Jatoi et al. (2002): Dronabinol Versus Megestrol Acetate Versus Combination Therapy for Cancer-Associated Anorexia: A North Central Cancer Treatment Group Study

Reference ↗
Title	Dronabinol Versus Megestrol Acetate Versus Combination Therapy for Cancer-Associated Anorexia: A North Central Cancer Treatment Group Study
Topic	Cannabinoids
Author	Jatoi, A, Windschitl, HE, Loprinzi, CL, Sloan, JA, Dakhil, SR, Mailliard, JA, Pundaleeka, S, Kardinal, CG, Fitch, TR, Krook, JE, Novotny, PJ, Christensen, B
Year	2002
Journal	Journal of Clinical Oncology
DOI	https://doi.org/10.1200/JCO.2002.20.2.567

Brief summary

The study included 469 patients with different types of cancer. Randomly divided into three arms, one arm received Megestrol acetate, one arm received Dronabinol and one arm received both drugs. After an estimated two to three months, there was an advantage for the Megestrol arm over the Dronabinol arm for self-assessed/self-measured appetite increase and weight gain at any point in the study. There were no differences between the Megestrol arm and the combined arm. There were also some advantages of Megestrol over Dronabinol in terms of improving quality of life. The study is characterized by a large sample size. However, there are ambiguities in the procedure. For example, no clear end of the study was defined, only average participation times are given in the article, and the reasons and times at which patients withdrew from the study are not clearly stated.

In der Studie wurden 469 Patienten mit verschiedenen Krebsarten eingeschlossen. Zufällig in drei Gruppen eingeteilt, bekam eine Gruppe Megestrol Acetat, eine Gruppe Dronabinol und eine Gruppe beide Mittel. Nach schätzungsweise 2-3 Monaten zeigte sich ein Vorteil für die Megestrol Gruppe gegenüber der Dronabinol Gruppe für selbsteingeschätzte/ selbstgemessene Appetitsteigerung und Gewichtszunahme zu irgendeinem Punkt in der Studie. Zwischen der Megestrol Gruppe und der kombinierten Gruppe zeigten sich keine Unterschiede. Es zeigten sich auch einige Vorteile von Megestrol gegenüber Dronabinol bezüglich der Verbesserung der Lebensqualität. Die Studie zeichnet sich durch eine große Stichprobe aus. Jedoch gibt es Unklarheiten im Ablauf. So wurde kein klares Studienende definiert, im Artikel werden nur mittlere Teilnahmezeiten angegeben, auch sind die Gründe und Zeitpunkte des Ausstiegs von Patienten der Studie nicht deutlich aufgeführt.

Study Design

Prospective / Retrospective Prospective: forward-looking, examples include clinical trials, cohort studies, and long-term observational studies;</br>Retrospective: backward-looking, relying on existing data, examples include case-control studies and retrospective cohort studies	Prospective
Monocentric / Multicentric Monocentric: conducted in one center/ hospital; </br>Multicentric: conducted in multiple centers/ hospitals	Multicentric
Blinding No: Open, all parties are aware of group assignments;</br>Single: one party is unaware of group assignments (generally participants);</br>Double: two parties are unaware of group assignments (generally the participants and the researchers); </br>Triple: concealing group assignment from additional parties	Double
Is randomized	Yes
Cross-over Participants alternate between different treatment groups or conditions over a specified period, allowing each participant to serve as their own control	No
Number of arms	3

Study characteristics

Inclusion criteria	Adult patients (≥18 years of age) with histologic evidence of an incurable malignancy other than brain, breast, ovarian, or endometrial cancer; estimated life expectancy of ≥3 months; Eastern Cooperative Oncology Group performance status of 0 to 2, as judged by their primary oncologist; self-reported weight loss of at least 5 pounds (2.3 kg) during the preceding 2 months and/or a physician-estimated caloric intake of less than 20 calories/kg of body weight per day; believe, that loss of appetite or loss of weight was an ongoing problem
Exclusion criteria	Ongoing use of tube feedings or parenteral nutrition; edema or ascites; treatment with adrenal corticosteroids (except for short-term dexamethasone during the time of chemotherapy), androgens, progestational agents, or other appetite stimulants within the previous month; brain metastases; insulin-requiring diabetes; pregnancy or lactation or unwillingness to use oral contraceptives; anticipated alcohol or barbiturate use during the study period; poorly controlled hypertension or congestive heart failure; history of thromboembolic disease; mechanical obstruction of the alimentary tract, malabsorption, or intractable vomiting
N randomized	469
Analysis PP: Per Protocol analysis, i.e. only participants included who adhered to the study protocol.</br>ITT: Intention-to-treat analysis, i.e. all randomized participants included regardless of any drop-outs or changes in assignment.</br>mITT: modified Intention-to-treat analysis can refer to analyses in which participants with missing outcome data are excluded or it can refer to analyses in which only participants who received at least one treatment dose are included. In this case, participants dropped out of the study prematurely for reasons unrelated to the treatment.	ITT Analysis
Specifications on analyses	No information provided on intent-to-treat analyses, but according to the tables all randomized patients appear to have been included in the analyses.
Countries of data collection	Canada, Mexico, United States
LoE Level of evidence	Level 2 Oxford 2011
Outcome timeline Data collection times	T0: baseline T1: end of study (no clear end of study defined)

Characteristics of participants

Setting Refers to cancer therapy setting.</br>- Curative therapy: aims to completely eradicate a disease and achieve a full recovery; </br>- Neo-adjuvant therapy: form of curative therapy, given before the primary treatment for cancer (usually surgery); </br>- Adjuvant therapy: form of curative therapy, given after the primary treatment for cancer (usually surgery); </br>- Palliative therapy: focuses on providing relief from symptoms and improving the quality of life for patients, without necessarily targeting the underlying disease; </br>- Active surveillance: involves close monitoring of disease progression without any intervention (typically used for prostate cancer);</br>- No therapy setting: Patients who completed therapy/are currently not in cancer treatment, cancer survivors.	Palliative
Types of cancer "Other Cancers" means that only a subpopulation was specified, but further unspecified cancer types were included	Gastrointestinal Cancers, Lung Cancer, Other Cancers
Cancer stages Early Stage: generally refers to cancer that is localized to the area where it started, mostly stages I and II;</br>Advanced Stage: cancer that has spread beyond its original site, mostly stages III and IV, with stage IV indicating distant metastasis	Advanced Stage
Specifications on cancer stages	NI
Comorbidities	NI
Current cancer therapies	Chemotherapy, Radiation therapy, No therapy
Specifications on cancer therapies	Planned concurrent chemotherapy, %, per arm None: Megestrol Acetate = 30; Dronabinol = 30; Megestrol Acetate + Dronabinol= 30 With cisplatinum: Megestrol Acetate = 15; Dronabinol = 14; Megestrol Acetate + Dronabinol = 14 Without cisplatinum: Megestrol Acetate= 55; Dronabinol = 56; Megestrol Acetate + Dronabinol = 56 Planned concurrent radiation, % Yes: Megestrol Acetate = 21; Dronabinol = 20; Megestrol Acetate + Dronabinol = 20 No: Megestrol Acetate = 79; Dronabinol = 80; Megestrol Acetate + Dronabinol = 80
Previous cancer therapies	NI
Gender	Mixed
Gender specifications	Sex (%) per arm Megestrol Acetate: male = 65; female = 36 Dronabinol: male = 66; female = 34 Megestrol Acetate + Dronabinol: male = 66; female = 34
Age groups	Adults (18+)
Age groups specification	Mean (SD) age per arm: Megestrol Acetate = 65 (11) years Dronabinol = 67 (10) years Megestrol Acetate + Dronabinol = 67 (10) years

Arms

Arm type Active control: group receives active treatment; </br>Passive control: for example treatment as usual, waiting control, no treatment	Intervention
Number of participants (arm) N randomized	159
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	106
Drop-out reasons	Patient refusal and/or toxicity (45%, respectively); patient death (22%, respectively)
Intervention	Megestrol Acetate
Dosage and regime	Oral, 800mg/day liquid + placebo
One-time application	No
Duration in days For long-term interventions, the number of days is an estimation.</br>A value of -999 indicates that the exact duration cannot be extracted from the study due to ambiguous or incomplete information. See Outcome timeline or Dosage and regime for further information.	80
Side effects / Interactions	Impotence in 18 % of men; vomiting; fluid retention; confused thinking; drowsiness; loss of coordination; inappropriate behavior

Arm type Active control: group receives active treatment; </br>Passive control: for example treatment as usual, waiting control, no treatment	Intervention
Number of participants (arm) N randomized	152
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	111
Drop-out reasons	Patient refusal and/or toxicity (58%, respectively); patient death (15%, respectively)
Intervention	Dronabinol
Dosage and regime	Oral, 2.5mg 2 times a day + liquid placebo
One-time application	No
Duration in days For long-term interventions, the number of days is an estimation.</br>A value of -999 indicates that the exact duration cannot be extracted from the study due to ambiguous or incomplete information. See Outcome timeline or Dosage and regime for further information.	57
Side effects / Interactions	Impotence in 4% of men; vomiting; fluid retention; confused thinking; drowsiness; loss of coordination; inappropriate behavior

Arm type Active control: group receives active treatment; </br>Passive control: for example treatment as usual, waiting control, no treatment	Intervention
Number of participants (arm) N randomized	185
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	124
Drop-out reasons	Patient refusal and/or toxicity (41%, respectively); patient death (26%, respectively)
Intervention	Megestrol Acetate + Dronabinol
Dosage and regime	Combination of Megestrol Acetate (oral, 800mg/day liquid) and Dronabinol (oral, 2.5mg 2 times a day)
One-time application	No
Duration in days For long-term interventions, the number of days is an estimation.</br>A value of -999 indicates that the exact duration cannot be extracted from the study due to ambiguous or incomplete information. See Outcome timeline or Dosage and regime for further information.	74
Side effects / Interactions	Impotence in 14% of men; vomiting; fluid retention; confused thinking; drowsiness; loss of coordination; inappropriate behavior

Outcomes

Appetite

Outcome type As specificed by the authors	Primary
Outcome specification	Increase in appetite
Type of measurement	Observation
Results during intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	Patients reporting increase in appetite at any point in the study (6-week median time): Significant benefit for Megestrol Acetate arm compared to Dronabinol arm (75% vs. 49%; p=0.0001) No differences between Megestrol Acetate + Dronabinol arm (66%) and Megestrol Acetate arm (p=0.17)
Results after intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	NA

Risk of Bias Assessment: Cochrane RoB tool 2.0
Bias arising from the randomization process	some concerns
Bias due to deviation from intended intervention (assignment to intervention)	high risk
Bias due to deviation from intended intervention (adhering to intervention)	NA
Bias due to missing outcome data	high risk
Bias in measurement of the outcome	some concerns
Bias in selection of the reported result	some concerns
Other sources of bias	some concerns
Overall RoB judgment	high risk

Weight

Outcome type As specificed by the authors	Primary
Outcome specification	Weight gain (10% of own weight)
Type of measurement	Scale
Results during intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	Patients reporting that weight had increased by 10% at any point in the study (6-week median time): Significant benefit for Megestrol Acetate arm compared to Dronabinol arm (11% vs. 3%; p=0.02) No differences between Megestrol Acetate + Dronabinol arm (8%) and Megestrol Acetate arm (p=0.34) Physician data: Megestrol Acetate arm 14%, Dronabinol arm 5% (Megestrol Acetate arm vs. Dronabinol arm p=0.009) Megestrol Acetate + Dronabinol arm 11% (Megestrol Acetate arm vs. Megestrol Acetate + Dronabinol arm, p=0.49)
Results after intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	NA

Risk of Bias Assessment: Cochrane RoB tool 2.0
Bias arising from the randomization process	some concerns
Bias due to deviation from intended intervention (assignment to intervention)	high risk
Bias due to deviation from intended intervention (adhering to intervention)	NA
Bias due to missing outcome data	high risk
Bias in measurement of the outcome	some concerns
Bias in selection of the reported result	some concerns
Other sources of bias	some concerns
Overall RoB judgment	high risk

Quality of life

Outcome type As specificed by the authors	Primary
Outcome specification	Quality of life (single Item Uniscale and FAACT-AN)
Type of measurement	FAACT (Functional Assessment of Anorexia-Cachexia Therapy)
Results during intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	Difference baseline to end of study (6-week median time): No differences for Uniscale; in the FAACT-AN significant advantage for Megestrol Acetate arm over Dronabinol arm (p=0.002), as well as in individual scales physical and emotional constructs; except for emotional constructs (Megestrol Acetate arm better than Megestrol Acetate + Dronabinol arm) No differences between Megestrol Acetate arm and Megestrol Acetate + Dronabinol arm
Results after intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	NA

Risk of Bias Assessment: Cochrane RoB tool 2.0
Bias arising from the randomization process	some concerns
Bias due to deviation from intended intervention (assignment to intervention)	high risk
Bias due to deviation from intended intervention (adhering to intervention)	NA
Bias due to missing outcome data	high risk
Bias in measurement of the outcome	some concerns
Bias in selection of the reported result	some concerns
Other sources of bias	some concerns
Overall RoB judgment	high risk

OS (Overall Survival)

Outcome type As specificed by the authors	Others
Outcome specification	Overall survival rate
Type of measurement	Observation
Results during intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	NA
Results after intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	No significant difference (123 vs. 141 vs. 113 days) between the Megestrol Acetate versus Dronabinol versus the combination arm, respectively (log Rank p=0.66)

Risk of Bias Assessment: Cochrane RoB tool 2.0
Bias arising from the randomization process	some concerns
Bias due to deviation from intended intervention (assignment to intervention)	low risk
Bias due to deviation from intended intervention (adhering to intervention)	NA
Bias due to missing outcome data	low risk
Bias in measurement of the outcome	some concerns
Bias in selection of the reported result	some concerns
Other sources of bias	some concerns
Overall RoB judgment	some concerns

Funding and Conflicts of Interest

Funding	Collaborative study by the North Central Cancer Treatment Group and Mayo Clinic. Dronabinol was provided by Roxane Laboratories,Columbus, OH. Magestrol acetate was provided by: Bristol-Myers Squibb, princeton, NJ.
Conflicts of Interest	NI

Further points for assessing the study

Sample

Power analysis performed	Yes
- Sample size corresponds to power analysis	Yes
- Reasons for insufficient sample size based on power analysis	NA
If no power analysis performed: at least moderate sample size (n >= 30 per arm)	NA
Ethnicity mentioned	Yes

Alternative Explanation

Other explanations for an effect besides the investigated intervention	Yes
- Possibility of attention effects	NA
- Possibility of placebo effects	NA
- Other reasons	Unclear statistic: Only 45% completed questionnaires after 1 month, no information provided on intent-to-treat analyses, but according to tables all randomized patients appear to have been included in the analyses (patients who dropped out were considered treatment failure) Different weights reported by patients and physicians No clear indication of time course (end of study), different median times for participation in studies per arm withdrawal due to withdrawal of consent and/or side effect (45%, 58%, and 41%) or death (22%, 15% and 26%) No flow chart, so unclear when drop-out/attrition occurred

Statistics

Correct use of parametric and non-parametric tests Testing for normal distribution only necessary if parametric tests are used, NI: use of parametric tests without report of normal distribution testing	Yes
Correction for multiple testing	No
Measurement of compliance	NI
Consistent reporting in numbers (figures, flowchart, abstract, results)	Yes
Comprehensive and coherent reporting	Yes
Cross-over	No
- Sufficient washout period	NA
- Tested for carry-over effects	NA
- Tested for sequence effects	NA

Interpretation of results

Effect sizes reported (clinical vs. statistical significance)	No
Side effects systematically recorded	NI
Side effects considered in result interpretation	Yes
Ethics votum	Yes

Additional Notes

PRO:

• Ethical approval
• Stratified randomization
• Power analysis
• Baseline comparability of groups

CONTRA:

• Discrepancies in weight data reported by patients vs. doctors
• No clear timeline for study completion, with varying median participation times across arms (dropouts due to consent withdrawal and/or side effects: 45%, 58%, and 41%; or death: 22%, 15%, and 26%)
• Lack of a flowchart, making the timing of dropouts/attrition unclear
• Only 45% completed questionnaires after one month; no details on intent-to-treat analysis, though tables suggest all randomized patients were included (dropouts were classified as "treatment failure")