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California Research Advisory Panel

Cannabis Therapeutic Program


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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