence of specific effects with specific drugs. 5-FLUOROURACIL (5-FU) 5-FU has been reported to cause neurotoxicity in about 1% of patients receiving the drug. 5-FU causes CEREBELLAR toxicity, and patients present with ATAXIA of t he trun or extremities, DYSMETRIA, coarse NYSTAGMUS and, subjectively, DIZZINES S. Although cerebellar toxicity has been observed in association with a variety of doses and schedules of 5-FU, there appears to be a higher incidence with high er wee ly doses (ie. greater than 15mg/ g/wee ) or more intense daily doses. The syndrome is reversible within one to six wee s after stopping therapy -in some cases doses have been reduced, in some cases intervals between treatments have b een prolonged, or in some cases, treatment schedules haven't been altered at all . Symptoms do not necessarily recur with subsequent doses. It has been suggested that 5-FU cerebellar toxicity is due to accumulation of FL UOROCITRATE, a neurotoxic metabolite, in the CNS. However, it has also been note d that the combination of thymidine and 5-FU may cause more neurotoxicity than 5 -FU alone - and thymidine bloc s catabolism of 5-FU, decreasing the amount of fl

uorocitrate produced. CYTARABINE (Ara-C) Ara-C causes central nervous system toxicity when it is administered in high dos es (eg. 3gm/m2, in contrast to "standard" doses of about 100mg/m2). Toxicity is primarily CEREBELLAR, manifest as NYSTAGMUS, truncal ATAXIA, DYSMETRIA, DYSARTHR IA, DYSDIADOCHOKINESIA. Occasionally, CEREBRAL manifestations are seen: headache , somnolence, seizures, altered personality, difficulty with calculations. Cereb ral toxicity is rare without cerebellar toxicity. Symptoms begin within three to eight days of beginning treatment, and usually last for three to ten days. Occa sionally, symptoms persist for longer than a month. This persistence seems to be more li ely in patients older than 50 years. VINCA ALKALOIDS - VINCRISTINE (VCR) and VINBLASTINE (VLB) Although both drugs are neurotoxic, neurotoxicity is the dose-limiting toxicity for VCR. Myelosuppression is dose-limiting for VLB. Thus VCR is quantitatively m ore neurotoxic and the clinical manifestations described below are seen primaril y with VCR. The earliest and most common manifestation of VCR neuropathy is decreased Achill es tendon reflex. This occurs in about 100% of patients, frequently after only o ne or two does. The earliest symptoms noted by the patient are usually paresthes ias li e NUMBNESS and TINGLING in hands or feet. Both loss of deep tendon reflex es and sensory symptoms are slowly reversible upon discontinuation of the drug. With continued dosing, motor involvement is seen: AREFLEXIA, MOTOR WEAKNESS, and gait disorders such as FOOT DROP. Motor neuropathy may be PAINFUL. Another common manifestation of VCR neurotoxicity, seen in about 50% of patients , is CONSTIPATION. It can occur within a few days of a dose and may cause abdomi nal pain. VCR can cause fecal impaction high in the colon. Patients on VCR often require laxatives. Occasionally patients may experience severe JAW PAIN after t he first or second dose of VCR. This represents neuropathy involving the trigemi nal nerve. It disappears over a few days but may require analgesics. The jaw pai n doesn't usually recur with subsequent doses. HOARSENESS, due to vocal cord par alysis, may be another manifestation of VCR neuropathy. ORTHOSTATIC HYPOTENSION due to autonomic dysfunction may also be seen. PACLITAXEL Paclitaxel is a common cause of peripheral neuropathy. In addition, myalgias/art hralgias are often seen following infusions. Opioids, adjuvant analgesics, and n onsedating antihistamines have all been suggested to treat these reversible myal gias/arthralgias. PROCARBAZINE A common form of neurological disturbance reported with procarbazine was alterat ion in the level of consciousness. Alteration may range from mild drowsiness to somnolence and confusion to profound stupor. Rarely, hallucinations or manic psy chosis have been reported. Paresthesias of the extremities and painful myopathie s have also been reported. It seems that much of the neurotoxicity reported with procarbazine was seen with continuous daily dosing, not a common schedule today . CNS depression is also said to be additive with other CNS depressants. However , since many CNS depressants might be used in patients receiving procarbazine (e g. antiemetics, analgesics), it should be noted that this doesn't represent a co ntraindication. Again, CNS toxicity is not usually of much clinical importance w ith the current use of procarbazine. CISPLATIN As nephrotoxicity from cisplatin became more easily preventable, attention focus ed on neurotoxicity, seen especially after high cumulative doses. Cisplatin caus es a somewhat dose-related SENSORY NEUROPATHY. Early signs (300-400mg/m2 cumulat ive dose) include DECREASED VIBRATORY SENSATION and DECREASED DEEP TENDON REFLEX in the an le. With continued therapy, findings progress proximally and PARESTHE SIAS may develop. Neuropathy may be DISABLING and recovery may be very slow. AMI FOSTINE may minimize cisplatin-induced neurotoxicity. It is important to conside r functional and subjective improvement, as well as objective improvement, in ev aluating such protectants. L-ASPARAGINASE

L-asparaginase-induced neurotoxicity manifests as CEREBRAL DYSFUNCTION with dist urbances in the degree (LETHARGY, SOMNOLENCE, STUPOR, COMA) or quality (CONFUSIO N, DEPRESSION, HALLUCINATIONS, PERSONALITY CHANGES) of consciousness. The incide nce appears to be about 25-50% in adults. It usually occurs within about a day o f drug administration and improves within a few days after treatment. It is not clearly dose-related. Neurotoxicity is thought to be due to metabolic abnormalit ies induced by l-asparaginase (eg. increased levels of aspartic and glutamic aci ds and ammonia, and decreased levels of asparagine and glutamine). IFOSFAMIDE Ifosfamide, unli e the related compound cyclophosphamide, has been reported to c ause neurotoxicity in up to 30% of patients. Manifestations include ALTERATIONS IN CONSCIOUSNESS, ATAXIA, MYOCLONUS, SEIZURES, and COMA. Fatal neurotoxicity has been reported. Several factors have been suggested as increasing the ris of de velopment of neurotoxicity, including low albumin, elevated creatinine, and pelv ic disease. These are not universally accepted as ris factors, however. It has been suggested that toxicity is due to high serum chloroacetaldehyde, via either increased production or decreased elimination. Discontinuation of the drug when signs and symptoms are mild seems more li ely to lead to reversibility than con tinued exposure to drug. Several other ALKYLATING AGENTS have been implicated as causes of neurotoxicity. Toxicity has been reported with high doses (eg. in preparation for bone marrow transplant, overdose) of MECHLORETHAMINE or CHLORAMBUCIL. Lastly, several neurotoxic syndromes have been reported after the use of INTRATH ECAL METHOTREXATE. They may be related, at least in part, to prolonged high CSF levels. MENINGEAL IRRITATION or ARACHNOIDITIS has been reported to occur in up to 61% of patients. Symptoms (stiff nec , headache, nausea, vomiting, fever, CSF pleocyto sis) occur 2-4 hours after intrathecal injection and last for 12-72 hours. PARAPLEGIA due to intrathecal methotrexate may be transient or permanent. Intrat hecal CYTARABINE has also been implicated. This is not a common form of toxicity . Onset has been reported to be from minutes to hours after intrathecal injectio n. Improvement has been noted from 48 hours to 5 months, and in some cases, not at all. Finally, CHRONIC ENCEPHALOPATHIC SYNDROMES have developed in patients receiving intrathecal methotrexate. Intrathecal CYTARABINE and THIOTEPA and cranial IRRADI ATION as well as systemic methotrexate have all been implicated. ________________________________________ Previous Next SyllabusThe College of Pharmacy UICPHARM@uic.eduThe University of Illinois at Chicago Last modified: Dec 19, 1997

Extravasation Injuries L. Bressler November, 1997 ________________________________________ OBJECTIVES 1. List those antineoplastic drugs that are vesicants. 2. Discuss the differentiation of extravasations from other venous reactions. 3. Recommend, in writing, treatment for extravasation of specific vesicant antin eoplastic agents. REQUIRED READING NONE SUGGESTED READING 1. Larson DL: What is the appropriate management of tissue extravasation of anti tumor agents?; Plastic and Reconstr Surg 75:397-402, 1985

2. Dorr RT: Discussion - What is the appropriate management of tissue extravasat ion of antitumor agents?; Plastic and Reconstr Surg 75:403-405, 1985 ________________________________________ EXTRAVASATION INJURIES I. EXTRAVASATION = lea age of fluid outside of the vasculature into the perivasc ular and subcutaneous spaces; infiltration. Some substances, upon lea age into subcutaneous tissue, have the potential to ca use severe tissue damage and even necrosis. These substances are nown as VESICA NTS. The following chemotherapeutic agents are vesicants: actinomycin-D daunorubicin doxorubicin idarubicin mechlorethamine mitomycin-C paclitaxel streptozocin vinblastine vincristine vinorelbine Some chemotherapeutic agents can cause pain or burning on administration, even t hough they may remain in the vasculature: carmustine (BCNU) dacarbazine (DTIC) Pain or burning can be minimized by infusing these drugs slowly, as dilute solut ions (eg. 100-250ml over 30-60 minutes, as opposed to IV push injections) ________________________________________ II. OTHER VENOUS REACTIONS A. MECHLORETHAMINE (nitrogen mustard) frequently causes phlebitis, irritating the v ein independent of the possibility of extravasation. Some clinicians find that t he use of hydrocortisone prior to or during (separated by saline flush) injectio n of mechlorethamine preserves the integrity of the vessel. This is a subjective finding. B. 5-FLUOROURACIL frequently causes dar ening of the veins. This is referred to as "serpentine veins". It may be embarrassing for patients, although it is merely a discoloration. That is, the vein(s) can still be utilized for administration of chemotherapy, etc. This venous discoloration is particularly prominent in blac patients. C. DOXORUBICIN (as well as DAUNORUBICIN) can cause redness and itching along the di stribution of the vein through which it has been administered. This is nown as a "flare". Usually the flare is self-limited. It disappears in several minutes t o half an hour with or without treatment (antihistamines, steroids). The cause i s not nown, although it has been suggested that the incidence is less when the diluent for doxorubicin is normal saline instead of water for injection. Rarely, the flare has been associated with systemic allergic symptoms. Management invol ves ma ing sure a systemic allergic reaction is not present, and ma ing sure the reaction does not represent an extravasation. ________________________________________ III. Several factors may influence the occurrence of or the severity of extravasation injuries. These factors include the location, size and fragility of the vessel, the age of the patient, site(s) of previous venipuncture, lymph node dissection s, and the concentration of drug. These should be considered when selecting veno us sites or ways to administer vesicant drugs. Practically spea ing, however, on

e may have to use less than preferred sites in patients with poor or limited ven ous access. Fragile, low flow, or small diameter vessels, or previously irradiated sites may all have relatively decreased vascularity. Thus, extravasated fluid is more li ely to remain concentrated in a given area. Use of vessels close to tendons or muscles can lead to greater functional loss i n the event of extravasation of a vesicant agent. Administration of drug distal to the site of a recent venipuncture can lead to l ea age of the drug as it passes the venipuncture site. The size of subsequent ulceration following extravasation of vesicant agents is related to the concentration and the total amount of drug that has extravasated. In an animal model, a critical concentration of doxorubicin was determined to b e 0.01-0.02mg/ml. That is, when doxorubicin was diluted to this concentration, a nd volume of extravasated drug ept constant, the size of the subsequent ulcer w as significantly decreased from that seen with more concentrated solutions. Note that pain is not necessarily present at the time of extravasation. Thus abs ence of pain does not rule out an extravasation. When extravasation cannot be co mfortably ruled out, drug administration should be discontinued and restarted in another vessel. PATTERNS OF INJURY - The onset of injury is earlier with vinca al aloids and mec hlorethamine, and later with anthracyclines (eg. doxorubicin). The vinca al aloi ds tend to produce blistering, not necessarily necrosis. Mechlorethamine leads t o ulceration which reaches its maximum severity faster than that seen with anthr acyclines. Tissue damage from anthracyclines is progressive over wee s to months . A full thic ness ulcer can be seen and damage can extend to underlying structu res li e muscles and tendons. ________________________________________ IV. MANAGEMENT OF EXTRAVASATION A. The goal of treatment is to prevent severe tissue damage and preserve function. B. The majority of extravasations are suspected (eg. all of the sudden, blood retur n diminishes), when venous patency/blood return is chec ed frequently. C. Primary prevention (see above): choice of vessel technique IV push injections may be preferred when possible. Infusions may be more li ely to be left unattended, allowing for lea age of a greater amount of fluid before the extravasation is detected. D. Aspirate bac fluid, to avoid extravasation of any more fluid remaining in the n eedle/catheter. Then remove the needle. E. Aspirate any bleb if possible. F. Administer antidote. G. Follow up. Continued pain or ulceration after 1-2 wee s is an indication for sur gery/s in grafting. (Plastic) surgery should be consulted at this point. H. ANTIDOTES 1. SODIUM THIOSULFATE 1/6M (4ml 10% sodium thiosulfate + 6ml water = 1/6M). Inst ill via multiple injections in and around the area of extravasation (ie. SQ/ID) using a small gauge needle (eg. 25g). Sodium thiosulfate is recommended as an antidote for extravasation of MECHLORETH AMINE. It provides a substrate for al ylation by mechlorethamine, preventing the al ylation and subsequent destruction in subcutaneous tissue. 2. HYALURONIDASE 150U (1ml). Instill via multiple injections in and around the a rea of extravasation (ie. SQ/ID) using a small gauge needle (eg. 25g). Hyaluronidase is recommended as an antidote for extravasation of VINCRISTINE, VI

NBLASTINE, and VINORELBINE. It brea s down hyaluronic acid ("cement") in connect ive/soft tissue, allowing for dispersion of the extravasated drug. 3. DIMETHYLSULFOXIDE (DMSO) 50-70% solution 1.5ml. Apply topically (ie. "paint" on the s in) QID x 14 days. Leave uncovered. DMSO has been recommended as an antidote for extravasation of DOXORUBICIN and DA UNORUBICIN as well as MITOMYCIN. There is conflicting data in animals regarding its effectiveness. Some reports of prevention/decreased ulcer formation were obt ained when DMSO was used in conjunction with Vitamin E. There is one series of p atients reported in whom topical application of 99% DMSO was thought to have pre vented ulceration. Little other information is presented (eg. amount of drug ext ravasated, whether or not cold was used). Note that the only commercially availa ble concentration of DMSO is 50%. DMSO may wor by virtue of its free radical sc avenging property. 4. COLD - Apply cold pac s for 20 minutes QID x 3 days. Cold is recommended as an antidote for extravasation of DOXORUBICIN and DAUNORUB ICIN. Initially, cold was suggested as a general measure for extravasation of a variety of drugs. The rationale for cold was vasoconstriction, thereby "containi ng" the drug at the site of extravasation and minimizing the size of the subsequ ent ulceration. Studies in animal models, however, have shown that the concentra tion of doxorubicin at the site of extravasation was not different from that at a distal site following the application of cold. But ulceration was still not se en. Thus it appears that cold prevents ulceration from doxorubicin or daunorubic in by a mechanism other than vasoconstriction and "containing" the drug. This me chanism has been suggested to be decreased cellular upta e of drug at lower temp eratures - the same rationale as that for the use of scalp cooling to prevent al opecia. 5. HEAT - Apply heat pac s for 20 minutes QID x 3 days. Heat is recommended, in conjunction with hyaluronidase, as an antidote for extra vasation of VINCRISTINE and VINBLASTINE. Initially, heat was suggested as a gene ral measure for extravasation of a variety of drugs. The rationale for heat was vasodilation, thereby "diluting" the drug and minimizing the size of the subsequ ent ulcer. It seems unli ely that heat can result in a change in concentration o f the magnitude noted above to decrease ulcer size. Yet, in the mouse model heat did decrease ulceration due to extravasation of vinca al aloids, and not that d ue to anthracyclines. 6. SUMMARY - Although several drugs have been well studied in animals (eg. doxor ubicin), there is less data available on the management of extravasation of some of the other agents. The following represents my recommendations for acute trea tment of extravasation of vesicant antineoplastic agents: doxorubicin, daunorubicin, idarubicin, mitomycin, actinomycin - cold " DMSO vincristine, vinblastine, vinorelbine - hyaluronidase and heat mechlorethamine - sodium thiosulfate streptozocin - cold paclitaxel - recent reports indicate that paclitaxel is a vesicant, although the re are also reports of extravasation without resulting necrosis; there is as yet no universally recommended treatment for paclitaxel extravasation; my recommend ation would be to treat it li e extravasation of the vinca al aloids ________________________________________ Previous Next SyllabusThe College of Pharmacy UICPHARM@uic.eduThe University of Illinois at Chicago Last modified: Dec 19, 1997

Occupational Exposure Ris s

L. Bressler November, 1997 I. Occupational Exposure Ris s II. Effects on Pregnancy Outcomes III. Selected Recommendations ________________________________________ OBJECTIVES 1. Describe the ris s, potential or actual, related to occupational exposure to cytotoxic drugs. 2. Discuss the outcomes that have been reported in the literature and now the d ifference between potential and actual ris s. 3. Develop a written plan for minimizing occupational exposure to cytotoxic drug s. Explain the rationale for each step included in such a plan. REQUIRED READING 1. ASHP technical assistance bulletin on handling cytotoxic and hazardous drugs; Am J Hosp Pharm 47:1033-1049, 1990 SUGGESTED READING NONE ________________________________________ OCCUPATIONAL EXPOSURE RISKS Three "negative outcomes" or ris s of occupational exposure to cytotoxic drugs m ight be: MUTAGENICITY, CARCINOGENICITY and ADVERSE OUTCOMES OF PREGNANCY. MUTAGENICITY - causing an alteration in one or more genes (ie. a change in DNA) DNA repair is an ongoing process. For our purposes, the importance of mutagenic properties of cytotoxic drugs lies in the fact that many carcinogens are mutagen s. Mutagenicity is easier to study than carcinogenicity. CARCINOGENICITY - causing cancer In ANIMALS, some cytotoxic drugs are carcinogenic. Clinically, cytotoxic drugs h ave been implicated as carcinogens in PATIENTS RECEIVING THERAPEUTIC DOSES OF TH ESE DRUGS. Most commonly, ALKYLATING AGENTS (eg. chlorambucil, nitrogen mustard, melphalan) have been reported to cause SECONDARY LEUKEMIAS. More equivocal is a relationship between antibiotics and carcinogenicity, and the antimetabolites a re thought to be the "safest" with regard to carcinogenicity. There are no conclusive reports of cancers developing in health personnel as a r esult of occupational exposure to cytotoxic drugs. Obviously, occupational exposure is much, much less than therapeutic exposure. ROUTES of occupational exposure are via INHALATION of aerosolized particles and TRANSCUTANEOUS absorption. Various manipulations in the preparation and administ ration of cytotoxic drugs could lead to exposure by these routes. Aerosolization might occur when one brea s open an ampul, withdraws solution form a vial, or i njects liquid into a powder. Transcutaneous absorption could occur following spi lls on the s in. Drug "contamination" in the environment around areas of preparation has been doc umented (ie. aerosolization has been measured). Anecdotal reports of adverse effects (eg. dizziness) in health professionals wor ing with cytotoxic drugs prompted much attention to this issue in recent years. More controlled studies (albeit with limitations related to urine mutagenicity studies) demonstrated exposure to drugs in health professionals, and demonstrate d the protective effect of vertical-flow biological-safety cabinets. What is not nown is the "safe level" of occupational exposure. Is exposure cumu lative??? Is there a level of exposure above which irreversible damage might occ ur??? Several methods have been used for detecting low levels of exposure to pot entially carcinogenic substances: 1. AMES TEST FOR MUTAGENICITY: Utilizes a strain of Salmonella bacteria sensitiv e to mutagenic changes. The bacteria require histidine to grow. In the test syst em, urine from the subject "exposed" is incubated with the bacteria. Bacterial g

rowth in a histidine-free medium indicates that the Salmonella has mutated, thus there are "mutagenic substances" in the urine. Both positive and negative results have been reported using urinary mutagenicity tests. Some of the discrepancy may be that, in fact, negative results represent prevention/minimizing exposure. Timing might also be a factor. The mutagenic su bstance must be excreted into the urine and this might occur at various times fo llowing exposure, depending on the particular drug. Cigarette smo e, other non-c ytotoxic drugs, or some dietary factors may also be responsible for mutagenic ac tivity in the urine, resulting in false positive urine mutagenicity tests. 2. Analytical methods (eg. HPLC) for determination of CYTOTOXIC DRUG (or metabol ite) CONCENTRATION in BLOOD or URINE. These methods have been developed primarily for use in patients receiving therap eutic doses of cytotoxic drugs. They may lac the sensitivity to detect the low levels assumed to be associated with occupational exposure. 3. CYTOGENETIC EFFECTS - analysis of CHROMOSOMAL DAMAGE (eg. structural chromoso me aberrations [CA], sister chromatid exchanges [SCE]) in peripheral blood lymph ocytes. Both positive and negative results have been reported. The persistence of the cy togenetic effect also depends on the type of damage (ie. SCE are short-lived whi le CA persist for years). In addition, there may be a wide distribution of SCE i n normal individuals (ie. SCE without exposure to cytotoxic drugs). 4. Measurement of NUCLEIC ACID ADDUCTS - ie. determination of drug/DNA complex i n the urine, has been suggested as a means of monitoring occupational exposure. At present this technique is not perfected to the point of being useful in the w or place. None of these methods for detecting low levels of exposure are routinely utilize d in the wor place. There is no standard "test" for detecting exposure or monito ring for potential adverse consequences that can be recommended at the present t ime. ________________________________________ EFFECTS ON PREGNANCY OUTCOMES Several papers have addressed the incidence of SPONTANEOUS ABORTIONS and MALFORM ATIONS in the offspring of health professionals with occupational exposure to cy totoxic drugs. The conclusions have met with some questions and concerns. A study in Finland examined outcomes in nurses exposed to anesthetic gases, ster ilizing gases and soaps, x-rays and cytotoxic drugs. Data on exposure were obtai ned retrospectively by means of questionnaires sent to head nurses. Cytotoxic ex posure in the first trimester was reported to be associated with malformations i n offspring. The same investigators, in a subsequent study, reported an increased ris of spo ntaneous abortions (not malformations) in nurses exposed to cytotoxic drugs. Aga in, data were obtained retrospectively by questionnaire. One wonders about the a bility to recall how many does per wee were prepared several years prior. Spont aneous abortions occurred in women who also had (other) ris factors for spontan eous abortion. In both studies, nurses were responsible for preparing, as well as administering , cytotoxic drugs. Both studies covered a period in time before attempts at mini mizing exposure were recommended in the literature. QUANTITATIVE ASSESSMENT OF RISK - We cannot quantitate the ris of exposure at t his time. Much of the ris appears to be POTENTIAL (based on nown effects of th erapeutic doses in patients, or animal data), NOT ACTUAL. However, because of th e seriousness of the potential ris , it ma es sense to minimize occupational exp osure to cytotoxic drugs as much as possible. ________________________________________ SELECT RECOMMENDATIONS A VERTICAL FLOW BIOLOGICAL SAFETY CABINET (as opposed to horizontal laminar flow ) should be used for preparation of cytotoxic drugs. This offers protection of t

he product AND the operator. Most commonly used is a Class II biological safety cabinet, in which 30% of the air is filtered and recirculated (or alternatively, vented to the outside). When no vertical flow hood is available, it has been recommended that a quiet wo r space, away from heating and cooling vents and other personnel be used. (ie. not a horizontal flow hood) GLOVES - SURGICAL LATEX GLOVES appear to offer the best protection. In general, the shorter the contact time (with drug) and the thic er the glove, the less pen etration through the glove. Gloves should be changed after 30 minutes of continu ous wearing (or sooner if a spill occurs). GOWNS - closed front and cuffs TECHNIQUES Usual ASEPTIC TECHNIQUE NEGATIVE PRESSURE to withdraw solutions from vials (ie. inject less air than the volume to remove.) This will minimize aerosolization. Alternatively, several de vices that absorb or prevent aerosolization have been mar eted for use in the pr eparation of cytotoxic drugs. For related issues (eg. pregnancy), the policies and procedures at specific inst itutions, as well as current laws, should be reviewed. ________________________________________ Previous Next SyllabusThe College of Pharmacy UICPHARM@uic.eduThe University of Illinois at Chicago Last modified: Dec 19, 1997