antiemetics and cancer chemotherapy table of ...

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Chapter 10

ANTIEMETICS AND CANCER CHEMOTHERAPY M. Brigden and J. Barnett

TABLE OF CONTENTS I.

Introduction ............................................................ 206

II.

Individual Antiemetic Agents .......................................... 211 A. Phenothiazines .................................................. 211 B. Butyrophenones ................................................ 214 C. Metoclopramide ................................................ 215 D. ~-9-Tetrahydrocannabinol ...................................... 218 E. Nabilone ........................................................ 221 F. Other Cannabinoids ............................................ 222 G. Steroids ........................................................ 222 H. Antihistamines/ Anticholinergics ................................ 225 I. 5-Hydroxytryptamine Receptor Antagonists .................... 225 J. Benzodiazepines ................................................ 226

III.

Multiagent Trials ....................................................... 227

IV.

Selected Antiemetic Protocols ......................................... 232

Acknowledgments ............................................................. 233 References ..................................................................... 233

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Nausea and Vomiting: Recent Research and Clinical Advances

I. INTRODUCTION Nausea and vomiting are predictable and well-publicized side effects of modern cancer chemotherapy. 1 Indeed, the frequency and morbidity of such side effects would make these drugs clinically unacceptable except for their efficacy and the life-threatening nature of cancer. The general public is well aware of the emetic potential of chemotherapy and this knowledge accounts for much of the initial apprehension patients display when referred for oncologic treatment. Some patients ultimately refuse curative chemotherapy because of these side effects. 2 Unfortunately, many cancer chemotherapeutic programs have a steep doseresponse curve for efficacy. In animal models equivalent response rates can be obtained by using lower doses of a drug program, but cure is often only achieved by the same drugs given in a high dose regime. 3 Physicians who lower the dose of cancer chemotherapy to make treatment more palatable may have more patients completing therapy but are likely to produce inferior results. This has been documented for Hodgkin's disease and the non-Hodgkin's lymphomas, and in several studies of adjuvant therapy for breast cancer. 4 · 5 The potential medical complications associated with chemotherapy-induced nausea and vomiting are reviewed elsewhere in this volume. It is important to realize, however, that a variety of emetic syndromes may ensue following a bolus of i.v. chemotherapy. Acute chemotherapy-induced nausea and vomiting has been the most frequently studied, but syndromes of persistent or delayed emesis and anticipatory emesis have been increasingly recognized. Obviously, studies involving patients with the syndromes of delayed emesis or anticipatory nausea require different types and periods of observation, as opposed to those involving patients with acute chemotherapy-induced emesis. Research interest in the improved use of antiemetics in cancer chemotherapy is relatively recent. Reasons for this include the facts that nausea and vomiting have not been considered major complications of cancer chemotherapy, and supportive care generally has not enjoyed much glamor as a research area. The first controlled trials of antiemetic drugs for chemotherapy-induced emesis were reported from the Mayo Clinic in 1963. 6 These studies established a role for antiemetics in the treatment of emesis induced by 5-fluorouracil (5-FU) and laid a foundation for antiemetic trial methodology. The next series of antiemetic trials published in the 1970s addressed the question of emesis induced by moderate to severe cancer chemotherapy regimes such as those developed for adjuvant breast therapy and the non-Hodgkin's lymphomas. A third phase in antiemetic studies was heralded by the introduction of the highly emetogenic antitumor drug cisplatin. This drug has been described by younger patients as the most ''barfogenic'' agent in the modern chemotherapy arsenal. 7 In recent years, there has been a profusion of antiemetic trials which, unfortunately, are very hard to contrast and compare. Study designs vary from open label pilot trials to randomized double-blind comparisons with the occasional use


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TABLE 1 Important Variables in Antiemetic Study Populations Proven Emetogenicity of chemotherapy given Prior exposure to chemotherapy Prior use of antiemetics (e.g., prochlorperazine) Concurrent use of other potentially antiemetic drugs (e.g., steroids) Location of treatment (inpatient vs. outpatient) Age Suspected Stress or depression Social support systems Curable vs. incurable disease

of placebo controls. Furthermore, individual antiemetic drugs have been given in a variety of different doses, schedules, and combinations, making comparisons difficult or impossible. When the chemotherapeutic emetic stimulus is nonuniform, and the patient population is heterogeneous, methodological issues become very critical. This important area has been well reviewed by Oliver et al. x and by Will an and Pater. 9 The three major problem areas in antiemetic studies outlined by these authors include variables in the study population, variables in study design, and problems with outcome assessment and analysis. Important characteristics of antiemetic study populations are listed in Table I. A major consideration is a history of prior chemotherapy as patients who have experienced nausea and vomiting with previous chemotherapy tend to have poorer responses to antiemetic agents than those who have never been treated. 10 One hypothesis is that patients who have vomited repeatedly with prior chemotherapy develop pretreatment nausea and vomiting as a conditioned response in anticipation of future therapy. Such anticipatory nausea and vomiting has proven to be particularly refractory to antiemetics. 10 Since this anticipatory effect may carryover from one treatment to the next, if an inferior treatment precedes a superior treatment, this can be a major defect in the randomized crossover type of trial discussed later in the chapter. 9 For these reasons, it is important that in any trial, patients previously exposed to chemotherapy be analyzed separately from those with no prior exposure. As noted earlier, the type of chemotherapy patients receive is another major variable since individual drugs ditfer so significantly in their emetogenic potential. While part of this variability is related to the drug class, dose and schedule are also important for individual agents. For instance, methotrexate is frequently ranked as nonemetogenic but can be very emetogenic when given in high dose. In one study of the efficacy of high dose dexamethasone in patients treated with cisplatin multivariate regression analysis revealed that only the total cisplatin dosage was a significant predicator of emesis. 11 It has also been shown with cisplatin that changing


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the administration schedule from 1 to 8 h results in a significant decrease in emetic episodes. 12 Other authors noted that the circadian timing of cisplatin administration had a greater effect upon the frequency of vomiting than whether an antiemetic was used. These investigators urged that future cisplatin trials specify the circadian stage of drug administration. 13 Since the dose and schedule of emetogenic chemotherapy can make such a major difference in a patient's response, these variables must be considered separately when analyzing the results of different antiemetic trials. H Similarly, concurrent therapy, especially with potentially antiemetic drugs such as corticosteroids, must be avoided. 9 Age is another patient characteristic that can affect response in specific antiemetic studies and may have other unrecognized impacts. For example, in ~-9tetrahydrocannabinol (THC) trials, the greatest efficacy was reported in studies involving young patients, especially those with prior exposure to marijuana. 14 Conversely, older patients in THC trials appeared more prone to central nervous system (CNS) toxicity. In contrast, high dose metoclopromide causes more extrapyramidal dystonic reactions in younger patients than among the aged. 15 The setting in which the patient receives chemotherapy (either as an inpatient or outpatient) can have a major impact on efficacy. Several studies have suggested that inpatients tend to be more tolerant of side effects because of greater emotional security and staff support. H Other psychosocial variables such as stress or depression have also been thought to play a major role in the tolerance of toxic side effects. In particular, psychological stresses, both acute and chronic, have been associated with poor physical and mental outcomes, whereas social support systems appear to help protect individuals from the negative aspects of chemotherapy. 16 A major area of difficulty when attempting to compare trials is study design. The advantages and disadvantages of the common antiemetic trial designs have been well outlined by Pater and Willan 9 and are listed in Table 2. While nonrandomized trials using sequential historical controls are suitable for pilot studies of antiemetics, a double-blind design is essential to ensure an unbiased evaluation of any effects due to expectation or suggestion on the part of the investigator or patient. This is particularly true in antiemetic studies where many of the criteria for patient response and assessment are subjective; however, several investigators have noted that effective blinding may be impossible to achieve with certain antiemetic drugs. 14 For example, Seipp 17 found when attempting to use a placebo vs. THC, both patients and nurses could identify individual antiemetic agents based on response and side effects. The two major study types that have been used to evaluate antiemetics are parallel trials and crossover designs. 9 In a parallel trial, patients are randomized to receive either study drug or control over several courses of therapy and then the two groups are compared. In the randomized crossover design, the same patient receives both the study drug and the control substance in random order. In this type of study, each patient serves as his/her own control. A major advantage in having the patient serve as their own control is a reduction in variance, resulting in much


209 TABLE 2 Advantages and Disadvantages of Antiemetic Trial Designs Design

Advantages

Nonrandomized, sequential (historical controls)

Ease of implementation; smaller sample size

Randomized, parallel

Unbiased assignment of treatment; allows blinding As above, but more efficient - reduced sample size; allows global assessment of treatment preference

Randomized, crossover

Disadvantages Blinding impossible; will not control for variability in response between institutions and over time Increased sample size; implementation difficulties with consent and randomization As above but more complex; susceptible to psychological carryover that can bias interpretation; potential patient dropout before crossover complete

greater power for the given sample size when compared to a parallel design. Theoretically, a small overall difference between regimes can be statistically detected if it is consistently present in each patient. Crossover trials allow patients on a variety of chemotherapeutic regimes to evaluate a given antiemetic agent. Very importantly, crossover trials also permit patients to state a global preference for antiemetic regimes. While the crossover design has been most frequently utilized in published antiemetic trials, there are certain disadvantages to this type of study. s Crossover designs are clearly inappropriate when a patient's condition is changing rapidly. Also, patients who fail to complete the crossover are not available for further evaluation. Another major problem may be that the relative efficacy of two treatments can differ from the first period to the second. Such psychological carryover can result when patients are conditioned by their experiences in the first treatment period to have more nausea and vomiting in the second. The Biometric and Epidemiological Advisory Committee of the Food and Drug Administration (FDA) actually discourages the use of crossover studies. 18 While psychological carryover is not a problem in parallel treatment trials, the sample size required to detect a difference between treatments can be large. For example, 95 patients per arm are needed in order to detect a 25% difference in efficacy between two treatments. 19 However, since a number of patients on alternating chemotherapy regimes, or those taking other treatments between chemotherapy courses are not ordinarily eligible for crossover studies, it is possible that a parallel design trial (which in fact required more patients than a crossover study) could still have a shorter accrual period. 9 The third and perhaps greatest problem area resides in the definition and assessment of response to antiemetics (Table 3). Currently there are no consistently accepted definitions of response similar to those used for characterizing the complete


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TABLE 3 Important Issues in the Assessment of Antiemetic Response Difficulty in defining and quantitating nausea and vomiting Time of assessment Type of assessment scales Individual performing the assessment Differing definitions of antiemetic toxicity

or partial responses of tumors to chemotherapy. The wide variation in methods used to assess nausea and vomiting as well as for grading antiemetic efficacy make individual studies very difficult to compare. 14 At first glance it would seem that many aspects of vomiting, or emesis, should be easily quantitated; however, difficulty exists in evaluating continuous or prolonged vomiting and wretching that does not result in expulsion of the stomach contents, but is a similar response to emetic stimuli. Also, when a patient vomits continuously over a period of time, it is hard to determine the exact number of individual episodes. Some investigators may choose to count each as a separate event. The duration of observation of the number of vomiting episodes should be appropriate for the expected time course of vomiting associated with the given emetic stimulus, otherwise the total risk period will not be monitored. Some investigators have attempted to resolve this problem by using time lapse video recording of inpatients. 20 Unfortunately, in many trials the time period over which the outcome was assessed is still not reported. The actual volume of emesis often depends on the patient's consumption before chemotherapy. Unless food and drink are controlled during the trial, these measurements are suspect. Lastly, clinical research experience has shown that the actual collection of vomitus is unpleasant for subjects and investigators, which in tum affects the accuracy of reported measurements. 14 Since nausea is a more subjective sensation, the patient's self-assessment must be used as a primary tool. Various rating scales have been developed, including numerical scales and the more recent visual analog scales. The reliability and validity of using visual analog scales for evaluation of nausea have been found to be acceptable. 21 The problem of who should perform the assessment of antiemetic responses still exists. A high percentage of all chemotherapy is given to outpatients who may not cooperate if asked to complete a lengthy assessment of symptoms. In the ideal situation, both the patient and an observer would make simultaneous assessments since some antiemetics have sedative or amnesic properties that may impair an individual patient's observations. 8 Since the side effects of an antiemetic must be balanced against its therapeutic effect, any trial must also evaluate antiemetic toxicity. The fact that current differing definitions of antiemetic toxicity are a problem is illustrated by some studies of


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metoclopramide where akathisia was not considered as a side effect, while it has been the major adverse reaction reported in a number of other trials. 22 Conversely, sometimes drug side effects may be partially responsible for the antiemetic effect, as in the case of the sedation that occurs with phenothiazines, THC, and the benzodiazepines. The type of statistical analysis used is another important variable in the overall assessment of antiemetic efficacy. Recent reviews 9 have outlined a number of issues pertinent to the statistical analysis of trials. In summary, a large and growing literature exists on antiemetics that is difficult, if not impossible, to compare. The major patient variables appear to be na·ivety to chemotherapy and the emetogenic potential of the particular drugs given. In analyzing emetogenic potential, attention must be paid not only to drug dose and scheduling, but also to the timing of administration and even the circadian rhythm. Although crossover trial designs have been most frequently utilized, randomized parallel studies may be superior. Subjective responses such as nausea are best assessed separately with simple scales and antiemetic side effects must always be evaluated. A standardized system for determining efficacy would be ideal and a consensus among investigators to use such a system would constitute a major advance. In the interim, anyone attempting to compare the efficacy of various antiemetic agents must separately analyze the many variables included in each trial and draw their own conclusions.

II. INDIVIDUAL ANTIEMETIC AGENTS The antiemetic properties of individual drugs when used as single agents are reviewed separately. The use of various drugs in combination programs is discussed in a concluding section.

A. PHENOTHIAZINES Phenothiazines are thought to work by blocking dopamine receptors in the chemoreceptor trigger zone (CTZ). This blockade is not complete as it is not equivalent to surgical ablation nor is it effective against all chemicals that stimulate the CTZ. 19 Initial trials in the early 1960s using phenothiazines as antiemetics led to a study of Moertel et al. 6 of prochlorperazine, thiethylperazine, and thiopropazate in 5-FU-induced emesis. This was a double-blind, randomized placebo-controlled trial involving 300 patients with advanced cancer of the gastrointestinal (GI) tract. Patients were randomized to placebo, prochlorperazine 5 mg t. i. d. , thiopropazate 10 mg t.i.d., pipamazine 10 mg t.i.d., cinnarizine 10 mg t.i.d., or trimethobenzamide 20 mg t.i.d., all given orally. The results of this study showed that patients receiving prochlorperazine or thiopropazate had better control of nausea and vomiting than those receiving placebo. The remaining drugs were no more effective than placebo. Trial patients also expressed a preference for thiopropazate and proch-


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lorperazine over placebo. In 1973 Moertel et al. 23 completed a controlled doubleblind trial that compared prochlorperazine and metopimazine to placebo in patients receiving 5-FU by rapid i.v. infusion. The antiemetics used were metopimazine 10 mg t.i.d. p.o. or prochlorperazine 5 mg t.i.d. p.o. In both arms of the study, patients preferred metopimazine and prochlorperazine to placebo. A further study by Orr et al., 24 which involved various chemotherapy regimens including adriamycin, cyclophosphamide, 5-FU, nitrogen mustard, decarbazine, and cytosine demonstrated a limited usefulness for prochlorperazine. This was a double-blind randomized crossover placebo-controlled trial involving 79 patients. All patients had previously experienced vomiting with chemotherapy and had failed standard antiemetics. The antiemetics given in this trial were placebo, prochlorperazine 7 mg/m 2 p.o. every 4 h X 4 doses and THC 7 mg/m2 p.o. every 4 h x 4 doses. Among 55 evaluable patients there was a marked preference for THC over both prochlorperazine and placebo. Actually, in this study prochlorperazine appeared to be no better than placebo. Comparative trials of prochlorperazine with other antiemetic agents in the prevention of chemotherapy-induced emesis have also demonstrated the limitations of prochlorperazine as an antiemetic. Herman et al. 25 performed a double-blind randomized crossover trial involving 152 patients with various diagnoses. The chemotherapy regimens consisted of cisplatin, vinblastin, bleomycin, dactinomycin, 5-FU, and other agents given alone or in combination. In the first part of the trial, patients received nabilone 2 mg p.o. or prochlorperazine 10 mg p.o. every 8 h beginning 2 h prechemotherapy. In the second part of the trial, patients received nabilone 2 mg or prochlorperazine 10 mg every 6 h starting 30 min prechemotherapy. Of 113 evaluable patients, all who showed complete (no nausea and vomiting) or partial responses (nausea and vomiting decreased by 50%) had a marked preference for nabilone over prochlorperazine. Patients who had lesser decreases in vomiting also showed a preference for nabilone over prochlorperazine. A study by Gralla et al. 26 of 41 patients who received cisplatin 120 mg/m 2 i. v. over 20 min noted a marked preference for metoclopramide vs. prochlorperazine. In this double-blind randomized paired trial patients received prochlorperazine 10 mg i.m. or metoclopramide 2 mg/kg i.v. 30 min before and at 1.5, 3.5, 5.5, and 8. 5 h after chemotherapy. Patients in this study had not received prior chemotherapy. The patients treated with metoclopramide showed a significant decrease in the number of emetic episodes when compared to placebo or prochlorperazine, and there was a marked preference for metoclopramide vs. prochlorperazine. A trial by Ettinger et al. 27 involving a comparison of dexamethasone with prochlorperazine also showed an inferior response for prochlorperazine. This was a double-blind crossover trial with patients receiving various forms of noncisplatin chemotherapy. Dexamethasone was given 20 mg i. v. 0. 5 h prechemotherapy and 10 mg orally every 6 h for 24 h post-treatment. The prochlorperazine was given 10 mg i. v. 0. 5 h prechemotherapy followed by 10 mg every 6 h for 24 h posttreatment. There was a marked preference for dexamethasone over prochlorperazine


213 TABLE 4 Possible Side Effects of Phenothiazines Antidopaminergic effects Parkinsonian-like effects: tremor, rigidity, spasms Dystonia: opisthontonus, torticollis, oculogyric crisis Akathisia: restlessness, insominia, agitation Tardive dyskinesia: rhythmical involuntary movements Anticholinergic/antihistaminic effects Dry mouth, nasal congestion Drowsiness, dizziness, blurred vision Constipation, urinary retention Tachycardia, hypotension, syncope Hypersensitivity reactions Dermatologic: skin rash, itching erythema, skin photosensitivity Blood dyscrasia: leukopenia, pancytopenia, anemia Cholestatic jaundice Miscellaneous reactions Headache Asthma Weight gain Abnormal lactation

with 50% of 42 patients preferring dexamethasone while 12% preferred prochlorperazine. The antidopaminergic action of phenothiazines is also responsible for much of the toxicity associated with these agents (Table 4). Individual phenothiazines vary markedly in the degree of side effects produced and it is for this reason that a particular agent such as prochlorperazine is chosen. Some phenothiazines with more potent antiemetic effects such as fluphenazine and trifluoperazine are associated with undesirably severe extrapyramidal side effects. 19 These can include tremor, rigidity, akathisia, dystonia, dyskinesia, tardive dyskinesia, and oculogyric crisis. The latter side effect can be very disconcerting as the patient may present in a mute state with the eyeballs rotated upward, seeming to disappear into the top of the forehead (Figure 1). Fortunately, oculogyric crisis is readily reversed by the i. v. administration of anticholinergic agents such as diphenhydramine (Benadryl®) or benztropine (Cogentin®). The usual diphenhydramine dose is 50 mg i.v. This is often administered prophylactically with the initial dose of phenothiazine antiemetic. The use dose of benztropine is 2 mg given i. v. To summarize, as single agents, the phenothiazines are proven antiemetics of low to moderate efficacy. In potency they appear inferior to cannabinoids, metoclopramide, or steroids when used alone. They are inadequate as single agents for cisplatin-based chemotherapy. A current role for phenothiazines as single agents is in chemotherapy programs of low emetogenic potential such as 5-FU or vinca alkaloid therapy.


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FIGURE 1. Drug-induced oculogyric cns1s. Note the typical facial expression. Patients may present in a mute state with extreme upward rotation of the eyes.

B. BUTYROPHENONES In a fashion similar to metoclopramide, the butyrophenones came into vogue as antiemetics following the introduction of cisplatin chemotherapy. Agents in this group include haloperidol and droperidol. These drugs are more extensively used as major tranquilizers in psychiatric patients, but since they are potent blockers of dopamine receptors, they are also effective antiemetics. 19 Grossman et al. 28 initially reported anecdotal information on the use of droperidol given i.v. in a dose of 0.5 mg 1 h prechemotherapy and repeated every 4 h. They observed complete control of vomiting in patients receiving cisplatin. Anecdotal reports by Paladine et al. 29 and Wilson et al. 30 also claimed efficacy for droperidol in cisplatin-induced emesis. Jacobs et al. 31 compared the activity of droperidol and prochloperazine in ten women with ovarian cancer. Each patient received droperidol 1 mg i.m. every 4 h p.r.n. or prochlorperazine 10 mg i.m. every 4 h p.r.n. All patients in this trial


215 experienced shorter episodes of vomiting and were more comfortable when they received droperidol rather than prochloperazine. A double-blind crossover study by Owens et al. 32 evaluated the efficacy of prochlorperazine, droperidol, and haloperidol in 27 patients receiving cisplatin chemotherapy. Patients were randomly assigned to receive either prochlorperazine 6 mg/m 2 i.m., droperidol I mg/m 2 i.m., or haloperidol I mg/m 2 i.m. prechemotherapy and repeated every 3 h for a total of six doses. Patients were receiving either low dose cisplatin ( < 100 mg/m 2 ) or high dose cisplatin ( > 100 mg/m 2 ). In this study there was no significant difference between the three agents with regard to the number of emetic episodes or the duration of emesis experienced. The major side effects associated with the butyrophenones include sedation and extrapyramidal toxicity. The future use of these agents will probably be confined to combination therapy, as their utilization as single agents appears to be decreasing.

C. METOCLOPRAMIDE Metoclopramide is believed to act through both the CTZ as a dopamine antagonist and peripherally by increasing GI tract motility. Both actions may be mediated via dopaminergic receptors. 19 This agent was initially introduced by Justin- Besancon and Laville 33 in 1964 for the treatment of vomiting not caused by antineoplastics. The low doses initially tested in antineoplastic trials failed to show any significant antiemetic effect. As a result, metoclopramide was not re-examined as an antiemetic until the introduction of cisplatin chemotherapy in the late 1970s. Preliminary studies using low dose metoclopramide for the treatment of cisplatin-induced nausea and vomiting again provided low, disappointing response rates. A double-blind randomized crossover study by Frytak et al. 34 in 1981 involving 100 patients showed the superiority of metoclopramide over prochlorperazine. Patients received cisplatin in doses varying from 40 to 120 mg/m 2 • Metoclopramide was given 20 mg p.o. t.i.d. Prochlorperazine was given 10 mg p.o. t.i.d. Although metoclopramide was shown to be superior to prochlorperazine, both drugs were limited in their overall effectiveness. An open trial by Kahn et al. 35 with 35 patients receiving cisplatin in a dose of I 00 mg/m 2 suggested a more beneficial role for this drug. In this study, a single metoclopramide dose of 20 mg p.o. seemed to provide 92% protection against vomiting. However, the results of this trial were not confirmed in our studies, such as that of Moertel et al. 36 in 1969 which utilized oral metoclopramide 20 mg in a double-blind randomized crossover design. In this trial metoclopramide appeared ineffective. The conflicting results of early studies ultimately led to the investigation of high-dose metoclopramide in cisplatin-induced emesis. Gralla et al. 37 performed a phase I trial involving 40 patients receiving cisplatin 120 mg/m 2 • Metoclopramide in ten incremental doses of 0.4 to 3 mg/kg was given i. v. 0. 5 h before cisplatin, 2 h post-treatment, and then three hourly doses for a total of five doses. In this study, metoclopramide toxicity was noted to be minimal at all dosage levels. While mild sedation occurred frequently, moderate sedation was noted in only a few


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patients. The most common serious side effect associated with metoclopramide therapy was extrapyramidal toxicity which occurred in only 2% of patients. This study (1.75 mg/kg per dose or 7.5 mg/kg total dose per course) exhibited a 75% response rate vs. a 56% response rate in patients who received lower doses. Once it was shown that metoclopramide could be safely administered i. v. in high doses, a logical step was to compare this regime to other agents. In a further series of three trials, Grall a et al. compared the antiemetic efficacy of metoclopramide to placebo, prochlorperazine, and THC. 8 The chemotherapy given was cisplatin 120 mg/m 2 • In design, the trials were double-blind randomized crossover studies and were limited to patients who had not received prior chemotherapy. The dose of metoclopramide was 2 mg/kg i. v. given 30 min prechemotherapy and 1.5, 3. 5, 5. 5, and 8. 5 h postchemotherapy. The first trial compared metoclopramide to placebo. It showed a significant reduction in the number of vomiting episodes from 10.5 to I and a shortening of the median duration of emesis from 3.6 to 2 h. The second trial compared metoclopramide to prochlorperazine 10 i.m. with both drugs given as per the original schedule. When compared with prochlorperazine, metoclopramide reduced the median number of vomiting episodes from 12 to 1.5. An interesting feature was the fact that prochlorperazine appeared to perform no better than the placebo. The third trial compared THC given in a dose of 10 mg/m 2 orally beginning 1.5 h before cisplatin and repeated at three hourly intervals for a total of five doses, to metoclopramide given as per the original schedule. Compared to the prochlorperazine study, patients did note some benefit with THC, but again metoclopramide appeared to be superior. Attention has focused on a number of practical aspects of metoclopramide delivery and dosing. A report by Agostinucci et al. 39 suggested that a continuous infusion of metoclopramide at 0.5 mg/kg/h for 12 h given after an initial bolus of 3 mg/kg provided better protection with fewer side effects than conventional intermittent bolus therapy. N avari et al. 40 compared metoclopramide as part of a multiagent antiemetic program given in a dose of 1 mg/kg every 2 h for six doses vs. the same drug given at a dose of 1 mg/kg i. v. bolus, followed by the continuous infusion of 0.5 mg/kg/h over 10 h. Other drugs included in the antiemetic cocktail were lorazepam, dexamethasone, and diphenhydramine. A continuous infusion regime resulted in better control, fewer dystonic reactions, and was 50% less costly. 40 Venner et al. 41 compared the continuous subcutaneous (s.c.) infusion of metoclopramide in a dose of 3 mg/kg given over 24 h via Travenol infusor with bolus i. v. metoclopramide in a dose of 1 mg/kg given 2, 4, 6 h after cisplatin chemotherapy. Both regimes were included in the initial i. v. dose of metoclopramide of 1 mg/kg given 15 min prechemotherapy. Based on efficacy, both patients and investigators generally preferred the i. v. bolus regime and there was no difference in toxicity between the two programs. 41 Several trials have also compared the effectiveness of bolus oral vs. bolus i. v. metoclopramide. Anthony et al., 42 in a double-blind randomized trial, studied the efficacy of high dose oral metoclopramide in 66 previously untreated patients.


2l9 Patients received cisplatin 60 mg/m 2 • Of 28 patients who received oral metoclopramide, 43% experienced no vomiting episodes within a 24-h period. This compared favorably with 58% of 32 patients in the i. v. group. Further, 33% of patients in the oral group experienced no nausea compared to 34% of 32 patients in the i. v. group. In terms of side effects, there was also little difference between the two treatments other than for an increased frequency of stools following oral metoclopramide therapy. Other trials have provided similar results, suggesting that the availability of high dose oral metoclopramide would allow such antiemetic therapy to be safely administered at home instead of requiring hospitalization. However, such outpatient therapy is currently limited by the fact that there is no commercial 50 mg metoclopramide preparation available. Another novel approach with potential application for outpatient therapy involves the use of intranasal metoclopramide. Citron et al. 43 administered intranasal metoclopramide as part of a multiagent antiemetic regime also containing lorazepam, prochlorperazine, and dexamethasone in patients receiving cisplatin chemotherapy in doses of 50 mg/m 2 or greater. The intranasal metoclopramide was administered 2.5, 6, IO, 14, and 18 h after initial antiemetic therapy. The optimal intranasal dose appeared to be 40 mg of metoclopramide in 0.1 cm 3 of gel. After 10 h, the intranasal therapy resulted in a significant decrease in the mean number of vomiting episodes and degree of nausea. Nasal irritation was not noted and plasma levels of metoclopramide correlated with the dose of drug administered. Several authors have suggested a relationship between metoclopramide blood levels and the therapeutic effectiveness of the drug. Meyer et al. 44 administered metoclopramide at 2 mg/kg body weight every 2 h for four doses in patients receiving cisplatin at 60 or 100 mg/m2 • Serum metoclopramide levels were measured by high pressure liquid chromatography (HPLC). In this study, no patient with a serum level 85 ng/ ml produced excellent control of emesis with complete success occurring in more than 75% of patients. This report also suggested that elderly patients showed an increased drug sensitivity that resulted in fewer emetic episodes when compared to younger patients with similar serum levels. However, other authors 45 have been unable to demonstrate a clear correlation between measured serum levels of metoclopramide and the prevention of cisplatininduced emesis. In McDermed's study of high-dose metoclopramide, any antiemetic response observed appeared more closely related to the dose of cisplatin used. Several recent trials have also documented that high dose bolus metoclopramide may be a less effective antiemetic than earlier studies had suggested. As noted previously, a study by Roemeling et al. 13 of high dose metoclopramide therapy in patients receiving cisplatin and doxorubicin found that the circadian timing of cisplatin administration appeared to be the major determinant of the frequency of vomiting, not the dose of metoclopramide administered. The toxicity associated with metoclopramide therapy is an extension of its pharmacological action. Side effects include sedation, diarrhea, and extrapyramidal toxicity. A high incidence


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of extrapyramidal effects, especially akathisia, has been reported in up to 30% of patients. 15 These extrapyramidal effects occur more frequently in young males. As in the case of phenothiazines, the prophylactic use of diphenhydramine or benztropine is usually effective. Symptoms such as akathisia may have a subtle onset. Drug-induced restlessness in such patients may be misinterpreted as being due to anxiety. It is important to recognize such extrapyramidal side effects early since they are preventable and may cause patients to refuse further treatments. Other side effects noted with metoclopramide include salt retention with edema and hypertension following high dose therapy. Two recent case reports indicate the drug may cause reversible impotence secondary to its effect in raising prolactin levels. 46 In summary, metoclopramide is an antiemetic of proven value nearly equivalent in efficacy to steroids and slightly superior in potency to cannabinoids or prochlorperazine. High dose metoclopramide has become a standard agent for use in combination with other antiemetics in the treatment of cisplatin-induced emesis. This is discussed in Section IV. D. 4-9-TETRAHYDROCANNABINOL Anecdotal reports of the effectiveness of marijuana in alleviating chemotherapyinduced nausea and vomiting first suggested its potential usefulness in antiemetic therapy. THC, the principal active agent of marijuana, and the semisynthetic derivative nabilone have been among the most widely studied antiemetics to date. 14 The precise mode of action of THC as an antiemetic is not known. THC inhibits prostaglandin synthesis in vitro and also possesses antiadrenergic activity. 19 Sallan et al. ,47 in a randomized double-blind crossover study compared THC to placebo in patients receiving a variety of noncisplatin containing regimens. Of 22 patients, 91% had symptoms refractory to other antiemetics, and all patients received prior chemotherapy. THC was given in a dose of 10 mg/m 2 p.o. every 4 h for three doses. Most patients had prior marijuana experience. In this study, complete or partial relief was obtained in 70% of patients treated with THC and none of those treated with placebo. A "high" often accompanied the antiemetic effect of THC and maintaining the ''high'' with additional THC sustained the antiemetic effectiveness. Frytak et al. ,48 in a randomized double-blind crossover trial compared THC to placebo and prochlorperazine in patients receiving 5-FU and methyl-CCNU (lomustine) for GI cancer. No patient was a known user of marijuana and all patients were new to chemotherapy. THC was given 15 mg p.o. every 4 h for three doses with the first dose 2 h prechemotherapy. Oral prochlorperazine 10 mg was given in the same schedule. In this trial, THC had superior antiemetic activity when compared to placebo, but showed no advantage over prochlorperazine. CNS toxicity was significantly more frequent and severe with THC. Ataxia, muddled thinking, abnormalities of perception, hallucinations, paresthesias, and hypotension were the most prominent side effects noted. However, the median patient age in this trial


p

219 (61 years) was considerably older than in any of the other THC studies reported in the literature. It has also been postulated that the lowered efficacy and increased toxicity noted in this study were related to the relatively large dose of THC and the shorter dose interval, which could result in erratic THC blood levels. With the dose schedule that was used, the emetic stimulus would not necessarily be counteracted, although toxicity could still occur. 14 Several trials have compared THC to phenothiazines. In a second randomized double-blind crossover trial, Sallan et al. 49 compared THC to prochlorperazine in patients receiving a variety of chemotherapeutic agents who failed to benefit from standard antiemetic therapy. Of patients studied, 20% were prior marijuana users and almost all received prior chemotherapy. THC was given 10 mg/m 2 p.o. every 4 h for three doses, with the first dose administered I h prechemotherapy. Prochlorperazine was given 10 mg/m 2 p.o. following the same schedule. Regardless of the chemotherapeutic regimen used, there were more complete responses to THC and 80% of 25 patients preferred this antiemetic. There was a higher proportion of complete responses to THC among younger patients and complete antiemetic responses tended to be associated with the occurrence of a "high". Four patients in this trial experienced THC toxicity which was described as being ''too high''. THC has also been compared to metoclopramide. In a randomized double-blind crossover trial, Gralla et al. 50 compared THC to metoclopramide in patients receiving cisplatin 120 mg/m 2 • Patients were at the same stage of chemotherapy and prior marijuana use was not described. THC was given 10 mg/m 2 p.o. 1.5 h prechemotherapy and l.5, 4.5, 7.5, and 10.5 h post-treatment. Metoclopramide was given 2 mg/kg i.v. 0.5 h pretreatment and l.5, 3.5, 5.5, and 8.5 h post-therapy. Patients receiving metoclopramide had significantly fewer episodes of vomiting (median two vs. eight) and better major antiemetic control as defined by two or fewer vomiting episodes. Both metoclopramide and THC were generally well tolerated by patients, but overall side effects, especially dizziness, orthostatic hypotension, and dry mouth, were more common in those receiving THC. The overall role of THC as an antiemetic in cancer chemotherapy was reviewed by Carey et al. 14 While 10 of the 17 studies examined showed THC to be superior to other antiemetic drugs and placebo, the authors concluded that differences in research design, patient populations, and pharmacological variables make it impossible to compare trial results properly. Moreover, even in studies that showed THC to be beneficial, it was not possible to isolate specific factors that predicted efficacy. For example, investigators have shown that the bioavailability of oral THC varies widely in individual patients, ranging from 8 to 24% of a given dose. Furthermore, while a number of authors have tried to relate plasma THC concentrations to THC efficacy, no consistent dose-response has been documented. The difficulty in performing double-blind studies of drugs with marked psychotropic side effects also complicates any evaluation.


220


TABLE 5 Possible Side Effects of Cannabinoids Central nervous system Somnolence "High" -relaxed feeling, euphoria Faintness, ataxia, peripheral paresthesia, headache Dysphoria, anxiety, confusion, depression, and paranoia Toxic delirium, depersonalization, and hallucinations Cardiovascular Orthostatic hypotension Syncope Tachycardia S-T segment and T-wave changes Autonomic Increased perspiration Dry mouth, blurred vision Difficulty in micturition Gastrointestinal Nausea, vomiting, and diarrhea Abdominal cramps Fecal incontinence Neuromuscular Loss of muscle strength Involuntary muscle jerking Decreased fine motor coordination Reproductive Depressed testosterone Decreased sperm count Abnormal menstruation Failure to ovulate Fetal damage

Potential adverse reactions to THC and nabilone are noted in Table 5. Toxicities severe enough to require withdrawal of THC, such as marked dysphoria or hallucinations, have been noted in 2% of younger patients and up to 35% of older individuals. 51 In summary, trials have shown THC to be an effective antiemetic in certain groups of patients. Used alone, it is equivalent or slightly superior in potency to prochlorperazine, but inferior to metoclopramide for cisplatin-based chemotherapy. Patients' attitudes toward THC and its side effects obviously play a major role in the extent to which this drug is tolerated and effective. THC is generally more effective in younger patients and this may be related to prior marijuana exposure. Certainly the high incidence of toxicity noted by Frytak et al. appeared to be agerelated. Any antiemetic benefit resulting from THC appears to be associated with subjective reports of a "high". The most frequent treatment schedule used has been 10 mg/m2 p.o. every 3 h beginning at least 2 h prechemotherapy and continuing


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for several doses. Lower doses in the range of 5 mg/m 2 may be just as effective, while increasing the dose to 15 mg/m 2 may result in a higher incidence of somnolence and toxicity. 14 In most countries THC remains a controlled substance, but a commercial formulation known generally as dronabinol (Maronol) has recently been marketed in the U.S. 52

E. NABILONE Nabilone is a synthetic cannabinoid that was developed in an attempt to improve absorption but decrease the euphoric effects of THC. The site of action of nabilone is unknown, but as with THC, research has attributed some of its antiemetic effect to the prostaglandin cyclic-nucleotide system. 19 The plasma half-life of nabilone is 2 h and its absorption from the gut is more uniform and predictable than THC. 53 Nabilone is an effective antiemetic. In a double-blind crossover trial, Wada et al. 54 compared nabilone to placebo in 114 chemotherapy patients, 40 of whom were receiving cisplatin. The cisplatin dose was not specified. Approximately half the patients received prior chemotherapy. The first nabilone dose of 2 mg was given 12 h prechemotherapy, the second within 1 to 3 h of treatment, while one further dose was administered 12 h postchemotherapy. Both nausea and vomiting were significantly reduced in the nabilone-treated group. Of 92 patients, 70% preferred nabilone to placebo. Mild to moderate adverse reactions were common and included drowsiness, dry mouth, and euphoria (25 to 40%); dysphoria, ataxia, and lightheadedness (9 to 10%); hypotension (5%); and hallucinations (

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