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California Research Advisory Panel
DETAILED PROTOCOL RESULTS
Interpretations of efficacy of THC are limited by the fact that in this
study no control group could be established for comparison with the treatment group. Thus,
some of the findings are more anecdotal than quantitative. However, the following results
are clear, reasonable and documented.
Number of Patients Treated
A total of 2,475 patients were treated with THC or smoked marijuana
under one or more of the following protocols:
Smoked Marijuana Protocols 119
The compassionate access
THC protocols 2400
Dexamethasone Protocol 4
Transderm-V Protocol 65
Delta-8-THC Protocol 10
Pilot Protocol (protocol
exceptions) 19
Glaucoma Protocol 9
Because of the protocol revisions previously described, data had to be
tabulated separately for each of the several compassionate access THC protocols (subjects
who received THC for nausea and vomiting associated with cancer chemotherapy):
a) Initial Trial 856 patients enrolled in the initial Protocols I, II, and III
between November 1980 and April 1982, and followed until October 1982.
b) Cumulative Dose Protocol 365 patients enrolled in the Cumulative Dose Protocol.
c) Combination Antiemetic Protocol 657 patients enrolled in the
Combination Antiemetic Protocol, whose treatment report forms were returned to RAP after
January 1, 1984.
Initial Trial
Summary. These first results reflect data from an open multisite cooperative study
conducted to evaluate delta-9-tetrahydrocannabinol (THC) in patients receiving anticancer
therapy who previously had been treated with other antiemetics.
Oral THC was found to be effective in reducing nausea, vomiting and anorexia.
Effectiveness was related to chemotherapeutic regimen, generally being
most effective with the less emetogenic agents.
Side effects were common. Serious adverse reactions were reported by physicians for nine
patients, but none of these were life threatening. There was no significant difference
between the effectiveness of the 5mg/m2 and 7.5mg/m2 doses, but 5mg/M2 was associated with
fewer side effects, a lower dropout rate due to side effects and a greater number of
patients continuing THC treatment. Thus, 5mg/m2 is the preferred dose. The incidence of
clinically serious adverse reactions to oral THC was less than one percent.
Patient and Investigator
Demographics Of about 300 board certified and eligible
oncologists, one hundred seventy-nine enrolled 856 patients, of which 706 were evaluable.
Patients were enrolled between November 1980 and April 1982, and were followed until
October 1982, at which time a final disposition was obtained on each patient. A total of
150 patients were excluded from analysis due to incomplete report forms, enrollment at
dosages other than 5mg/m2 or 7.5mg/m and enrollment by 26 investigators who did not adhere
to the protocol.
To avoid bias caused by selective dropping-out, only results from the
first treatment episode are analyze in this report, although over half the patients
received THC in two or more discrete episodes for a total of 1622 treatments in this
initial trial. Results of second and subsequent episodes are statistically more favorable
since patients with disturbing side effects and those with good results self-select for
continuation or termination.
Sixty percent entered the study at a THC dose of 7.5m 2g/m2 ; 40% entered at the 5mg/ml dose level. Sixty-two percent of the patients were female. The median age for women was 49, and for men was 38. Sixty-four percent of the patients had breast, lung. ovarian, or hematopoietic neoplasms. Seventyseven percent of the patients were able to carry on normal activities despite their disease (Karnofsky performance status of 80 or more).
Ninety-nine percent of patients had failed to benefit significantly from
other antiemetics, which were phenothiazines (87Z), butyrophenones (6%), metoclopramide
(6%), and others (3%). A wide variety of chemotherapeutic agents were used, usually in
combinations. The number of patients per participating physician varied widely: 69
physicians or 41% of them had one or two patients while 25 physicians (15%) had 10 or more
patients in the program (Table B).
Proportionately, among men there were more young persons than among
women: 30% of the men compared with only 132 of the women were below 30 years. 44% of the
men and 611 of the women were in the age group 30-59 years. The age groups above 60 years
were equally represented among men and women (26%) (Table C).
The tumor sites most commonly represented among the patients in the THC
program were, for women, carcinoma of the breast (38%) and cancer of the ovary or uterus
(21%). The most common primary tumor sites among the men were Hodgkin's lymphoma (18%) and
lung carcinoma (18%) (Table D). It should be emphasized, however, that the distribution of
primary organ locations is not representative of the prevalence by site in the general
population.
Table B
Frequency Distribution of 167 Physicians
by Number of Patients Treated with THC Capsules
------------------------------------------------
Number Frequency Number Frequency
of of of of
Patients Physicians Patients Physicians
-------- ---------- -------- ----------
1 33 13 2
2 36 14 3
3 18 15 2
4 18
5 12 15 1
6 5 1
7 8 21 1
8 5
9 5 28 1
10 6
11 3 29 1
12 5
---------------------------------------------------------
167 physicians treated 809 patients with THC capsules.
Table C
Characteristics of Study
Population of the Initial Trial
-------------------------------
Male Female
No. Percent No. Percent
--- ------- --- -------
Sex: 306 37.92 501 62.08
Age Distribution:
19 yrs or less 23 7.52 29 5.79
20 - 29 yrs 67 21.90 36 7.19
30 - 39 yrs 57 18.63 81 16.17
40 - 49 yrs 30 9.80 99 19.76
50 - 59 yrs 44 14.38 125 24.95
60 - 69 yrs 56 18.30 96 19.16
70 yrs or more 23 7.52 32 6.39
Unknown 6 1.96 3 0.60
--------------------------------------------------------
Base: 890 patients receiving capsules.
Exclusions: 2 patients with sex unreported.
Table D
Distribution of Primary Tumor Site by Sex
-----------------------------------------
Primary Tumor Site Males Females
No. Percent No. Percent
Lip. Oral Cavity & Pharynx 7 2.3 5 1.0
Digestive Organs &
Peritoneum 36 12.0 21 4.2
Examples:
Stomach 6 2.0 1 0.2
Colon, Caecum, 11 3.7 10 2.0
Pancreas 6 2.0 4 0.8
Respiratorv & Intra-
thoracic Organs 68 22.6 49 9.8
Examples:
Lung-Trachea 53 17.6 40 8.0
Thymus, Heart &
Mediastinum 12 4.0 6 1.2
Bone. Connective-Tissue,
Skin & breast 39 13.0 216 43.3
Examples:
Bone & Articular
Cartilage 20 6.6 10 2.0
Connective & Other
Soft Tissue 10 3.3 11 2.2
Female Breast 191 38.3
Genitourinarv Organs 41 .13.6 124 .24.8
Examples:
Uterus 6 1.2
Ovary & Other Uterine
Adnexa 106 21.2
Prostate 10 3.3
Testis 24 8.0
Lymphatic & heamatopoeitic
Tissue 73 24.3 46 9.2
Examples:
Hodgkin's Disease 55 18.3 30 6.0
Myeloid Leukemia 9 3.0 8 1.6
Other unspecified sites 37 12.3 38 7.6
-----------------------------------------------------------------
499 100.0
Total (n-800)
301 100.0
Study design. The California statute that established the
cannabis program includes the objective of providing 'compassionate access' to marijuana
for cancer patients receiving chemotherapy and radiotherapy. Strict experimental control
measures were thereby precluded. Patients served as their own controls. however, through
comparison with previous antiemetic trials.
Drug dose and schedule. The drug was supplied by the National
Cancer Institute as soft gelatin capsules containing 2.5, 5 and 10mg
delta-9tetrahydrocannabinol dissolved in sesame oil. Based on dosage, two cohorts of
patients participated in this initial study. Patients in the first cohort received 7.5mg
THC/m2 every four hours while awake starting six hours prior to anticancer therapy, and
continuing for 24 to 48 hours after its completion. If severe side effects occurred, the
physician had the option to either delay, omit, or reduce the next dose, or discontinue
THC treatment. Preliminary results from the 7.5mg/m2 dose regimen indicated that a lower
starting dose of THC might be better tolerated. Thus, patients in the second cohort were
those given 5mg THC/m2 in the same manner.
Efficacy. In 482 patients, the identical anticancer treatment was
used with the THC treatment episode and with the prior treatment episode, allowing
comparison of the efficacy of THC to a standard antiemetic. As illustrated in Table E,
nausea and vomiting were better controlled by THC than by previous antiemetics in 752 and
731 of patients respectively. Fifty-five percent of patients reported improved food
intake. Although some nausea and vomiting occurred in most patients during the THC trial,
as shown in Tables F and G, nausea was absent in 17% and mild in 38% of the patients.
Vomiting was absent in 30% of the population. and in another 33% occurred an average of
less than four times daily. As illustrated in Table B. 62% of patients rated THC
moderately to very effective. Physicians' effectiveness ratings for THC used in
conjunction with various chemotherapy agents are summarized in Table I. Depending on the
anticancer agent used, THC was effective in anywhere from 38% to 662 of the patients. No
statistically significant associations were found between effectiveness and age, sex or
primary tumor site.
Effectiveness and Chemotherapeutic Drugs. Because of the size of this statewide cooperative study, assessment of effectiveness of THC was possible with specific chemotherapeutic regimens. As rated by physicians THC was most effective with chemotherapy regimens known as CMF5*, FAC**, and AC***. Physicians rated THC as moderately or very effective in 82 percent of the treatment episodes involving CMF, 76 percent of those involving FAC, and 75 percent of those involving AC. THC was least effective with DTA**** and
CISCA*****, yet over 40 percent of these patients benefitted
significantly.
5. CMF Is Cyclophosphamide. nethotrexate & 5-FU
FAC is 5-FU. Adriamycin & cyclophosphamide
*** AC Is Adriamycin & cyclophosphaside
*** DTA Is Decarbazine & Adriamycin
:**** CISCA in Cisplatin, cyclophosphamide & Adriemycin
Table E
Patient's Assessment of Symptoms:
THC Compared to Previous Antiemetic*
-----------------------------------
Severity of Nausea Vomiting Anorexia
Symptoms No. No. % No.
----------- ---------- ----------- ------------
Less with THC 363 75 350 73 264 55
Same 78 16 61 13 119 25
Greater with THC 41 9 67 14 93 20
Total 482 100 478 100 476 100
----------------------------------------------------------------Only
includes patients whose anticancer treatment was unchanged.
Table F
Nausea during THC Protected
Anticancer Treatment
---------------------------
Nausea Rating Number of Patients Percent
------------- ------------------ -------
None 112 17
Mild 248 38
Moderate 166 25
Severe 130 20
Total 656 100
----------------------------------------------
Table G
Vomiting during THC Protected
Anticancer Treatment
-----------------------------
Amount of Vomiting Number of Patients Percent
------------------ ------------------ -------
None 197 30
1-3 times 218 33
4-6 times 83 13
7 or more times 158 24
Total 656 100
-----------------------------------------------------
Table H
Patient Overall Assessment
of THC Effectiveness
--------------------------
Degree of Effectiveness Number of Patients Percent
----------------------- ------------------ -------
None 152 24
Slight 92 14
Moderate 196 30
Very 203 32
Total 643 100
Table I
Physician's Effectiveness Rating of
THC by Chemotherapy Regimen
-----------------------------------
Chemotherapy Regimen Total Number Moderate or Very
of Patients Effective Rating
-------------------- ------------ ----------------
No.
5 Fluorouracil, Adriamycin
and cyclophosphamide 32 21 66
Cyclophosphamide, metho-
trexate and 5 fluorouracil 56 37 66
Adriamycin and cyclophosphamide 90 57 63
Cyclophosphamide, Adriamycin,
vincristine and prednisone 51 28 55
Cisplatin, cyclophosphamide
and Adriamycin 50 20 40
Dacarbazine and Adriamycin 34 13 38
Safety. Physicians were required to make a separate report of any
clinically serious adverse reaction, defined as a reaction while taking THC that required
the use of drugs or hospitalization of the patient. During the course of this trial, five
clinically serious adverse reactions were reported among the first 856 patients treated
with THC. There were two instances of severe psychological distress (anxiety), and one
case each of myoclonic jerking, postural hypotension, and grand mal seizure. Complicating
factors, for example, brain metastasis associated with the seizure, were present in three
cases. All patients with serious adverse reactions had the drug immediately discontinued
and recovered fully with no sequelae. Generally, no other drug treatment was needed.
Side Effects. Side effects were common: even at the lower dose,
about 80% of patients had at least one side effect, and in 26% of those patients, at least
one side effect was considered severe. The severe side effects with an incidence of 5% or
greater were all central nervous system effects. A significant difference between the
sexes was observed: nine percent of women reported severe anxiety as compared to 4% of men
(p=.025).
Influence of Dose Level. The THC dose level was found to
influence the frequency of side effects and drug-related reasons for dropping out of the
study, but did not influence drug effectiveness.
The frequency and nature of various side effects rated as moderate and
severe for both THC dose levels are listed in Table J. Dose level
influenced which side effects were reported most frequently as severe. At 7.5mg/m2, the
two most common severe side effects were confusion and anxiety. At 5mg/m2, these were
sedation and confusion. Patients receiving 5mg/m2 reported an average of 3.3 moderate and
severe side effects, compared with 4.4 per patient receiving 7.5mg/m2. Side effects were
almost always less severe when the lower dose of THC was used, and this difference was
significant for seven of the 13 categories of side effects.
While there was no statistically significant difference between the high
overall dropout rates associated with either dose level, patients receiving the higher
dose were more likely to drop out because of side effects than were those on the lower
dose. Forty seven percent of the patients receiving 5mg/m2 and 492 receiving 7.5mg/M2
dropped out of the study before receiving a second THC treatment. Approximately 20% of
patients in both groups dropped out for non-drug reasons (e.g., moved, died, completed
chemotherapy). 2 Of the patients who received 5mg/m 682 dropped out because THC was
ineffective, and 32%dropped out because THC produced side effects judged by the patient to
be intolerable. In contrast, in the 7.5mg/m2 group, only 521 dropped out due to drug
ineffectiveness, and 48% dropped out due to intolerable side effects, a significant
difference between doses (P<.05). There was no difference in the overall drop-out rate
between the two dosage groups.
Safety. Physicians were required to make a separate report of any
clinically serious adverse reaction, defined as a reaction while taking THC that required
the use of drugs or hospitalization of the patient. During the course of this trial, five
clinically serious adverse reactions were reported among the first 856 patients treated
with THC. There were two instances of severe psychological distress (anxiety), and one
case each of myoclonic jerking, postural hypotension, and grand mal seizure. Complicating
factors, for example, brain metastasis associated with the seizure, were present in three
cases. All patients with serious adverse reactions had the drug immediately discontinued
and recovered fully with no sequelae. Generally, no other drug treatment was needed.
Side Effects. Side effects were common: even at the lower dose,
about 80% of patients had at least one side effect, and in 262 of those patients, at least
one side effect was considered severe. The severe side effects with an incidence of 5% or
greater were all central nervous system effects. A significant difference between the
sexes was observed: nine percent of women reported severe anxiety as compared to 42 of men
(p=.025).
Influence of Dose Level. The THC dose level was found to
influence the frequency of side effects and drug-related reasons for dropping out of the
study, but did not influence drug effectiveness.
The frequency and nature of various side effects rated as moderate and
severe for both THC dose levels are listed in Table J. Dose level influenced which side
effects were reported most frequently as severe. At 7.5mg/m2, the two most common severe
side effects were confusion and anxiety. At 5mg/m2, these were sedation and confusion.
Patients receiving 5mg/m2 reported an average of 3.3 moderate and severe side effects,
compared with 4.4 per patient receiving 7.5mg/m2. Side effects were almost always less
severe when the lower dose of THC was used, and this difference was significant for seven
of the 13 categories of side effects.
While there was no statistically significant difference between the high
overall dropout rates associated with either dose level, patients receiving the higher
dose were more likely to drop out because of side effects than were those on the lower
dose. Fortyseven percent of the patients receiving 5mg/m2 and 492 receiving 7.5mg/M2
dropped out of the study before receiving a second THC treatment. Approximately 20% of
patients in both groups dropped out for non-drug reasons (e.g., moved, died, completed
chemotherapy). Of the patients who received 5mg/M2, 681 dropped out because THC was
ineffective, and 32Z dropped out because THC produced side effects judged by the patient
to be intolerable. In contrast, in the 7.5mg/m2 group, only 52% dropped out due to drug
ineffectiveness, and 482 dropped out due to intolerable side effects, a significant
difference between doses (P<.05). There was no difference in the overall drop-out rate
between the two dosage groups.
Table J
Comparison of the Incidence of Side
Effects with 5/mg/m2 vs. 7.5mg/m2 THC
-------------------------------------
Side Effect
(Incidence as Moderate Severe
percentage)
7.5mg/m2 5mg/m2 7.5mg/m2 5mg/m2
------------- ------ -------- ------
Dry mouth** 46.5 35.4 3.9 3.2
Tachycardia 12.0 10.9 2.0 1.1
Ataxia** 21.9 18.3 5.4 1.1
Dizziness 41.7 27.1 8.7 4.6
Orthostatic
hypotension 16.8 14.1 3.0 2.5.
Anxiety** 22.3 14.4 3.8
Sedation* 56.9 47.7 6.8 7.0
Depressed mood*** 24.0 13.3 7.1 3.5
Elated mood 31.1 35.4 4.1 3.9
Panic 7.6 4.6 6.4 4.2
Confusion** 34.4 27.5 10.4 5.6
Distortion of
perception 26.3 22.1 6.6 3.5
Fantasizing 16.0 15.1 4.0 2.1
----------------------------------------------------------------
· (5mg) - 285-285 n (7.5mg) - 404-413
* P<.05 ** P<.Ol *** P<.001
However, in those patients reporting two or more severe side effects
isolated as separate groups, patients receiving 5mg/m2 were more likely to continue on to
a second THC treatment, regardless of the number of severe side effects reported.
Forty-three percent of the patients who had experienced two or more severe side effects
continued on to a second THC treatment when started at 5mg/m2. This compared with 29% of
those started at 7.5mg/m2.
Discussion. This first study included patients with a wide
variety of cancer types, covering a broad age range, and receiving treatment from
oncologists in community as well as university settings. It thus served as a test of the
antiemetic effect of THC under conditions similar to those which would exist in clinical
practice were the drug generally available.
Oral THC was found to be a safe and effective antiemetic for most cancer
chemotherapy patients. This study shows that a single THC dose of 5mg/m2 causes fewer side
effects than 7.5mg/m2 while maintaining equal effectiveness. The larger dose, 7.5mg/m2,
should be considered for patients not deriving sufficient protection from 5mg/m2
The results of this study are particularly noteworthy for two reasons:
1) The large number of patients studied strengthens conclusions reached
regarding the effectiveness and safety of THC. As of Cocchetto's 1981 review of the
literature, the largest sample size of the studies reported was only 116 patients.
Ungerleider, et al., reported on 214 patients in 1982. This Research Advisory Panel study,
on the other hand, collected detailed treatment reports and patient histories from 706
patients.
2) Most of the patients enrolled in this initial program had not
responded to conventional antiemetics, thus posing a more difficult therapeutic test than
if THC had been the first antiemetic drug used.
The high drop-out rate and observations of individual patients suggested that the rapid
appearance of side effects in patients with limited experience with disinhibiting drugs
led to anxiety and even panic. THC has an appreciable latent period, and, if the drug is
given immediately before chemotherapy a relatively large single dose must be given to get
a rapid effect. Such doses may be effective but, when the effect is fully developed, will
cause more pronounced side effects. THC is known to have a long half-life. Giving THC in a
cumulative manner, that is, giving repeated smaller doses at a longer time period prior to
chemotherapy, should allow more time for behavioral tolerance to develop and achieve
better patient acceptance but maintain efficacy. To test that hypothesis a second trial
was designed.
Cumulative Dose Study
Summary. The Cumulative Dose Protocol was designed to test the above hypothesis,
that the patient acceptance of oral THC could be improved by using a cumulative dose
schedule without the lose of efficacy. The data below support that hypothesis.
Patient and Investigator
Demographics. Patient demographics are similar to those of the
first study and are summarized for both protocols in Table K. Patients had a wide variety
of tumor types and received an assortment of chemotherapeutic agents. In age, sex
distribution, tumor types, and anticancer treatment, the two cohorts did not differ
significantly. All patients had failed to achieve satisfactory benefit from standard
antiemetic before starting the study. The most common antiemetic drug used prior to THC
was prochlorperazine.
Study design. Patients enrolled in the Cumulative Dose Protocol
received 2.5mg THC/m2 orally q4h, starting 4 doses prior to anticance treatment. These
patients were compared to a previous group of patients who were treated under the standard
protocol in which they received 5.Omg THC/m2 orally q4h, starting only 2 doses prior to
anticancer treatment.
Results. The following is an analysis of the results reported by
California oncologists of their patients enrolled in the Cumulative Dose Protocol. In this
report, only the first THC treatment was used in the comparative analysis of the
effectiveness and side effects to avoid bias due to over representation of results from
repeated trials on patients with good response.
Efficacy. Physician ratings of nausea, vomiting and overall
effectiveness were similar in the initial and the cumulative protocols. Table L compares
the two cohorts as regards oncologists or nurses ratings of nausea, vomiting and overall
THC effectiveness. Although there is a slight trend toward less nausea and less vomiting
with higher dose, with 952 confidence it is found that the distribution of nausea and
vomiting ratings are similar for both protocols.' Similarly, 571 of patients rated THC as
'moderately' or 'very' effective, exactly the same for the two dosage schedules,
indicating that side effects influence the overall evaluation.
Side Effects. Table M summarizes the reports of moderate and
severe THC side effects and their severity as recorded by oncologists or nurses on a
standardized list. In no case was the percentage for a moderate or severe side effect
increased by the cumulative dosing regimen; and the incidence of twelve of the thirteen
side effects listed was significantly reduced when compared to patients using the initial
THC protocol.
THC Related Dropouts. After the first treatment episode 27.5% of
patients receiving the cumulative dosing regimen and 22.9% of those receiving the standard
THC dosage dropped out of the trial. There is no statistically significant difference in
these dropout rates.
Conclusion. Based on the preceding findings, it appears that
prolonged exposure to low dose THC is superior to standard THC therapy as an antiemetic
regimen for cancer chemotherapy patients. The cumulative dose method decreases the number
of moderate and severe side effects. The cumulative dose method had no affect on the
drug's reported efficacy and had no affect on drop-out rate.
Table K
Patient Demographics
--------------------
Cumulative Dose Initial
Protocol Protocol
------------------ ----------------
(2.5mg THC/m2 with (5.Omg THC with
4 loading doses) 2 loading doses)
n - 134 n - 231
Sex
Males 38 % 46 %
Females 62 % 54 %
Age
19 yrs or younger 7% 8%
20 - 39 years 28% 34%
40 - 59 years 44% 34%
60 yrs or older 19% 23%
--------------------------------------------------------------
Table L
Comparison of Nausea, Vomiting and Overall Effectiveness
Between two THC Treatment Regimens
--------------------------------------------------------
Ratings of Cumulative Single Dose
---------- ---------- -----------
Nausea n - 124 n - 221
None 17% 18%
Mild 27% 32%
Moderate 34% 31%
Severe 22% 19%
Vomiting n - 124 n - 221
None 32% 33%
1 - 3 times 23% 29%
3 - 4 times 14% 13%
> 4 times 31% 26%
Overall Effectiveness n - 122 n - 221
Not Effective 25% 20%
Slightly 18% 23%
Moderately 25% 25%
Very 33% 32%
Table M
Comparison of the Incidence & Severity of Side Effects from THC
Using Two Different Dosing Methods
---------------------------------------------------------------
Side Effect Rated as Moderate Rated as Severe
(Incidence
as Cumulative* Single Cumulative* Single
percentage) Dose** Dose**
----------- ---------- ------ ---------- ------
Dry mouth** 19 40 3 6
Tachycardia 2 5 0 1
Ataxia** 2 15 2 1
Dizziness 11 19 6 5
Orthostatic
hypotension 3 8 2 5
Anxiety** 2 8 2 2
Sedation* 19 46 9 9
Elated mood 5 20 0 7
Confusion** 8 24 2 5
Distortion of
perception 5 14 0 2
Fantasizing 6 13 0 C
Depressed mood 5 7 0 4
Panic or fear 2 0 0 4
-------------------------------------------------------------
* Cumulative N - 134 ** Single Dose N - 224
Combination Protocol
Summary. To provide a more systematic and structured approach to
the common practice of combination antiemetic therapy, the Panel offered a protocol for
the optional use of THC alone or THC in combination with prochlorperazine or other
antiemetics. The Panel hoped that required reporting of combinations of antiemetics used.
would provide additional information about efficacy and side effects of various
combinations. Under the Combination Protocol, the majority of investigators either chose
to use THC alone or THC in combination with prochlorperazine.
The results of the Combination Protocol study support prior Cannabis
Therapeutic Program studies in terms of effectiveness and side effects. Only one
clinically serious adverse reaction was reported during the treatment of an additional 657
patients with THC. Also, tabulation of the data demonstrates no significant differences in
reports of efficacy or side effects between those cases where THC was used alone, cases
where THC was used in combination with prochlorperazine or other antiemetics. Too few
treatment reports alluded to combined use of THC with other antiemetics to draw
conclusions on the individual combinations.
Patient Demographics. The Panel tabulated 2,263-reports of treatment episodes on a total of 657 patients treated after January 1, 1984, the effective date for the combination protocol. These numbers include treatment reports for 98 patients who were administered marijuana cigarettes (including all prior protocols which permitted use of smoked marijuana) and records for 70 patients who had received prior treatments with THC capsules pursuant to protocols other than the Combination Protocol. There were 489 patients who had not been previously treated with THC under a prior protocol and who first received oral THC under the Combination Protocol. A total of 1,674 discrete treatment episodes were reported for these 489 patients. See Table N for a description of patient characteristics. Table 0 tabulates the emetogenicity ratings of the chemotherapy for the first treatment episodes and Table P presents the distribution of types of tumors treated.
Study design. The Panel had indications that some physicians were
using other antiemetics in combination with oral THC but not informing the Panel or
including such data on the treatment report forms. Aside from THC as an antiemetic, it was
clear that many oncologists were now using polypharmacy antiemetic therapy, with
some of the cocktails ranging up to 5 or 6 antiemetic drugs. The combination protocol gave
oncologists the option to start patients either on THC alone or in combination with
prochlorperazine or dexamethasone. These combinations were encouraged by the protocol but
other combinations were permitted.
Table N
Patient Demographics
--------------------
THC THC and Combination
used other Protocol
alone Antiemetics Totals
n - 257 n - 232 n - 489
No. % No. % No. %
--- ----- --- ----- --- -----
Sex
Males 118 45.9 104 44.8 222 45.4
Females 139 54.1 128 55.2 267 54.6
Age 19 yrs or younger 31 12.1 31 13.4 62 12.7
20 - 39 yrs 74 28.8 101 43.5 175 35.8
40 - 59 yrs 85 33.1 63 27.2 148 30.3
60 yrs or more 67 26.1 37 15.9 104 21.3
---------------------------------------------------------------------
Table 0
Comparative Ratings of Emetogenicity
of the Chemotherapy
------------------------------------
THC THC and Combination
used other Protocol
alone Antiemetics Totals
n - 257 n - 232 n - 489
No. % No. % No. %
----- --- -----
Emetogenicity Rating
Mild 17 6.7 13 5.6 30 6.1
Moderate 138 54.1 95 41.1 233 47.6
Severe 61 23.9 85 36.8 146 29.9
Radiation 22 8.6 25 10.8 47 9.6
Unknown 19 8.5 14 6.0 33 6.7
-----------------------------------------------------------------------
Table P
Distribution of Tumor Types
---------------------------
THC THC and Combination
used other Protocol
alone Antiemetics Totals
n 257 n 232 n 489
No. % No. % No. %
--- ----- --- ----- --- -----
Primary Tumor Site
01 Hodgkins 24 9.3 44 19.0 68 13.9
02 Other lymphomas 15 5.8 32 13.8 47 9.6
04 Lymphoid leukemia 7 2.7 6 2.6 13 2.7
05 Myeloid leukemia 3 1.2 2 0.9 5 1.0
07 Other leukemia 2 0.8 2 0.4
08 Leukemia unspec. 2 0.9 2 0.4
09 Lymphosarcoma 5 1.9 5 2.2 10 2.0
41 Tongue 2 0.9 2 0.4
47 Nasopharynx 2 0.8 1 0.4 3 0.6
49 Other oral cav. 1 0.4 1 0.2
50 Esophagus 1 0.4 1 0.4 2 0.4
51 Stomach 4 1.6 3 1.3 7 1.4
53 Colon 11 4.3 1 0.4 12 2.5
54 Rectum, rectosigmoid 2 0.8 1 0.4 3 0.6
55 Liver and intra 3 1.2 3 1.3 6 1.2
56 Gallbladder ... 1 0.4 1 0.2
57 Pancreas 3 1.2 5 2.2 8 1.6
59 Other dig,torg. 3 1.2 3 0.6
60 Nasal cavities ... 1 0.4 1 0.2
62 Trachea, bronchi 40 15.6 18 7.8 58 11.9
64 Thymus, heart ... 2 0.8 8 3.4 10 2.0
70 Bone and articul 12 4.7 6 2.6 18 3.7
71 Connective, other 12 4.7 4 1.7 16 3.3
72 Melanoma of skin 3 1.2 2 0.9 5 1.0
74 Female breast 58 22.6 41 17.7 99 20.2
79 Uterus ... 2 0.8 1 0.4 3 0.6
80 Cervex, uteri ... 2 0.9 2 0.4
83 Ovary... 24 9.3 19 8.2 43 8.8
85 Prostate 3 1.2 1 0.4 4 0.8
86 Testis 4 1.6 5 2.2 9 1.8
88 Bladder 2 0.9 2 0.4
89 Kidney and .... 2 0.8 2 0.9 4 0.8
90 Eye 1 0.4 1 0.2
91 Brain 2 0.8 5 2.2 7 1.4
95 Other and ill-def 3 1.2 2 0.9 5 1.0
96 Secondary... lymph 1 0.4 1 0.2
99 Without spec. o 3 1.2 3 0.6
Missing 3 1.3 3 0.6
----------------------------------------------------------------------
Objectives of the study included:
1. Does THC have a greater therapeutic effect when used in combination
with other standard antiemetics?
2. Are THC/Compazine, THC/dexamethasone and THC/Compazine/ dexamethasone
combinations safe and free from intolerable side effects?
3. Which THC antiemetic combination is preferred by cancer patients?
Drug Dose and Schedule. THC was to be given using the cumulative
dose method. Prochlorperazine, at a dose of 10mg orally, was to be administered at the
same time as the THC. Dexamethasone was to be given 2 hours prior to chemotherapy as a
single oral dose of 20mg. If a patient had not received a good response from the
THC/prochlorperazine or THC/dexamethasone combinations, in subsequent treatment episodes
the patient could be given THC, plus both prochlorperazine and dexamethasone (at the
dosage and schedule outlined above.) Results from first treatment episodes are
emphasized because of the self-selection bias expected in results from subsequent
treatment episodes.
Approximately one half of the treatment reports indicated that the
physician investigator chose to use THC alone. Thus, in the tabulation of these reports
"THC alone' serves as a 'control' for presentation of data for the 'THC used in
combinations group. Little or no differences are noted.
The results of the Combination Protocol study support prior Cannabis
Therapeutic Program studies in terms of effectiveness and side effects.
Tabulation of data did not provide an answer to the question of which
THC antiemetic combination is preferred by cancer patients. This is due in part to the
small numbers of reports on many of the antiemetic combinations. Also, in general, the
reports of efficacy and side effects are very similar regardless of 'THC used alone' or
'THC used in all combinations'.
Tabulation of this data also did not demonstrate any significant
differences when results reported for women were compared to results reported for men, nor
for young vs. old subjects.
Efficacy. Table Q provides a summary of nausea and
vomiting ratings for the first treatment episodes which were protected by THC alone, THC
combined with other antiemetics and as a total for the overall experience with the 489
patients analyzed for this phase of the Cannabis Therapeutic Program. Table R similarly
summarizes the overall effectiveness ratings.
Side Effects. Overall, side effects do not constitute a major
problem in the therapeutic use of THC. This study not only confirms the first study, but
serious side effects ceased being reported as physicians learned better how to use THC,
lower doses, and cumulative doses, and not on persons with brain damage. Table S tabulates
side effects reported for the first treatment episode for patients treated with THC,
treated with various combinations of THC and other antiemetics, as well as the totals for
the Combination Protocol Study.
Dropout Rate. Table T summarizes the reasons for dropping out
from the study after the first treatment episode.
Discussion. The only significant difference between this and the
first THC study is the use of combinations of antiemetics. Data on subjects receiving
polypharmacy have been compared with data on subjects receiving THC alone. The
similarities of results of the two groups is remarkable. The only apparent difference is
percent of subjects willing to continue to additional treatment episodes using
combinations of antiemetics (70%) as opposed to those treated with THC alone (46%).
This study tended to confirm the findings of the first study. An
additional 657 patients were treated with THC and their reports of impression of efficacy
were similar to those of the first study. Similar side effects were noted and only one
serious adverse reaction was reported. The lower dose, and to a large extent, the
cumulative dosing was being used.
Additional information. The popular polypharmacy does not appear
to offer any advantage in terms of effectiveness and little if any advantage in terms of
side effects. Again, no differences were found when these data were analyzed by sex, or
age.
Table Q
Comparative Ratings of Nausea and Vomiting
------------------------------------------
THC THC and Combination
used other Protocol
alone Antiemetics Totals
n 257 n 232 n 489
No. % No. % No. %
----- --- ----- --- ----
Nausea Rating
None 38 15.1 50 21.7 88 18.0
Mild 85 33.9 71 30.9 156 31.9
Moderate 73 29.1 57 24.8 130 26.6
Severe 55 21.9 52 22.6 107 21.9
Missing 6 2 8 1.6
Vomiting Rating
None 89 35.3 70 30.4 159 32.5
1 - 3 times 69 27.4 58 25.2 127 26.0
4 - 6 times 35 13.9 40 17.4 75 15.3
> 6 times 59 23.4 62 27.0 121 24.7
Missing 5 2 7 1.4
----------------------------------------------------------------------
Table R
Comparative Ratings of Overall Effectiveness
--------------------------------------------
THC THC and Combination
used other Protocol
alone Antiemetics Totals
n - 257 n - 232 n - 489
No. % No. % No. %
--- ----- --- ----- --- -----
Overall Effectiveness
Not effective 62 24.7 35 15.2 97 19.8
Slightly 45 17.9 55 23.8 100 20.4
Moderately 68 27.1 60 26.0 128 26.2
Very 76 30.3 81 35.1 157 32.1
Missing 6 1 7 1.4
----------------------------------------------------------------------
Table S
Comparative Ratings of Side Effects
-----------------------------------
THC THC and Combination
used other Protocol
alone Antiemetics Totals
n 257 n - 232 n 489
No. % No. % No. %
--- ----- --- ----- --- -----
Incidence of
Side Effects
Dry mouth
Severe 4 1.6 4 1.7 8 1.6
Moderate 31 12.4 31 13.5 62 12.7
Mild 77 30.8 57 24.8 134 27.4
None 138 55.2 138 60 276 56.4
Missing 7 2 9 1.8
Tachycardia
Severe 0 0.0
Moderate 6 2.4 3 1.3 9 1.8
Mild 19 7.6 14 6.1 33 6.7
None 225 90 213 92.6 438 89.6
Missing 7 2 9 1.8
Ataxia
Severe 1 0.4 1 0.2
Moderate 4 1.6 7 3 11 2.2
Mild 26 10.4 23 10 49 10.0
None 219 87.6 200 87 419 85.7
Missing 7 2 9 1.8
Dizziness
Severe 5 2 1 0.4 6 1.2
Moderate 16 6.4 19 8.3 35 7.2
Mild 46 18.4 50 21.7 96 19.6
None 183 73.2 160 69.6 343 70.1
Missing 7 2 9 1.8
Orthostatic
hypotension
Severe 1 0.4 1 0.4 2 0.4
Moderate 4 1.6 10 4.3 14 2.9
Mild 27 10.8 31 13.5 58 11.9
None 218 87.2 188 81.7 406 83.0
Missing 7 2 9 1.8
Anxiety
Severe 7 2.8 1 0.4 8 1.6
Moderate 8 3.2 15 6.6 23 4.7
Mild 32 12.8 34 14.8 66 13.5
None 203 81.2 179 78.2 382 78.1
Missing 7 3 10 2.0
Table S (Cont.)
THC THC and Combination
used other Protocol
alone Antiemetics Totals
No. % No. % No. %
--- ----- --- ----- --- -----
Sedation
Severe 13 5.2 15 6.6 28 5.7
Moderate 46 18.4 54 23.6 100 20.4
Mild 101 40.4 74 32.3 175 35.8
None 90 36 86 37.6 176 36.0
Missing 7 3 10 2.0
Elated mood
Severe 6 2.4 8 3.5 14 2.9
Moderate 22 8.8 20 8.7 42 8.6
Mild 33 13.2 49 21.3 82 16.8
None 189 75.6 153 66.5 342 69.9
missing 7 2 9 1.8
Confusion
Severe 2 0.8 5 2.2 7 1.4
Moderate 30 12 19 8.3 49 10.0
Mild 47 18.8 65 28.4 112 22.9
None 171 68.4 140 61.1 311 63.6
Missing 7 3 10 2.0
Distortion of
perception
Severe 2 0.8 1 0.4 3 0.6
Moderate 12 4.8 13 5.7 25 5.1
'Mild 43 17.2 32 13.9 75 15.3
None 193 77.2 184 80 377 77.1
Missing 7 2 9 1.8
Fantasizing
Severe 3 1.3 3 0.6
Moderate 7 2.8 7 3 14 2.9
Mild 22 8.8 15 6.5 37 7.6
None 221 88.4 205 89.1 426 87.1
Missing 7 2 9 1.8
Depressed mood
Severe 3 1.2 1 0.4 4 0.8
Moderate 11 4.4 8 3.5 19 3.9
Mild 19 7.6 18 7.9 37 7.6
None 217 86.8 202 88.2 419 85.7
Missing 7 3 10 2.0
Panic or fear
Severe 3 1.2 3 1.3 6 1.2
Moderate 4 1.6 2 0.9 6 1.2
Mild 12 4.8 13 5.7 25 5.1
None. 231 92.4 212 92.2 443 90.6
Missing 7 7 1.4
-----------------------------------------------------------------------
Table T
Comparison of Reasons for Termination
-------------------------------------
THC THC and Combination
used other Protocol
alone Antiemetics Totals
n 257 n - 232 n - 489
No. % No. % No. %
--- ----- --- ----- ---
Reasons for
Termination
Ineffective as
an antiemetic 40 15.6 20 8.6 60 12.3
Side effects
too severe 23 8.9 13 5.6 36 7.4
Expired or
completed treatment 69 26.8 26 11.2 95 19.4
Other 6 2.3 11 4.7 17 3.5
Continued study 119 46.3 162 69.8 281 57.5
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