Cancer Investigation, 4(5), 379-385 ( 1986)

ORIGINAL ARTICLES

Comparison of Metoclopramide and Metoclopramide Plus Dexamethasone for Complete Protection from Cisplatinum- Induced Emesis

Steven M. Grunberg, M.D., Wallace L. Akerley, M.D., Mark D. Krailo, Ph.D., Kay B. Johnson, R.N., Carole R. Baker, M.N., and Penelope A. Cariffe, M.N. Division of Medical Oncology USC Comprehensive Cancer Center and LAC-USC Medical Center and Department of Preventive Medicine University of Southern California School of Medicine Los Angeles, California

ABSTRACT

Metoclopramide was compared to a metoclopramide plus dexamethasone com- bination in patients receiving high-dose cisplatinum. Metoclopramide 2 mglkg in- travenously was given ever?, 2 hours for 4 doses during two consecutive chemotherapy cycles. A randomized double-blind crossover was used with placebo or dexamethasone 20 mg given intravenously before the$rst metoclopramide dose. nirty-six patients completed both study arms. There was no difference in mean vomiting episodes (1.92 for metoclopramide versus 1.33 for the combination, p = 0.20). However complete protection (no vomiting episodes) was achieved in 56 % receiving the combination but only 36% receiving metoclopramide alone (p < 0.08). No signijkant difference in toxicity or patient preference was noted. Late nausea or vomiting lasting 2 to 7 days appeared in 26% of cycles and was associated with but not completely ex- plained by a greater number of acute vomiting episodes. Combination antiemetic therapy can achieve a higher incidence of complete protection from cisplatinum- induced vomiting. However, late nausea and vomiting may require modijication of present regimens.

Presented in part at the 21st Annual Meeting of the American Society of Clinical Oncology, held in Houston. Texas. May 1985.

Copyright 1986 by Marcel Dekker. Inc.

379

0735-7907/S6/0405-0379$3.50/0

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380 Grunberg et al.

INTRODUCTION

Cisplatinum has proven to be one of the most powerful of the chemotherapeutic agents but also one of the most emetogenic (1). Where nausea and vomiting induced by earlier chemotherapeutic agents had been, in many cases, adequately controlled by moderate dose phenothiazines. cisplatinum-induced nausea and vomiting is relatively resistant to such control (2). The introduction and widespread use of this agent therefore led to a need for correspondingly more potent antiemetics.

Major strides in antiemetic therapy have been made in the last five years. The description by Gralla et al. (2) of high-dose intravenous metoclopramide as an effective antiemetic agent for cisplatinum-induced vomiting established a new benchmark for antiemetic effectiveness. In this study the median number of vomiting episodes after high-dose cisplatinum was reduced from 10.5 with placebo to 1.0 with metoclopramide. Our group ( 3 ) demonstrated in a previous study that haloperidol, a butyrophenone, can produce significant protection from cisplatinum-induced vomiting and that such protection can be correlated with protection afforded by metoclopramide itself. Dexamethasone has also been suggested as an ef- fective antiemetic agent for both non-cisplatinum- containing ( 4 3 and cisplatinum-containing (6) regimens. Using a combined oral and intravenous regimen in a group receiving mainly cisplatinum-containing chemotherapy. Aapro et al. (7) demonstrated that either dexamethasone or metoclopramide has significant activity with a 25% to 30% major response rate in each group.

Identification of a number of effective single antiemetic agents naturally led to the concept of combination anti- emetic therapy as a possible method of increasing efficacy in a manner similar to the increased efficacy noted with combination chemotherapy. However a basic principle of combination therapy is that agents to be combined should be non-cross resistant; that is, that a different spectrum of activity or mechanism of action would be required to increase the efficacy of the combination over that of the individual agents (8).

Emetogenic stimuli are known to arrive at the vomiting center through several afferent pathways including the chemoreceptor trigger zone, the peripheral pathway, and the cerebral pathway (9). However, it is striking that many of the major antiemetic families including phenothiazines, butyrophenones. and metoclopramide itself are all thought to act through antidopaminergic pathways affecting the chemoreceptor trigger zone (9). In view of this similar mechanism of action, these agents may not be good can- didates for combination with each other. The mechanism

of action of dexamethasone as an antiemetic is not com- pletely understood (7) but would not necessarily follow the same biochemical pathway. Combination of dex- amethasone with other agents might therefore be par- ticularly promising.

We conducted the present study using a randomized double-blind crossover design to compare a combination of dexamethasone and metoclopramide to metoclopramide alone in the prevention of cisplatinum-induced vomiting. Dexamethasone was administered in a single dose before cisplatinum based on studies ( 10) suggesting equivalence of this regimen to a multidose dexamethasone regimen. Metoclopramide was administered in a multidose intra- venous regimen before and after cisplatinum. The results of this comparative study are now presented.

MATERIALS AND METHODS

Patient Selection

Adult patients with malignancy were eligible if they were scheduled to receive at least two similar cycles of cisplatinum-containing chemotherapy. Karnofsky performance status of at least 50% and life expectancy of at least 3 months were required. Adequate renal and hepatic reserve as indicated by a creatinine 5 2 mg% and serum glutamate oxaloacetic transaminase (SGOT) and bilirubin 5 2 X normal were required. Signed in- formed consent was obtained from all patients. Patients were considered ineligible if they had experienced prior adverse reactions to either dexamethasone or metoclopramide. Patients with persistent vomiting prior to chemotherapy and patients with other etiologies for vomiting including gastrointestinal obstruction, active pep- tic ulcer disease, or central nervous system metastases were not eligible for this study. Patients were not treated with other antiemetics, steroids, or sedatives for 24 hours prior to and during chemotherapy.

Study Design

Antiemetic efficacy was assessed using a randomized double-blind crossover design. Patients were randomized using the minimization method (1 1) with Karnofsky per- formance status and prior chemotherapy as stratification factors. Patients received either metoclopramide plus dex- amethasone or metoclopramide alone during the first cy- cle of chemotherapy and received the alternate regimen during the second cycle of chemotherapy. Blinding was maintained through preparation of a 5 cc coded syringe

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Combination Antiemetic Therapy 38 1

containing either dexamethasone 20 mg or placebo. The coded syringe was administered IV over 3 to S min and followed by metoclopramide 2 mg/kg IV q2h x 4. Each metoclopramide dose was administered in SO cc over 30 minutes. Cisplatinum was administered over 1 hour be- tween the first and second doses of metoclopramide. This study was performed after approval by the LAC-USC Medical Center Human Research Committee.

Patient Observation

Number of vomiting episodes was the primary index of efficacy of each regimen. Number of vomiting episodes was tabulated by oncology ward nurses and through pa- tient reporting. Patients were also interviewed by an on- cology research nurse on the morning following chemo- therapy to confirm the number of vomiting episodes and to evaluate possible drug-induced toxicity. Patients were observed in the hospital for 12 to 18 hours after the ad- ministration of cisplatinum. Patients were interviewed on follow-up clinic and hospital visits for additional toxicities and for occurrence of nausea or vomiting after the primary period of evaluation. At the completion of both cycles of antiemetic therapy, patient preference was also recorded.

Data Analysis

Patients were considered fully evaluable if they com- pleted both cycles of antiemetic therapy. The mean number of vomiting episodes was compared using a one sided t test (12). Number of patients achieving complete protection (no vomiting episodes) was compared using Fisher's exact test (13). Associations between the number of vomiting episodes and various concomitant variables such as order of treatment, type of malignancy, and other chemotherapeutic agents received were examined using the Wilcoxon test (12). The relationship of late nausea and vomiting to treatment regimen. type of malignancy. other chemotherapeutic agents received, and number of initial vomiting episodes was examined using logistic regression (13). The adequacy of fit of this modelling pro- cedure was assessed using a chi-square goodness of fit test (14).

RESULTS

Patient Characteristics

Forty-nine patients were entered on this protocol be- tween July 1983 and January 1985 (Table I ) . Of this group, 36 patients completed both cycles of antiemetic

Table 1

Patients Entered on Study

Patients entered 49 Patients evaluable 36 Patients inevaluable

Change of therapy 13

4 Extrapyramidal reaction 3 Protocol error

Early death 3

I Refused therapy 1

Lost to follow-up 1

therapy and are considered fully evaluable. The 13 in- evaluable patients included 5 patients in whom rapid pro- gression of disease prevented completion of planned anti- emetic therapy (4 patients who underwent a major change of chemotherapy between the two cycles. and 1 patient who suffered early death). Three patients were eliminated due to protocol errors and 1 patient was lost to follow- up. Also included are 4 patients removed from protocol due to severe drug toxicity. Three of these patients had significant extrapyramidal reactions, including 1 patient with difficulty breathing and rigid extremities relieved by Cogentin and diphenhydramine. 1 patient with oculogyric crisis, and 1 patient with torticollis. One patient refused a second cycle of therapy due to a severe anxiety reac- tion during the first cycle. Further analyses are restricted to the 36 fully evaluable patients.

The 36 fully evaluable patients are described in Tables 2 and 3. They were predominantly male (24 male) and predominantly older (27 patients over the age of 35 years). Division by stratification factors revealed that 3 1 patients had a high Karnofsky performance status and 30 patients had received no prior chemotherapy. Lung cancer was the most common tumor type, accounting for 14 patients. Head and neck cancer (8 patients) and testicular cancer (7 patients) were also common. A majority of the patients were receiving high-dose cisplatinum (mean dose 84 mg/m*; median dose 94 mg/m?). All patients were receiv- ing combination chemotherapy with the most common ad- ditional agent being bleomycin (17 patients) followed by vinblastine (12 patients) and etoposide ( I 1 patients).

Efficacy

Patients receiving metoclopramide alone suffered a mean of 1.92 vomiting episodes (range 0-8 episodes) as compared to a mean of 1.33 vomiting episodes (range 0-9

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382 Grunberg et al.

Table 2

Charucteri.7ric.s of Evuluable Patients

> 35 Yean 5 35 Years

Sex Male Female

Tumor type Lung Head and neck Testis Bladder Melanoma Uterus Unknown primary

Karnofsky status High (80-100%) LOW (50-70%)

Prior chemotherapy Yes No

episodes) in patients receiving metoclopramide plus dex- amethasone (Table 4). There was no significant difference in mean or median number of vomiting episodes between the two groups (p = 0.20, t test; p = 0.30. Wilcoxon

Table 3

Chemotherapy Administered

Patients ( % )

Cisplatinum dose 80- 100 mgini' 60-79 mg/mZ 40-59 mg/mz

Concomitant chemotherapy Bleomycin Vinblastine Etoposide Vincristine Mitomycin C Adriamycin Cyclophosphamide 5-Fluorouracil Megestrol acetate

24 (67) 10 (28) 2 ( 5 )

17 (47) 12 ( 3 3 ) I I (31) 8 (22) 7 (19) 5 (14)

1 ( 3 ) I ( 3 )

5 (14)

text). Comparison using the Wilcoxon test also indicated that number of vomiting episodes did not differ based on the order in which the antiemetic regimens were given. the patient's underlying disease, or the additional emetogenic chemotherapeutic agents administered. How- ever, complete protection (no vomiting episodes) was achieved in 20/36 patients (56%) receiving metoclopra- mide plus dexamethasone but in only 13/36 patients (36%) of those receiving metoclopramide alone. A significantly greater number of patients therefore achieved complete protection with the combination regimen (p < 0.08. Fisher's exact test). Of the 36 evaluable patients.

Table 4

Ef3scucy (36 Purients)

Metoclopramide Metoclopramide dexaniethasone

Episodes of vomiting Mean Range

1.92 I .33 0-8 0-9

p = 0.20

Complete protection 13 20 p < 0.08

Patient preference 8 I I

Late nausea or vomiting 10 (3 I patients)

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Combination Antiernetic Therapy 383

Table 5

Complete Protection

Metocloprarnide

Yes No

Metocloprarnide Yes 10 10

Dexarnethasone N o 3 13

10 patients achieved complete protection with both regimens, 13 patients achieved complete protection with neither regimen, and 13 patients achieved complete pro- tection with only one regimen (Table 5). Of the 13 pa- tients achieving complete protection with only one regimen, 10 patients achieved complete protection with metoclopramide plus dexamethasone while only 3 patients achieved complete protection with metoclopramide alone. Patient preference among those expressing a preference was evenly divided between the two regimens with 11 pa- tients preferring metoclopramide plus dexamethasone and 8 patients preferring metoclopramide alone (Table 4).

Late nausea or vomiting (nausea or vomiting occurring 2 to 7 days after chemotherapy) continues to be a signifi- cant problem (Table 4). Of the 31 patients who respond- ed to queries concerning this problem after both treatment cycles, 10131 (32%) reported late nausea or vomiting following metoclopramide alone and 6/3 1 (19%) reported late nausea or vomiting following metoclopramide plus dexamethasone (p = 0.38, Fisher’s exact test). The 16 cycles in which late nausea or vomiting were seen included

6 patients in whom late nausea or vomiting appeared after both antiemetic regimens and 4 patients in whom late nausea or vomiting appeared only after metoclopramide alone. Complete protection from acute nausea and vomiting did not guarantee protection from late nausea or vomiting since 3/16 (19%) of these episodes followed complete protection from acute nausea or vomiting. The range of number of vomiting episodes (0-9 episodes) in these 16 cycles was the same as that for the group of evaluable patients as a whole. However. the mean of 3.31 acute vomiting episodes per cycle for the cycles associated with late nausea or vomiting was significantly greater than the mean of 1.04 acute vomiting episodes per cycle for those without late nausea or vomiting (p = 0.0003, t test). Yet the chi-square goodness of fit test indicated that the number of acute vomiting episodes alone is not sufficient to explain the phenomenon (p < 0.01).

Toxicity

Toxicity was similar between the two regimens (Table 6). Fatigue and drowsiness was the most common toxicity and was reported slightly more frequently after metoclopramide alone. Diarrhea was also reported more commonly after metoclopramide alone while anxiety was reported more commonly after the combination. Depres- sion, anorexia, and dizziness were rarely seen with either regimen. Extrapyramidal reactions not requiring discon- tinuation of therapy were seen in 2 patients in each regimen and included 1 episode of difficulty with visual focus, 1 episode of eye spasm, 1 episode of mild jaw tightness, and 1 episode of mild tremor.

Table 6

Toxicity

Metocloprarnide Metocloprarnide (X) dexarnethasone ( % )

Tiredldrowsy 19 (53) 15 (42)

Diarrhea 13 (36) 10 (28)

Anxiety 7 (19) 10 (28)

Depression 2 (6) 2 (6)

Anorexia 1 (3) 1 (3 )

Dizziness 1 (3)

Extrapyramidal 2 (6)

3 (8)

2 (6)

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384 Grunberg et al.

DISCUSSION

We have demonstrated a significant advantage for metoclopramide plus dexamethasone over metoclopramide alone in achieving complete protection from cisplatinum- induced vomiting. Our study therefore confirms the im- provement in antiemetic control noted by Kris et al. (10) in a series of consecutive trials of individual regimens in which first dexamethasone and then diphenhydramine were added to metoclopramide. Since these trials were neither randomized nor simultaneous, the present study presents a more rigorous demonstration of the principle that two dissimilar agents can serve complementary func- tions in achieving an overall increase in antiemetic ef- ficacy. Our study also confirms that of Allan’s group (15) demonstrating an advantage for dexamethasone plus metoclopramide as compared to metoclopramide alone in patients receiving chemotherapy with high- or low-dose cisplatinum-containing regimens.

A major consideration in analysis of antiemetic studies is selection of an appropriate parameter of efficacy. In early studies of high-dose intravenous metoclopramide, total number of vomiting episodes was the parameter of interest (2,16). Since 10.5 vomiting episodes can be ex- pected after a course of high-dose cisplatinum treated with placebo alone, significant improvement could easily be detected using this parameter. However, the present benchmark for comparative studies is metoclopramide, which itself reduces the mean number of vomiting episodes to two or less. With only a small improvement possible in this parameter, Type I1 error (establishment of a false negative result) becomes a real consideration (17). Further antiemetic studies will therefore require either greatly increased numbers of patients in the study groups to detect small differences or identification of a more sensitive parameter of interest. Such a parameter does exist for antiemetic studies in the use GE complete protection as the ultimate goal. Just as efficacy studies of chemotherapy may use the parameter of response rate (complete response + partial response) until excellent regimens are identified and then concentrate upon com- plete response only, so antiemetic studies which originally concentrated upon reduction in the number of vomiting episodes may now concentrate upon complete protection as the preferred parameter. In the present study. com- parison of only the mean number of vomiting episodes would not have indicated a significant advantage for the combination regimen since both arms demonstrated a mean of less than two vomiting episodes. However, the combination regimen did show a significant advantage in the percentage of patients achieving complete protection,

a result of significant benefit to the patients themselves. By comparison, Strum et al. (18) utilized a similar ex- perimental design and also found a greater incidence of complete protection using the combination of metoclo- pramide plus dexamethasone but studied a smaller patient population and reported no statistically significant dif- ference between the groups.

Since butyrophenones are also antidopaminergic agents and have been shown to have antiemetic efficacy that cor- relates with and is comparable to the antiemetic efficacy of metoclopramide (3) , combinations of dexamethasone and a butyrophenone might also be considered promis- ing. In a single-arm study Mason et al. (19) did indeed report excellent antiemetic results with the combination of methylprednisolone and droperidol. More recently Donovitz and co-workers (20) reported a marked reduc- tion in vomiting episodes when methylprednisolone plus droperidol is compared to metoclopramide plus droperi- dol. Since metoclopramide and droperidol are both anti- dopaminergic agents, combination of the two would not be expected to provide additional benefit and the study could be considered to again show the advantage of a steroid plus a butyrophenone over a butyrophenone ef- fectively alone.

Toxicity of our two regimens were similar with fatigue and drowsiness being most common. Although diarrhea was slightly less common after metoclopramide plus dex- amethasone, we did not observe the marked reduction in toxicity with the combination regimen reported by others ( lO , l5 ) . We also did not observe a corresponding dif- ference in patient preference ( 1 8,20). Extrapyramidal reactions do continue to be noted. Three of the four pa- tients who were unable to complete the protocol due to drug toxicity were removed for extrapyramidal reactions and the fourth experienced a severe anxiety reaction that may also have been drug related. In addition, four pa- tients experienced possible minor extrapyramidal reactions during therapy. In their series of consecutive studies, Kris et al. ( 10) noted a disappearance of major extrapyramidal reactions when either dexamethasone o r diphenhydraminc was added to the metoclopramide regimen. In view of the potentially serious nature of such reactions and the lack of toxicity of diphenhydramine itself, addition of diphenhydramine to combination antiemetic regimens may be desirable.

We as well as others ( 2 I ) continue to be concerned by the incidence of late nausea and vomiting after cisplatinum chemotherapy. As in our previous study (3), approximate- ly 30% of the patients did experience nausea or vomiting from two to seven days after cisplatinum chemotherapy. Patients who experienced late nausea and vomiting did

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combination Antiemetic Therapy 385

have a significantly greater number of acute vomiting episodes than those who did not. suggesting either an an- ticipatory component or a carrjover effect u ith delayed recovery from acute nausea and vomiting. If poor acute control of nausea and vomiting were the explanation for the late effect, more potent regimens for the prevention of acute cisplatinum-induced vomiting would alleviate the problem. However complete protection from acute nausea and vomiting did not always prevent appearance of late nausea and vomiting and further analy\i\ revealed that thc occurrence of acute nausea and vomiting was not wff i - cient as the sole explanation for the late effect. Late nausea and vomiting may therefore be a separate entity requir- ing a separate therapeutic strategy. In view of the pres- ent exccllent control of acute nausea and vomiting with combination antiemetic regimens. late nausea and vomiting may become the ma.ior concern in antiemetic therapy and studies to develop a long-term oral outpatient regimen for control o f late nausea and vomiting are in progress.

In summary we have utilized a randomized double-blind crossover design t o demonstrate that a combination of anti- emetic agents from unrelated families (metoclopraniide and dexamethasone) can increase efficacy over that noted with metoclopramide alone. We have utilized evaluation of a more sensitive parameter (complete protection) to avoid potential Type I1 error inherent in the use of the traditional parameter of reduction in the number of vomiting episodes. Late nausea and vomiting continues to emerge as a significant problem that may require ad- ditional long-term regimens for control. Development o f more sophisticated antiemetic strategies should continue to improve the quality of life of patients undergoing emetogenic chemotherapy.

Addre\s reprint requests to Steven M. Grunherg. M.D . . l I i \ , i \ ion o f Medical Oncology. USC Comprehen\ive Cancer Center. 2015 7onal Avenue, Los Angelc\. C A 90033.

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( . i /~ lc , \ 1 1 1 l i i / i ' i - i i i t l A . l r ~ , l i c . / J i ~ , . Xth cd . L ~ I I L . ~ by G W Th0i-11. K I )

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