Chemotherapy-Induced Nausea an
Abstract
LIrorwbinol(MarinoP’. I\ltjxmtiLaboratories, Columbus, OH) and prochlorperazine wre !estedajane aad in combinatiou in TVmudontired, doctbk-blind, parallel group, ?&m(s uwe rcrttdoaired to receive either 1) dronabinol Ii) mg #w&o; 2) placebo plus prochlorpr amine 10 mg every 6 hr; or 3) #rachlor$erarine, each IO mg every 6 hr. Antiemetic treatnwnt was or to aud continued J~)Y24 hr aper the last dose of chemotherapy; all #x&Ws in group 3 versus 47% in group I and 60% naww after chemothera@. In addition, the median duration nausea were sign$icanti” less with combination therapy. emothera$y in 4l%, 55%, and 35% of /nztient.sin groups I, e median duration per episode of vomiting was 1 min in 1 and four in group 2. Side efleck, primarily CNS. were than in group 2; addition of prochlorperazine Codronabinol todecreawthe&quencyof$yphs one ’ e$ ecLFsem with the latter agent. Tlte
of
U.S. Camr Pain Relief Committee, 1991 Pubfiied by Elsevier. New York. New York
0885-3924/91/$3.50
Antiemetic, dronabinol, cannabhids, nausea and vomiting
tetrall~(lroca?llla.binol, chemolhe~a~-ind~lced
sesame oil, has been found to be an effective agent in a number of randomized trials.“.’ Its side effect profile is different from that of prorhlorperazine, a commonly used phe-
antiemetic Nausea and vomiting
of cancer
are common
chemotherapy.
cause significant
morbidity
so severe that patients
These
side effects symptoms
and are sometimes
stup treatment
to avoid
them. Several classes of drugs have been used to treat chemotherapy-induced nausea and vomiting. As with cytotoxics, combinations of antiemetics are often more effective than single agents.‘.’ Dronabinol, delta-9-tctrahydrocanrrabinol in
nothiazine
antiemetic.
chlorperazine
and
pro-
have been tested pr&ousIy,
~rot~a~~~~ol
ei-
ther comparatively’“-” or in coml~ination.7*H The purpose of this study was to compare the efficacy and toxicity of dronahinol and prochlorperazine, each alone and in coml)ination. fin control of chemotheiapy~i~~~i~~ce~~ nausea ;md vomiting.
Tulrl~ I Patient Characteristics Dronabinol N Sex.
M/F
Race White Black Hispanic Other
Age, yr Median Range BSA. m’ Median Range Primary tumorb Breast Colon
21 10111
Yrochlorperazine
Combination
Total
21
20
62
IO1I 1
9/l 1
29133
11
13
12
3 5 2
.5 3 0
4 ,t 0
47 20-68
49 22-64
55.5 25-65
52 20-68 I .3-2.4
1.6
1.8
Sti 12 12
2
1.3-2. I
I .5-2.4
1.8 1.3-2.1
8
S
8
I 3 5 4
I 3 6 3
1 2 6 3
Number of agents I 2 or 3 4 Withdrew prior to chemotherapy
1 15 2 3
2 17 I I
3 12 3 2
6 44 6 6
Number of days 1 2-5
15 3
14 6
15 3
44 12
Emetogenicity of chemotherapy High Low
16 2
I8 2
14 4
48 N
Lung Lymphoma Miscellaneous”
1.8 24 3 8 17 IO
aNot more than one per treatment arm of the following: esophagus, gastric, liver, mycloma. pancreas, testis, and tongue.
A total of 62 patients at 9 centers were enrolled in this randomized, parallel group. double-blind study. Patients were eligible if they were between the ages of 18 and 69 years, inclusive, and being treated cancer with other than agents or high-&se ( > 6Omg/m”) cisplatin. Patients with central nervous system primaries or metastases were excluded. Patients could receive ens lasting up to 5 days. The roved by the institutional reof each participating institution. Patient characteristics and the chemotherapy administered are shown in Table I. All patients had received prior chemotherapy and prior anApproximately one-half of tiemetic therapy.
each group had previously received pmchlorpwazine; no patient had previously received dronabinol or any other cannabinoid. Twentyseven percent of patients had experienced fewer than two episodes of nausea or vomiting with prior chemotherapylantiemetic regimen: riced between two and ten ephad experienced more than IO episodes of nausea or vomiting. There were no significant differences among groups in patient characteristics or chemotherapy. The most commonly used drugs were cyclaphosphamide and doxorubicin (26 patients each), Muorouracil (14 patients), vincristine (13 patients), and etoposide (10 patients). Seventy-nine percent of patients received either two or three drug cambinatians, All but six patients were treated as outpatients. All patients gave written informed consent. Patients were stratified by study center and by the emetogenieity of the chemotherapy used. Low-emetogenicity agents used included bleomycin, oral cyclophosphamide. fluorouracil. methotrexate. vinblastine, and vincristine. Patients were stratified to the high-emetogenicity gmup if they received at least one high-emetogenicity agent. All but eight patients received at least one high-emetogenicity agent. Twenty-four hours prior to the start of a CHUM of chemotherapy, patients were started on study medication. Antiemetics were continued for 24 hr after the last dose of chemotherapy* Up to a total of 6 days (1 day prior and up to 5 days on chemotherapy). Patients were randomized to one of three treztment arms: 1) dronabinol (Marinol@, Roxane Laboratories,
Columbus, OH) 10 mg by mouth every 6 hr plus placebo: 2) prochlorperazine 10 mg by mouth every 6 hr plus placebo: or 3) dronabinol (MarinoI@) plus prochlorperazine, each 10 mg by mouth every 6 hr. Patients were evaluated and treatment compliance was checked by pill count daily through 1 day after the last dose of chemotherapy. Parameters evaluated included number and duration of episodes of nausea and vomiting, and severity of nausea as indicated on a visual analogue scale,” which is a IO-cm line with the words “No nausea” and “Extreme nausea” at either end. Patients were instructed to mark the scale at any point for each episode of nausea to describe the intensity of the episode. Patients were questioned at each visit regarding the occurrence of side effects. For evaluation of patient characteristics, disposition, and side effects, Chi-square and Fisher’s Exact Test analyses were used. Wilcoxon’s Rank Test was used to compare medians in efficacy analyses. For statistical purposes when calculating medians per episode, patients not reporting nausea or vomiting were assigned a zero value for nausea frequency, duration and severity, or vomiting frequency and duration, respectively. Differences between groups were considered significant if the two-tailed P value was less than equal to .05.
Results Of the 62 patients entered into the study, 60 were evaluable for efficacy against anticipatory nausea and vomiting. One patient in the dronabinol group received a concomitant antiemetic, and one in the combination group was found during the study to have brain metastases. As shown in Table 2, 54 patients were evaluable for efficacy against chemotherapy-induced nausea and vomiting. Three patients in the dronabinol group and two in the combination group withdrew from the study due to adverse effects prior to chemotherapy administration. One patient who was randomized to the prochlorperazine group was withdrawn prior to chemotherapy due to a protocol violation. Fifteen evaluable patients discontinued study antiemetics prior to completion of the planned number of doses. Ten of these were in the dronabinol group. All but one of the patients who discontinued therapy because of adverse effects did so because of neuropsychotropic
N
21
Withdrawn prior to chemotherapy Evaluable for efficacy Completed at least 2 days of study medication Completed study Reasons for withdrawal Side effects’ Insufficient therapeutic effect Other”
3 I7
PI 1 20
HO 2 17
62 6 54
I3 7
‘LO 17
16 15
49 39
10 2 2
0 2 L’
4 0 I
14 4 5
“Dronabinol versus prochlorperazine P < 0.0 I, versus combination P = 0.06: prochlorpcra~ine version ccmrbirlarion P c 0.05. bOther (one each): dronabinol: intercurrent illness, protocol violation: pr~)chlolperarine: proli~co~ violation, noncompliance; combination: intercurrent illness. symptoms; one patient discontinued because of hypotension. Side effects began during the prechemotherapy day for all patients discontinuing study medication due to side effects. The median age of patients in the dronabinol group who completed the study was 55; for those discontinuing due to side effects, the median age
was 45.5. 1111the combination group, the median age for those completing was 57; for those discontinuing due IO side effects, it was 50.
Side Eflects All patients were evaluable for side effects, which are listed in Table 3. Significantly more Tablp 3
Side Effects Dronabinol
N Total number reporGng side effects” Neurologic’ Somnolence Dizziness Asthenia Vision disturbances Confusion Depersonalization Paranoid reaction Anxiety Depression Paresthesias Digestive Dry mouth Diarrhea Cardiovascular Tachycardia Respiratory Dyspnea Other body systems Headache
21 16 13 4 7 2 3 2 3 1 I 2 1 5 2 2 3 2 0 0 3 1
Note: Side effects reported by only one patient: dronabinol: paralysis, thirst, and urinary incontinence; prochlorperazine: insomnia, speech disorder, and tremor. “Dronabinol versus prochlorperazine P < 0.01. bDronabinol versus prochlorperazine P < 0.06.
Prochlorperazine 21 7 6 3 1 1 0 0 0 0 0 0 1 0 0 0 1 0 1 1 1 1
Combination 20 II 11 5 2 2 2 I 0 2 I 0 0 2 2 0 0 0 1 1 1 1
T%ltal 6r! rd.4 30 I2 10 5 5 3 3 3 2 2 2 7 4 2 4 2 2 I 5 3
agitation. chest pain, hypotension, increased appcGte. syncope and taste abnormality; combination: ataxia,
Vomilina
Nausea or Vomiting
90
OR0 PRO cow0
Fig. 1. Percent of patients withnut nausea andlar vomiting.
patientsin the dmllabinal than in the ptochlorside effects twine group experienced < .Ol), The differences between the dronabinol and combination groups and between the prochlorperaaine and combination groups in the proportion of patients reporting side effects were not statistically significant. Of those patients completing the study the dronabinol group, 6 (35 prochlorperazine group, and 7 (47%) of 15 in the combination group experienced side effects. Most side effects were mild or moderate. T~IW paticrria iu the dronabino!, none in the prochlorperaaine, and one in the combination
group experienced severe side effects. All patients with btvere side effects had neurological side effects; in addition, the patient in the combination group noted severe dyspnea and dry mouth as well. None of the side effects caused sequelae and all were manageable with observation or simple supportive measures. Neuropsychotropic side effects were the most common, occurring in 48% of all patients: 62% in the dronabinol group, 29% in the prochlorperazine group, and 55% in the combination group (dronabinol versus prochlorperazine P = 96: other comparisons were not significant). The symptoms occurring were those usually as-
IQa
1
NIluWIl
Vomiting Nausea or Vomiting
OR0 PRO COMBO
MI0 PRO COMBO
OR0 PRO COMBO
Fig. 2. Percent of patients with two or fewer episodes of nausea and/or vomiting.
Nausea 0’ Vomiting Vomiting
i,,,
.__J
DRO PRO COMBO
sociated with each ofthe drugs used in this trial: somnolence for botb drugs and dysphoric symptoms for dronabinol. Eight patients in the dronabinol group, none in the prochlorperazine, and three in the combination group experienced dysphoric symptoms. No correlation was found between the incidence of psychotropic effects and age or degree of antiemctic control.
Anticipatory nausea occurred in a total of I1 patients: 30% of the dronabinol, none of the prochlorperazine. and 26% of the combination group (dronabinol versus prochiorperazine and combination versus prochlorperazine each P < .05). One patient in the dronabinol group had a single 5-min episode of anticipatory vomiting; no anticipatory vomiting occurred in either of the other two groups. Data on the incidence of chemotherapy-induced nausea and vomiting are shown in Figures I and 2. Fewer patients in the dronabinol and combination groups than in the prochlor-
L--_,,
L-
____I
DA0 PRO COMBO
/(
I
DA0 PRO COMBO
perazine group experienced nause;~ an&~ vomiting; these differences were not Stiitistick3lly significant. Forty-one percent of’ patients in the dronabinol group, 47% in the combination croup, and only 30% in the proch!orperazine iroup experienced no nausea or vomiting. In many studies, two or fewer episodes of nausea or vomiting is used as a measure of adequate antiemetic control. Using this limit. 7 1% of the dronabinol, 65%. of’ the combination, and 45%, of the prochlorperazine group had good antiemetic controL Although these differences were not statistically significant, there is a consistent trend in the data favoring the groups receiving dronabinol. As shown in Figure 3, the median duration per episode of nausea or vomiting was significantly less in the combination group than for either single agent, 5 min for either single agent versus 2 min for the combination (P < .OOl for combination versus either single agent). Furthermore, for nausea or vomiting alone, the duration per episode was less for patients receiving
DA0
PRO
VISUAL ANALOG
SCALE SEVERENAUSEA
NO NAUSEA Fig. 4. Median severity OF tlausril.
dronabjnol than for those receiving prochlorperazme, 10 versus 15 min for nausea, and 2 versus 4 min for vomiting. There were no significant differences among the groups in the total duration of nausea or vomiting. Figure 4 shows the median severity per episode of nausea, as evaluated on a visual analogue scale. The severity of nausea was markedly less for patients receiving combination antiemetic therapy than for those receiving either single agent alone (I’ < 90 1).
0ver the past decade, many randomized studies have demonstrated the t#icacy of oral dmnabinol in controlling nausea and vomiting from a variety of chemotherapeutic regimens. Several studies have compared dronabinol with prochlorperazine, each used as single ts;q”‘Xa“gall were randomized. and all but the last was double-blinded. Data from the individual studies and the composite response rates are shown in Table 4. The overall complete response rates (absence of both nausea and vomiting) were 49% (97 of 198 patients) for dronabinol versus 17% (32 of 193 pas) for prochlorperazine (P < .QOQl). The complete response rate for dronabinol found in the present study is close to the composite complete response rate of 49%. The plete response rate in the er than ttre comThus, although the complete response rate to prochlorperazine in this study was somewhat higher than the corn ite rate in previous studies, the trend tow& improved antiemetic control found with
TableJ Complete Antiemetic Response Ihunabinol cR!T’reated
% CR
Pmchlorperazine CR/Treated
5%CR
29 15 %I
Y I? 36
WI
reFeerences cited.
Reference
Ref. 8 Ref. 4
Ref. (i Ref. 10 OreraIl* Present study
in previous studies has been confirmed in the present work. The combination of dronabinol and prochlorperazine has been compared to prochlorperazinc or thiethylperazine alone in two doubleblind crossover studies.‘.” In the first study, with ten evaluabie patients, eight responded better to the combination and two had equal responses to both arms. In the second study, of 20 evaluable patients had moderate to excellent control of nausea and vomiting with the c~u~bi~r~ti~t~vet’scls only I5 prochlorperazine alone. The present study confirms that patients respond better to a combination of dronabinol and prochlorperazine than to prochlorperazine alone. The overall proportion of patients experiencing nausea or vomiting was about the same for those treated with either dronabinol or the combination. The duration of episodes of nausea or vomiting was shorter for patients in the latter group than for those receiving either single agent. In addition, the combination markedly decreased the severity of nausea when compared with single-agent therapy. Although response to the combination is better than that to prochlorperazine alone, side effects with the former were more common. In most studies of dronabinol as a single agent, from two-thirds to four-fifths of patients have experienced psychotropic effects.‘* In the present study, neurologic or psychotropic effects were experienced hy 62% of patients on dtonabinol and 55% of those on the combination, as compared with 29% of those receiving prochlorperazine alone. However, only 14% of patients receiving dronabinol aione and 5% of those receiving the combination experienced severe side effects. Patients on the combination were much less likely to withdraw from therapy because of these effects than were those receiving dronabinol alone. In addition, dysphoric symptoms (depersonalization, depression, paranoia, etc.,) were only half as common in patients receiving the combination as in those taking dronabinol alone. Thus, prochlorperazine appears to have counteracted some of the unpleasant effects experienced by patients on dronabinol. The combination of dronabinol and prochlorperazine was significantly more effective than either single agent in controlling nausea and vomiting from cancer chemotherapy, as assessed by duration of episodes of nausea and
dronabinol
by severity
combination
of nausea. The two ower incidence of dys-
lll~C;lp)-il~d~~f~~ti
ronahinol
, d;olstc+il hlF, Elflinger DS. (:olving hi. ‘l’hr ~‘(;u~sc’of 19ausra ;nr~d ~,o~i~i~~~ atier high dosr ~.~~lop~9ol;~~I9;11nitlr. (:anccl- '8‘rcaf Kep I!~X:!;W: 1487-I,?Y3.
was an effective
alone.
The
antiemetic
men when administered with a variety of c manly used chemotherapeutic agents.
This study was supported by Koxane Laboratories and UNIMED. Inc.
efwences 1. MartinTJimenez M. Diaz-Rubio E. Sangro B. Results of two controlled studies on antiemetic combination against vomiting induced by 5-Fluorouracil. ‘l‘uaiori 1987;73:499-504. 2. Fortner CL, Finley KS, Grove WK. Combination antiemetic therapy in the comrol of chemotherapyinduced emesis. Drug Entell Clin Pharm 1985; l9:2 l24. 3. Kluin-Nelemans JC, Nelemans FA, Meuwissen OJATh. Maes RAA. Delta-9-tetrahydrocannabinol (THC) as an antiemetic in patients treated with cancer chemotherapy: A double-blind cross-over trial against placebo. Vet Hum Toxic01 1979;21:338-340. 4. Orr L. McKernan JF. Bloome B. Antiemetic effect of tetrahydrocannabino! compared with placebo and prochlorperazine in chemotherapy associated nausea and emesis. Arch Intern Med 1980;140:1431-1433. 5. Sallan SE. Cronin C, Zelen M, Zinberg NE. Antiemetics in patients receiving chemotherapy for cancer: A randomized comparison of Delta-9-Tetrahy drocannabinol and prochlorperazine. New Engl J Med 1980;302: 135-138. 6. Ungerleider JT. Andrysiak T, Fairbanks L. Goodnight J, Sarna G, Jamison K. Cannabis and cancer chemotherapy: A comparison of oral Delta-9-THC Cancer 1982;50:636-645. and prochlorperazine. 7. Garb S. Beers Jr AL, Bograd M, McMahon RT, Mengalik A, Ashmann AC, Levine S. Two-pronged study of tetrahydrocannabinoI (THC) prevention of vomiting from cancer chemotherapy. IRCS Medical Science 1980;8:203-204. 8. Kleinman S, Weitzman SA, Cassem N, Andrews E. Double blind trial of Delta-9-tetrahydrocannabinol (THC) as an adjunct to prochlorperazine for chemo-
vomiting.
(Iuri-
Res
I!)IJS;:l.l:1014-1017.
IO. Mrd:abe M. Sm;!P FP. MacDonald JS. Woolley I’V. (ioldberg I). Srbein PS. Efficary of tetrahydrocannabinol in pafients refractory to standard antiemetic therapy. ]Iuvest New Drugs IYXH;6:2~2:3-$4(i, 1 I. Artim K. IliBclla N. Tetrahydrocannabinol (‘I’HC) plus prochlorperdzinc (P(X) for refractory IIPUSM and vonking (N/V). Proc Amer Sor Clin Oncol l983;2:85.
! 2. !::xY!;~trrc; !?hl, Ck919k LA:,
Abstract
LIrorwbinol(MarinoP’. I\ltjxmtiLaboratories, Columbus, OH) and prochlorperazine wre !estedajane aad in combinatiou in TVmudontired, doctbk-blind, parallel group, ?&m(s uwe rcrttdoaired to receive either 1) dronabinol Ii) mg #w&o; 2) placebo plus prochlorpr amine 10 mg every 6 hr; or 3) #rachlor$erarine, each IO mg every 6 hr. Antiemetic treatnwnt was or to aud continued J~)Y24 hr aper the last dose of chemotherapy; all #x&Ws in group 3 versus 47% in group I and 60% naww after chemothera@. In addition, the median duration nausea were sign$icanti” less with combination therapy. emothera$y in 4l%, 55%, and 35% of /nztient.sin groups I, e median duration per episode of vomiting was 1 min in 1 and four in group 2. Side efleck, primarily CNS. were than in group 2; addition of prochlorperazine Codronabinol todecreawthe&quencyof$yphs one ’ e$ ecLFsem with the latter agent. Tlte
of
U.S. Camr Pain Relief Committee, 1991 Pubfiied by Elsevier. New York. New York
0885-3924/91/$3.50
Antiemetic, dronabinol, cannabhids, nausea and vomiting
tetrall~(lroca?llla.binol, chemolhe~a~-ind~lced
sesame oil, has been found to be an effective agent in a number of randomized trials.“.’ Its side effect profile is different from that of prorhlorperazine, a commonly used phe-
antiemetic Nausea and vomiting
of cancer
are common
chemotherapy.
cause significant
morbidity
so severe that patients
These
side effects symptoms
and are sometimes
stup treatment
to avoid
them. Several classes of drugs have been used to treat chemotherapy-induced nausea and vomiting. As with cytotoxics, combinations of antiemetics are often more effective than single agents.‘.’ Dronabinol, delta-9-tctrahydrocanrrabinol in
nothiazine
antiemetic.
chlorperazine
and
pro-
have been tested pr&ousIy,
~rot~a~~~~ol
ei-
ther comparatively’“-” or in coml~ination.7*H The purpose of this study was to compare the efficacy and toxicity of dronahinol and prochlorperazine, each alone and in coml)ination. fin control of chemotheiapy~i~~~i~~ce~~ nausea ;md vomiting.
Tulrl~ I Patient Characteristics Dronabinol N Sex.
M/F
Race White Black Hispanic Other
Age, yr Median Range BSA. m’ Median Range Primary tumorb Breast Colon
21 10111
Yrochlorperazine
Combination
Total
21
20
62
IO1I 1
9/l 1
29133
11
13
12
3 5 2
.5 3 0
4 ,t 0
47 20-68
49 22-64
55.5 25-65
52 20-68 I .3-2.4
1.6
1.8
Sti 12 12
2
1.3-2. I
I .5-2.4
1.8 1.3-2.1
8
S
8
I 3 5 4
I 3 6 3
1 2 6 3
Number of agents I 2 or 3 4 Withdrew prior to chemotherapy
1 15 2 3
2 17 I I
3 12 3 2
6 44 6 6
Number of days 1 2-5
15 3
14 6
15 3
44 12
Emetogenicity of chemotherapy High Low
16 2
I8 2
14 4
48 N
Lung Lymphoma Miscellaneous”
1.8 24 3 8 17 IO
aNot more than one per treatment arm of the following: esophagus, gastric, liver, mycloma. pancreas, testis, and tongue.
A total of 62 patients at 9 centers were enrolled in this randomized, parallel group. double-blind study. Patients were eligible if they were between the ages of 18 and 69 years, inclusive, and being treated cancer with other than agents or high-&se ( > 6Omg/m”) cisplatin. Patients with central nervous system primaries or metastases were excluded. Patients could receive ens lasting up to 5 days. The roved by the institutional reof each participating institution. Patient characteristics and the chemotherapy administered are shown in Table I. All patients had received prior chemotherapy and prior anApproximately one-half of tiemetic therapy.
each group had previously received pmchlorpwazine; no patient had previously received dronabinol or any other cannabinoid. Twentyseven percent of patients had experienced fewer than two episodes of nausea or vomiting with prior chemotherapylantiemetic regimen: riced between two and ten ephad experienced more than IO episodes of nausea or vomiting. There were no significant differences among groups in patient characteristics or chemotherapy. The most commonly used drugs were cyclaphosphamide and doxorubicin (26 patients each), Muorouracil (14 patients), vincristine (13 patients), and etoposide (10 patients). Seventy-nine percent of patients received either two or three drug cambinatians, All but six patients were treated as outpatients. All patients gave written informed consent. Patients were stratified by study center and by the emetogenieity of the chemotherapy used. Low-emetogenicity agents used included bleomycin, oral cyclophosphamide. fluorouracil. methotrexate. vinblastine, and vincristine. Patients were stratified to the high-emetogenicity gmup if they received at least one high-emetogenicity agent. All but eight patients received at least one high-emetogenicity agent. Twenty-four hours prior to the start of a CHUM of chemotherapy, patients were started on study medication. Antiemetics were continued for 24 hr after the last dose of chemotherapy* Up to a total of 6 days (1 day prior and up to 5 days on chemotherapy). Patients were randomized to one of three treztment arms: 1) dronabinol (Marinol@, Roxane Laboratories,
Columbus, OH) 10 mg by mouth every 6 hr plus placebo: 2) prochlorperazine 10 mg by mouth every 6 hr plus placebo: or 3) dronabinol (MarinoI@) plus prochlorperazine, each 10 mg by mouth every 6 hr. Patients were evaluated and treatment compliance was checked by pill count daily through 1 day after the last dose of chemotherapy. Parameters evaluated included number and duration of episodes of nausea and vomiting, and severity of nausea as indicated on a visual analogue scale,” which is a IO-cm line with the words “No nausea” and “Extreme nausea” at either end. Patients were instructed to mark the scale at any point for each episode of nausea to describe the intensity of the episode. Patients were questioned at each visit regarding the occurrence of side effects. For evaluation of patient characteristics, disposition, and side effects, Chi-square and Fisher’s Exact Test analyses were used. Wilcoxon’s Rank Test was used to compare medians in efficacy analyses. For statistical purposes when calculating medians per episode, patients not reporting nausea or vomiting were assigned a zero value for nausea frequency, duration and severity, or vomiting frequency and duration, respectively. Differences between groups were considered significant if the two-tailed P value was less than equal to .05.
Results Of the 62 patients entered into the study, 60 were evaluable for efficacy against anticipatory nausea and vomiting. One patient in the dronabinol group received a concomitant antiemetic, and one in the combination group was found during the study to have brain metastases. As shown in Table 2, 54 patients were evaluable for efficacy against chemotherapy-induced nausea and vomiting. Three patients in the dronabinol group and two in the combination group withdrew from the study due to adverse effects prior to chemotherapy administration. One patient who was randomized to the prochlorperazine group was withdrawn prior to chemotherapy due to a protocol violation. Fifteen evaluable patients discontinued study antiemetics prior to completion of the planned number of doses. Ten of these were in the dronabinol group. All but one of the patients who discontinued therapy because of adverse effects did so because of neuropsychotropic
N
21
Withdrawn prior to chemotherapy Evaluable for efficacy Completed at least 2 days of study medication Completed study Reasons for withdrawal Side effects’ Insufficient therapeutic effect Other”
3 I7
PI 1 20
HO 2 17
62 6 54
I3 7
‘LO 17
16 15
49 39
10 2 2
0 2 L’
4 0 I
14 4 5
“Dronabinol versus prochlorperazine P < 0.0 I, versus combination P = 0.06: prochlorpcra~ine version ccmrbirlarion P c 0.05. bOther (one each): dronabinol: intercurrent illness, protocol violation: pr~)chlolperarine: proli~co~ violation, noncompliance; combination: intercurrent illness. symptoms; one patient discontinued because of hypotension. Side effects began during the prechemotherapy day for all patients discontinuing study medication due to side effects. The median age of patients in the dronabinol group who completed the study was 55; for those discontinuing due to side effects, the median age
was 45.5. 1111the combination group, the median age for those completing was 57; for those discontinuing due IO side effects, it was 50.
Side Eflects All patients were evaluable for side effects, which are listed in Table 3. Significantly more Tablp 3
Side Effects Dronabinol
N Total number reporGng side effects” Neurologic’ Somnolence Dizziness Asthenia Vision disturbances Confusion Depersonalization Paranoid reaction Anxiety Depression Paresthesias Digestive Dry mouth Diarrhea Cardiovascular Tachycardia Respiratory Dyspnea Other body systems Headache
21 16 13 4 7 2 3 2 3 1 I 2 1 5 2 2 3 2 0 0 3 1
Note: Side effects reported by only one patient: dronabinol: paralysis, thirst, and urinary incontinence; prochlorperazine: insomnia, speech disorder, and tremor. “Dronabinol versus prochlorperazine P < 0.01. bDronabinol versus prochlorperazine P < 0.06.
Prochlorperazine 21 7 6 3 1 1 0 0 0 0 0 0 1 0 0 0 1 0 1 1 1 1
Combination 20 II 11 5 2 2 2 I 0 2 I 0 0 2 2 0 0 0 1 1 1 1
T%ltal 6r! rd.4 30 I2 10 5 5 3 3 3 2 2 2 7 4 2 4 2 2 I 5 3
agitation. chest pain, hypotension, increased appcGte. syncope and taste abnormality; combination: ataxia,
Vomilina
Nausea or Vomiting
90
OR0 PRO cow0
Fig. 1. Percent of patients withnut nausea andlar vomiting.
patientsin the dmllabinal than in the ptochlorside effects twine group experienced < .Ol), The differences between the dronabinol and combination groups and between the prochlorperaaine and combination groups in the proportion of patients reporting side effects were not statistically significant. Of those patients completing the study the dronabinol group, 6 (35 prochlorperazine group, and 7 (47%) of 15 in the combination group experienced side effects. Most side effects were mild or moderate. T~IW paticrria iu the dronabino!, none in the prochlorperaaine, and one in the combination
group experienced severe side effects. All patients with btvere side effects had neurological side effects; in addition, the patient in the combination group noted severe dyspnea and dry mouth as well. None of the side effects caused sequelae and all were manageable with observation or simple supportive measures. Neuropsychotropic side effects were the most common, occurring in 48% of all patients: 62% in the dronabinol group, 29% in the prochlorperazine group, and 55% in the combination group (dronabinol versus prochlorperazine P = 96: other comparisons were not significant). The symptoms occurring were those usually as-
IQa
1
NIluWIl
Vomiting Nausea or Vomiting
OR0 PRO COMBO
MI0 PRO COMBO
OR0 PRO COMBO
Fig. 2. Percent of patients with two or fewer episodes of nausea and/or vomiting.
Nausea 0’ Vomiting Vomiting
i,,,
.__J
DRO PRO COMBO
sociated with each ofthe drugs used in this trial: somnolence for botb drugs and dysphoric symptoms for dronabinol. Eight patients in the dronabinol group, none in the prochlorperazine, and three in the combination group experienced dysphoric symptoms. No correlation was found between the incidence of psychotropic effects and age or degree of antiemctic control.
Anticipatory nausea occurred in a total of I1 patients: 30% of the dronabinol, none of the prochlorperazine. and 26% of the combination group (dronabinol versus prochiorperazine and combination versus prochlorperazine each P < .05). One patient in the dronabinol group had a single 5-min episode of anticipatory vomiting; no anticipatory vomiting occurred in either of the other two groups. Data on the incidence of chemotherapy-induced nausea and vomiting are shown in Figures I and 2. Fewer patients in the dronabinol and combination groups than in the prochlor-
L--_,,
L-
____I
DA0 PRO COMBO
/(
I
DA0 PRO COMBO
perazine group experienced nause;~ an&~ vomiting; these differences were not Stiitistick3lly significant. Forty-one percent of’ patients in the dronabinol group, 47% in the combination croup, and only 30% in the proch!orperazine iroup experienced no nausea or vomiting. In many studies, two or fewer episodes of nausea or vomiting is used as a measure of adequate antiemetic control. Using this limit. 7 1% of the dronabinol, 65%. of’ the combination, and 45%, of the prochlorperazine group had good antiemetic controL Although these differences were not statistically significant, there is a consistent trend in the data favoring the groups receiving dronabinol. As shown in Figure 3, the median duration per episode of nausea or vomiting was significantly less in the combination group than for either single agent, 5 min for either single agent versus 2 min for the combination (P < .OOl for combination versus either single agent). Furthermore, for nausea or vomiting alone, the duration per episode was less for patients receiving
DA0
PRO
VISUAL ANALOG
SCALE SEVERENAUSEA
NO NAUSEA Fig. 4. Median severity OF tlausril.
dronabjnol than for those receiving prochlorperazme, 10 versus 15 min for nausea, and 2 versus 4 min for vomiting. There were no significant differences among the groups in the total duration of nausea or vomiting. Figure 4 shows the median severity per episode of nausea, as evaluated on a visual analogue scale. The severity of nausea was markedly less for patients receiving combination antiemetic therapy than for those receiving either single agent alone (I’ < 90 1).
0ver the past decade, many randomized studies have demonstrated the t#icacy of oral dmnabinol in controlling nausea and vomiting from a variety of chemotherapeutic regimens. Several studies have compared dronabinol with prochlorperazine, each used as single ts;q”‘Xa“gall were randomized. and all but the last was double-blinded. Data from the individual studies and the composite response rates are shown in Table 4. The overall complete response rates (absence of both nausea and vomiting) were 49% (97 of 198 patients) for dronabinol versus 17% (32 of 193 pas) for prochlorperazine (P < .QOQl). The complete response rate for dronabinol found in the present study is close to the composite complete response rate of 49%. The plete response rate in the er than ttre comThus, although the complete response rate to prochlorperazine in this study was somewhat higher than the corn ite rate in previous studies, the trend tow& improved antiemetic control found with
TableJ Complete Antiemetic Response Ihunabinol cR!T’reated
% CR
Pmchlorperazine CR/Treated
5%CR
29 15 %I
Y I? 36
WI
reFeerences cited.
Reference
Ref. 8 Ref. 4
Ref. (i Ref. 10 OreraIl* Present study
in previous studies has been confirmed in the present work. The combination of dronabinol and prochlorperazine has been compared to prochlorperazinc or thiethylperazine alone in two doubleblind crossover studies.‘.” In the first study, with ten evaluabie patients, eight responded better to the combination and two had equal responses to both arms. In the second study, of 20 evaluable patients had moderate to excellent control of nausea and vomiting with the c~u~bi~r~ti~t~vet’scls only I5 prochlorperazine alone. The present study confirms that patients respond better to a combination of dronabinol and prochlorperazine than to prochlorperazine alone. The overall proportion of patients experiencing nausea or vomiting was about the same for those treated with either dronabinol or the combination. The duration of episodes of nausea or vomiting was shorter for patients in the latter group than for those receiving either single agent. In addition, the combination markedly decreased the severity of nausea when compared with single-agent therapy. Although response to the combination is better than that to prochlorperazine alone, side effects with the former were more common. In most studies of dronabinol as a single agent, from two-thirds to four-fifths of patients have experienced psychotropic effects.‘* In the present study, neurologic or psychotropic effects were experienced hy 62% of patients on dtonabinol and 55% of those on the combination, as compared with 29% of those receiving prochlorperazine alone. However, only 14% of patients receiving dronabinol aione and 5% of those receiving the combination experienced severe side effects. Patients on the combination were much less likely to withdraw from therapy because of these effects than were those receiving dronabinol alone. In addition, dysphoric symptoms (depersonalization, depression, paranoia, etc.,) were only half as common in patients receiving the combination as in those taking dronabinol alone. Thus, prochlorperazine appears to have counteracted some of the unpleasant effects experienced by patients on dronabinol. The combination of dronabinol and prochlorperazine was significantly more effective than either single agent in controlling nausea and vomiting from cancer chemotherapy, as assessed by duration of episodes of nausea and
dronabinol
by severity
combination
of nausea. The two ower incidence of dys-
lll~C;lp)-il~d~~f~~ti
ronahinol
, d;olstc+il hlF, Elflinger DS. (:olving hi. ‘l’hr ~‘(;u~sc’of 19ausra ;nr~d ~,o~i~i~~~ atier high dosr ~.~~lop~9ol;~~I9;11nitlr. (:anccl- '8‘rcaf Kep I!~X:!;W: 1487-I,?Y3.
was an effective
alone.
The
antiemetic
men when administered with a variety of c manly used chemotherapeutic agents.
This study was supported by Koxane Laboratories and UNIMED. Inc.
efwences 1. MartinTJimenez M. Diaz-Rubio E. Sangro B. Results of two controlled studies on antiemetic combination against vomiting induced by 5-Fluorouracil. ‘l‘uaiori 1987;73:499-504. 2. Fortner CL, Finley KS, Grove WK. Combination antiemetic therapy in the comrol of chemotherapyinduced emesis. Drug Entell Clin Pharm 1985; l9:2 l24. 3. Kluin-Nelemans JC, Nelemans FA, Meuwissen OJATh. Maes RAA. Delta-9-tetrahydrocannabinol (THC) as an antiemetic in patients treated with cancer chemotherapy: A double-blind cross-over trial against placebo. Vet Hum Toxic01 1979;21:338-340. 4. Orr L. McKernan JF. Bloome B. Antiemetic effect of tetrahydrocannabino! compared with placebo and prochlorperazine in chemotherapy associated nausea and emesis. Arch Intern Med 1980;140:1431-1433. 5. Sallan SE. Cronin C, Zelen M, Zinberg NE. Antiemetics in patients receiving chemotherapy for cancer: A randomized comparison of Delta-9-Tetrahy drocannabinol and prochlorperazine. New Engl J Med 1980;302: 135-138. 6. Ungerleider JT. Andrysiak T, Fairbanks L. Goodnight J, Sarna G, Jamison K. Cannabis and cancer chemotherapy: A comparison of oral Delta-9-THC Cancer 1982;50:636-645. and prochlorperazine. 7. Garb S. Beers Jr AL, Bograd M, McMahon RT, Mengalik A, Ashmann AC, Levine S. Two-pronged study of tetrahydrocannabinoI (THC) prevention of vomiting from cancer chemotherapy. IRCS Medical Science 1980;8:203-204. 8. Kleinman S, Weitzman SA, Cassem N, Andrews E. Double blind trial of Delta-9-tetrahydrocannabinol (THC) as an adjunct to prochlorperazine for chemo-
vomiting.
(Iuri-
Res
I!)IJS;:l.l:1014-1017.
IO. Mrd:abe M. Sm;!P FP. MacDonald JS. Woolley I’V. (ioldberg I). Srbein PS. Efficary of tetrahydrocannabinol in pafients refractory to standard antiemetic therapy. ]Iuvest New Drugs IYXH;6:2~2:3-$4(i, 1 I. Artim K. IliBclla N. Tetrahydrocannabinol (‘I’HC) plus prochlorperdzinc (P(X) for refractory IIPUSM and vonking (N/V). Proc Amer Sor Clin Oncol l983;2:85.
! 2. !::xY!;~trrc; !?hl, Ck919k LA:,
