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2193
Are More Antiemetic Trials with a Placebo
Necessary?
Report of Patient Data from Randomized Trials of Placebo Antiemetics with Cisplatin
Mark G. Kris, M.D.'
Luigi X. Cubeddu, M.D?
Richard J. Gralla, M.D.~
Didier Cupissol, M.D."
Leslie 6. Tyson, R . N . ~
Ennpadam Venkatraman, P m . "
Howard D. Homesley, M.D?
' Thoracii: Oncology Service, Division of Solid
Tumor Oncology, Department of Medicine, Memorial Sloan-Kettering Cancer Center, Cornell
Medical College, New York, New York.
' Department of Pharmacology, School of Pharmacy, Central University of Venezuela, Caracas,
Venezuela.
Ochsner Cancer Institute, New Orleans, Louisiana.
Centre Regional de Lutte Contre Le Cancer,
Montpellier, France.
Department of Nursing, Memorial Sloan-Kettering Cancer Center, Cornell Medical College,
New York. New York.
Department of Biostatistics, Memorial SloanKettering Cancer Center, Cornell Medical College, New York, New York.
' Sectiori
of Gynecologic Oncology, Bowman
Gray School of Medicine, Winston-Salem, North
Carolina.
Address for reprints: Mark G. Kris, M.D., Memorial Sloan-Kettering Cancer Center, 1275 York
Avenue, New York, NY 10021.
Received May 13, 1996, revision received July
29, 1996, accepted July 29, 1996.
0 1996 American Cancer Society
BACKGROUND. Because of the predictability of significant emesis after its use, cisplatin serves as the standard emetic stimulus for trials of antiemetic drugs. To
define better the incidence, severity, and pattern of emesis that follows cisplatin,
facilitate the testing of new agents, and obviate the need for further placebocontrolled trials for this indication, individual patient data were compiled from
completed studies with placebo antiemetics and cisplatin.
METHODS. The time and number of emetic episodes during the 24 hours after
cisplatin were obtained for 48 patients given a placebo antiemetic. Each was treated
as part of a randomized, double-blind trial reported between 1981and 1990.Emesis
after antiemetic "rescue" therapy was also assessed.
RESULTS. Emesis occurred in 47 of 48 patients (98% observed rate, 95% confidence interval, 89-99%). The median number of emetic episodes during the 24
hours after cisplatin was 6. Emesis continued after rescue in 77% of patients.
CONCLUSIONS. Cisplatin caused severe emesis that persisted despite rescue in placebo-treated patients. Using the data presented, any therapy preventing acute emesis in 8 or more of the 48 individuals receiving cisplatin > 50 rngim' was an active
antiemetic ( P = 0.05). The four trials discussed here documented the antiemetic
effectiveness of granisetron, metoclopramide, and ondansetron. The placebo-treated
patients studied can serve as a control group for testing new therapies. Because of
the certainty of severe emesis after cisplatin, and the availability both of these data
and several proven drugs for this condition, prospective comparisons of antiemetics
should employ active control medications. Cancer 1996; 782193-8.
0 1996 American Cancer Society.
KEYWORDS: cisplatin, vomiting, antiemetics, placebo, metoclopramide, granisetron,
ondansetron.
P
atients with cancer continue to declare vomiting and nausea as the
most dreaded complications of cancer treatment. However, over the
last 20 years, many drugs that can effectively prevent emesis have become
widely available, including met~clopramide,'-~
ondansetron,"-' granisetron,8'9dexamethasone,'0-'2and dr~nabinol.'~,'~
Each of these five agents
has been proven effective in a controlled, randomized trial, tested against
either an active antiemetic or a placebo. Despite the usefulness and availability of these drugs used alone and in combination,'"'' acute vomiting
is not prevented in all patients. Few strategies exist to treat vomiting
despite prophylaxis (breakthrough emesis) or emesis during subsequent
cycles after poor vomiting control with prior treatment (refractoryemesis).
Research to combat these problems continues, focusing on new and
unique antiemetic drugs.
CANCER November 15, 1996 / Volume 78 / Number 10
2194
TABLE 1
Vomiting after Cisplatin: Summary Results
No. of patients
No. with zero emetic episodes
Median no. of emetic episodes (range)
Cisplatin (47-120 mglm‘)
Cisplatin 2100 mglm’
Cisplatin 50-80 mum’
48
28
1
6 (0-25)
1
20
0
5 (2-16)
7 (0-25)
TABLE 2
Individual Patient Data from Trials Testing Placebo Antiemetics in Patients Receiving Cisplatin as the Primary Emetic Stimulus
(TimesReported from the Start of the Cisplatin Infusion)
Cisplatin
dose (mglm’)
Cisplatin
infusion
(min)
Concomitant
chemotherapy
No. of
emetic
episodes
Age
Sex
Primary site of
cancer
Time or time range of
emetic episodes (hours)
T i e of rescue
antiemetics (hours)
61
M
Headand neck
120
20
Vindesine, bleomycin
9
1.3, 1.4, 1.7, 2,2.2, 2.6,
2.8, 3.3, 4.1
1.5, 1.9, 2.3, 2.6, 2.8, 3.5,
3.4, 4.3, 4.3, 5.3, 5.8,
11.3, 17.3
1.5, 1.8, 2.6, 2.7, 2.9, 3.6,
3.7, 4.5
1.5, 1.6, 1.8, 1.9, 2.1, 2.3,
2.5, 2.8, 2.9, 3, 3, 3.3,
3.4, 3.6, 3.8, 4.1, 4.4,
5.1, 5.8, 6.1,6.7,7.1,
7.4, 8.1, 8.8
1.3, 1.6, 1.8, 2, 2.2, 2.3,
2.5, 2.7, 2.9, 3.1, 3.3,
3.8, 4.4, 5.4,9
1.3, 1.6, 1.7, 1.9, 2.1, 2.2,
2.3, 2.5, 2.7, 3.2
2.3, 2.9, 3.3, 4, 5.1
1.6, 1.9, 2.1, 2.3, 2.7, 3.1,
3.3, 3.8, 4.1, 4.8, 6.2
2, 2.4, 2.8, 3.2, 3.8, 3.6
1.3, 1.7, 1.8, 1.8, 2, 2.5,
2.8, 3, 3.3, 3.3, 4.5,
4.5, 4.8, 4.8, 5.3, 5.3
1.8, 2.1, 2.2, 2.4, 4.9, 5,
5.5, 6.1, 7.8
2.9, 2.9, 3.4, 3.5, 3.6
None
32
M
Lung
120
20
Vindesine, bleomycin
13
66
M
Head and neck
120
20
Vindesine, bleomycin
8
22
M
Sarcoma
100
20
None
25
54
M
Head and neck
120
20
Bleomycin
15
46
M
Lung
120
20
Vindesine, bleomycin
10
56
66
M
M
Lung
Headandneck
120
111
20
20
Vindesine, bleomycin
Vindesine, bleomycin
5
11
60
45
M
M
Lung
Lung
120
120
20
20
Vindesine, bleomycin
Vindesine, bleomycin
6
16
46
F
Ovary
100
60
Doxorubicin
9
59
M
Head and neck
100
60
5
33
F
Ovary
100
60
5-FU, doxorubicine,
mitomycin
Doxorubicin,
cyclophosphamide
6.8
4
6
5
2.2, 3.3, 3.4, 3.4, 3.6, 3.9,
4.1,4.3,4.3, 4.4, 4.5,
4.6, 4.9
2.5, 2.7, 3.1, 3.2,3.2, 3.4,
3.4, 4, 4.2, 4.4, 5.3,
6.6
3.1, 3.1, 3.1,3.3,3.4
3.1, 3.4, 3.5, 3.5,3.7, 5.2,
7.8, 10.4
1.6, 1.9, 2.1, 2.2
3.7, 4.3, 4.6, 4.8, 5, 22.5
3.2, 3.7, 4, 4, 4.2
46
F
Ovary
50
60
Doxorubicin,
cyclophosphamide
12
65
53
F
F
Head and neck
Ovary
100
50
60
60
5
8
29
54
42
F
M
F
Head and neck
Esophagus
Ovary
100
100
50
60
60
60
41
M
Lung
80
60
5-FU
Doxorubicin,
cyclophospharnide
None
5-FU
Doxorubicin,
cyclophosphamide
Vinblastine,
mitomycin
3
2.1, 2.6, 2.7
13
None
None
3.2
3.2
2.8
None
5
None
3.8
2.5
-
4.3
3.4
3.3
2.2
4.9
4.3
2.4
(continuedl
Placebo Antiemetics with CisplatinlKris et al.
2195
TABLE 2 (continued)
Primary site of
cancer
Cisplatin
dose [mg/m*)
Cisplatin
infusion
(min)
Age
Sex
55
69
F
Head and neck
Ovary
50
50
60
60
40
F
Ovary
70
60
44
F
Ovary
50
60
62
F
Ovary
50
50
70
F
Ovary
50
50
M
Concomitant
chemotherapy
62
F
Ovary
50
50
ti5
F
Ovary
50
50
68
45
F
F
Uterine sarcoma
Cervix
50
50
50
50
None
Doxorubicin,
cyclophosphamide
Cyclophosphamide,
mitoxantrone
Doxorubcin,
cyclophosphamide
Cyclophosphamide,
doxorubicin
Cyclophosphamide,
doxorubicin
Cyclophosphamide,
doxorubicin
Cyclophosphamide,
doxorubicin
None
None
32
F
Cenix
100
100
None
No. of
emetic
episodes
Time or time range of
emetic episodes (hours)
Time of rescue
antiemetics [hours)
4
4
2.9, 3, 3.3, 3.4
3, 5.1, 8.6, 19.5
3
4
10
2.9, 3.6, 3.9, 4, 4.5, 4.8,
4.8, 5.8, 6.4, 7.5
2.7, 2.9, 3.2, 6.7
3.3
4
4
16
1.5-3.5 = 2
3.5-6.5 = 2
3.5, then continuous
3.8
3.8
= 16
8
6
5
4
7
None
1.5-3.5 = 3
3.5-6.6 = 5
1.5-3.5 = 3
3.5-6.5 = 3
1.5-3.5 = 5
3.5-6.5 = 3
6.5-9.5 = 1
1.5-3.5 = 7 then
None
3
None
4
continuous
64
F
Colon
50
50
Cyclophosphamide,
doxorubicin
11
60
F
Ovary
50
50
Cyclophosphamide,
doxorubicin
12
63
61
63
F
M
F
Head and neck
Head and neck
Endometrial
100
100
100
360
360
360
64
54
49
M
M
F
Head and neck
Head and neck
Fallopian tube
80
100
70
360
360
360
63
F
Ovary
80
360
76
F
Ovary
100
360
65
68
M
M
Head and neck
Lung
100
100
360
360
5-FU
5-FU
Vindesine, bleomycin,
mitomycin
5-FU
5-FU
Doxorubicin,
cyclophosphamide,
teniposide
Doxorubicin,
cyclophosphamide
Doxorubicin,
cyclophosphamide
5-FU
Etoposide, ifosfamide
63
F
Ovary
100
360
61
56
54
M
M
M
Esophagus
Lung
Lung
100
100
100
360
360
360
69
F
Cervix
50
50
1.5-3.5 = 5
3.5-6.5 = 3
6.5-9.5 = 2
9.5-12.5 = 1
1.5-3.5 = 6
3.5-6.5 = 3
6.5-9.5 = 2
9.5-12.5 = 1
4, 4.2, 8, 8.4, 12.2, 12.4
6, 6.2, 6.4
1, 1.3, 1.6, 2, 2.2, 4.2,
4.4, 6, 8.4
5.5, 6
12, 12.2, 12.4
3, 3.2, 3.4, 3.6, 4.2, 4.4
6.8
5
2.1, 2.4, 2.8, 3.2, 3.5
4
4
4.1, 4.2, 13, 13.4
4.5, 13.5
0
10
Bleomycin,
cyclophosphamide
3
5-FU
7
5
10
Etoposide, ifosfamide
Etoposide, ifosfamide
Cyclophosphamide,
doxorubicin
4
4.5
6.5
2.25, 18
6
12.3
3.5
-
None
6.1, 6.4, 7, 7.2, 7.4, 8,
8.4, 10, 10.2, 12
4, 4.2, 4.4
8. 12
4.2, 4.6, 5, 5.2, 5.4, 6, 17
3, 3.2, 6.2, 12, 18.2
4.1, 4.2, 4.4, 8, 8.2, 8.4,
8.8, 9, 9.2, 9.6
0-1.5 = 3
1.5-3.5 = 1
4.5, 17
8, 12, 18
6, 9
~~
M: male: F: female: min: minutes: 5-FU 5-fluorouracil.
3.8
~
4
~
None
2196
CANCER November 15,1996 I Volume 78 / Number 10
Cisplatin remains the most widely used chemotherapeutic agent that predictably causes emesis. Regardless of the dose and schedule employed, severe
vomiting follows cisplatin if antiemetics are not prescribed. For these reasons, cisplatin is the emetic stimulus most commonly chosen in the testing of antiemetic drugs. Investigators have postulated further
that any agent that prevented cisplatin-induced emesis would effectively control vomiting caused by lesser
emetogenic stimuli. This hypothesis has proved true
in practice.
The incidence and severity of vomiting with cisplatin observed in trials in which placebo antiemetics
were studied have been p~blished.’~”~~’
Despite these
results and the availability of safe and effective antiemetic drugs, placebo-control arms continue to be
proposed for comparison trials for new antiemetic
agents. To more precisely define the incidence, severity, and pattern of emesis after cisplatin, to make comparison information available to investigators testing
antiemetic therapies, and to obviate the need for further placebo-controlled antiemetic trials, this previously unpublished individual patient data were compiled from four randomized double-blind studies. In
addition, the success of “rescue” antiemetics to control ongoing vomiting after cisplatin in these same trials was examined.
PATIENTS AND METHODS
Four double-blind randomized trials comparing an
antiemetic agent (either granisetron, metoclopramide,
or ondansetron) with placebo among patients receiving cisplatin were published between 1981 and
1990.‘~3~5*.”
All four trials had similar entry criteria including cisplatin as the primary emetic stimulus, no
prior chemotherapy, no concomitant antiemetics, and
hematologic and biochemical studies sufficient for the
safe administration of cisplatin. In each trial, the number of emetic episodes (vomiting productive of liquid
or dry retches) and the time of each episode’,”’ or the
number of episodes during a given time period3 were
measured for 24 hours after the start of the cisplatin
infusion. Rescue antiemetics were administered in all
trials using varying criteria such as: “if patients experienced 3 episodes of emesis in 1hour or if the intensity
of emesis warranted immediate treatment,”5 or “in
the event that breakthrough symptoms continued.”.”
Informed consent was obtained from all subjects.
RESULTS
A total of 48 patients were randomized to and received
a placebo antiemetic in the 4 trials. Forty-seven of
48 patients receiving cisplatin vomited (98% observed
rate, 95% confidence interval, 89-99% (Table 1). The
median number of emetic episodes for all patients was
6, with a median of 5 episodes for individuals receiving
50-80 mg/m2of cisplatin and 7 in patients given 2100
mg/m2of cisplatin. The median time to the first emetic
episode was 2.9 hours (range, 1-12 hours). Individual
characteristics of the patients receiving placebo antiemetics with cisplatin are presented in (Table 2). According to the protocols, rescue antiemetics were administered to 36 patients (75%) after a median of 5
emetic episodes (range, 1- 13 episodes).
The time course of vomiting observed in the 24
hours after cisplatin and time of first “rescue” were
available for 37 patient^."^^." The results of “rescue”
therapy were available for 30 individuals. Despite rescue, 77% of patients continued to experience emetic
episodes (95% confidence interval, 58-90%) with a
median of 2 episodes after rescue (range, 0-15 episodes). Of the 10 patients given additional antiemetics
after experiencing only 1 or 2 episodes, 9 (90%)continued to vomit or retch.
Among the 49 patients enrolled on the 4 trials who
received active antiemetics prior to receiving cisplatin,
25 (51%) had their vomiting prevented.
DISCUSSION
The 98% incidence and severity of vomiting observed
after the administration of cisplatin given at doses of
50- 120 mg/m2in patients receiving placebo antiemetics confirm both the literature and clinical experience
for emesis after this chemotherapy agent. With only 1
of 48 patients free of vomiting, the upper 95% confidence limit for complete control of vomiting after cisplatin was 11%. Any therapy preventing emesis in 8
or more of 48 individuals receiving cisplatin was an
active antiemetic at the P = 0.05 level of significance.
In the course of obtaining the data presented,
granisetron, metoclopramide, and ondansetron were
proven to be safe and effective drugs for the prevention of emesis caused by cisplatin. Dexamethasone
and dronabinol have also been identified as antiemetics for patients receiving anticancer chemotherapy.
Given the near certainty of emesis after cisplatin, the
compelling and contemporary data from prior placebo
antiemetic trials available for comparison, and the
demonstrated safety and effectiveness of current antiemetic drugs, are any further trials comparing new
antiemetics with placebo in patients treated with cisplatin necessary or appropriate?
Placebo-controlled trials are recommended to assure an accurate comparison between an intervention
group and untreated individuals in situations in which
no established alternative exists and when the magni-
Placebo Antiemetics with Cisplatin/Kris et at.
tude of difference between the intervention and control
arms is real but small. Placebo-controlled trials remain
the “gold standard” for the determination of clinical outcomes and were instrumental in the identification of the
many antiemetic agents now in use with cisplatin.
Historic control groups are appropriate in trials
among individuals with conditions of high and predictable mortality and studies in which the effect of the
drug is self-evident.’* Vomiting after cisplatin clearly
meets this second criterion. Based on the data in the
trials reported here, severe emesis after cisplatin is
nearly universal. Any agent that reduces vomiting after
cisplatin is almost certainly an antiemetic drug. A
medication that prevents emesis in 8 or more of 48
individuals in this setting is definitely an antiemetic
agent. The experience detailed here provides a group
of control subjects for comparison that are well defined and reflect current medical practice. Furthermore, using prevention of vomiting in patients given
cisplatin as the standard provides an additional rigorous test for comparison, because no group of patients
has ever been described in whom vomiting does not
occur other than as an anecdote.’
Several authors have stated that placebo antiemetic trials may be unethi~al.’~-~’
In response, it has
been suggested that the use of a placebo hastens the
identification of new agents, is less costly, will result
in “cleaner” and indisputable data for regulatory authorities, and that individual patients can be protected
and effectively treated through the use of “rescue”
anti emetic^.^^,^^ The results of the use of rescue antiemetics in the placebo trials presented here demonstrate this strategy to be largely ineffective, with the
majority of patients continuing to vomit despite rescue. In addition, even though each of the protocols
provided for the administration of rescue medications,
rescue drugs were actually given only after a median of
five emetic episodes had already occurred. The rescue
drugs, schedules, and doses used varied among the
studies. However, there is no definitive trial proving
that any antiemetic effectively stops ongoing vomiting.
The availability of several safe and effective antiemetics has changed the rules for the development of
new agents to prevent acute chemotherapy-induced
emesis. Prevention is now the goal of treatment, and
complete control of vomiting (zero emetic episodes)
is the standard primary study endpoint. Candidate antiemetic agents should only be tested against active
comparators. The information presented in this study
further suggests that new candidate antiemetic agents
can reasonably be tested in smaller and faster single
arm Phase I1 studies with use of the implied historic
control. Because the best drugs individually prevent
2197
acute emesis caused by high dose cisplatin in a minority of patients, and the management of delayed, breakthrough, and refractory emesis is even less successful,
new agents and approaches are needed. More than a
decade of research, including the results from placebo-treated patients presented here, has paved the
path for this ongoing search.
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CANCER November 15,1996 / Volume 78 / Number 10
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