Grimison et al. (2020): Oral THC:CBD cannabis extract for refractory chemotherapy-induced nausea and vomiting: a randomised, placebo-controlled, phase II crossover trial: Difference between revisions
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|Reference=Publication: Oral THC:CBD cannabis extract for refractory chemotherapy-induced nausea and vomiting: a randomised, placebo-controlled, phase II crossover trial | |Reference=Publication: Oral THC:CBD cannabis extract for refractory chemotherapy-induced nausea and vomiting: a randomised, placebo-controlled, phase II crossover trial | ||
}} | }} | ||
=Brief summary= | =Brief summary= | ||
The study included 81 patients with different types of cancer and a history of nausea and vomiting due to chemotherapy. They were randomly divided into | The study included 81 patients with different types of cancer and a history of nausea and vomiting due to chemotherapy. They were randomly divided into two arms, one arm received THC and CBD daily and the other arm a placebo. After one cycle of chemotherapy, the arms were switched. At the end of two cycles (so that everyone was in each arm), there was overall less and less severe nausea and vomiting in the THC/CBD arm and an improvement on some quality of life measurement scales. However, the patients receiving THC/CBD had more side effects, such as dizziness and sedation, which were tolerable, according to the authors. The study has an elaborate study design. The statistics seem well thought out and take many factors into account, but a few methodological decisions remain unexplained. It should be noted in particular that many of the people involved in the article have direct contacts with the pharmaceutical industry. | ||
In der Studie wurden 81 Patienten mit verschiedenen Krebsarten und Vorgeschichte von Übelkeit und Erbrechen durch Chemotherapie eingeschlossen. Diese wurden zufällig in | In der Studie wurden 81 Patienten mit verschiedenen Krebsarten und Vorgeschichte von Übelkeit und Erbrechen durch Chemotherapie eingeschlossen. Diese wurden zufällig in zwei Gruppen eingeteilt, eine Gruppe bekam täglich THC und CBD und die andere Gruppe ein Placebo. Nach einem Zyklus Chemotherapie wurden die Gruppen getauscht. Am Ende von zwei Zyklen (sodass jeder in jeder Gruppe war) zeigte sich insgesamt weniger und weniger schwere Übelkeit und Erbrechen in der Gruppe mit THC/CBD und eine Verbesserung auf einigen Skalen der Messung der Lebensqualität. Jedoch hatten die Patienten die THC/CBD bekamen mehr Nebenwirkungen, wie Schwindel und Sedierung, die laut den Autoren jedoch tolerierbar waren. Die Studie hat ein aufwändiges Studiendesign. Die Statistik wirkt gut durchdacht und bezieht viele Faktoren mit ein, jedoch bleiben ein paar methodische Entscheidungen unerklärt. Besonders anzumerken ist, dass viele beteiligten Personen in dem Artikel direkte Kontakte zu Pharmaindustrien aufweisen. | ||
=Study Design= | =Study Design= | ||
| Line 33: | Line 32: | ||
|LoE=Level 2 Oxford 2011 | |LoE=Level 2 Oxford 2011 | ||
|Outcome timeline=T0: baseline | |Outcome timeline=T0: baseline | ||
T1: one day before chemotherapy | T1: one day before chemotherapy | ||
T2: day 8 of each cycle | T2: day 8 of each cycle | ||
T3: between 30-42 days after end of intervention | T3: between 30-42 days after end of intervention | ||
}} | }} | ||
| Line 40: | Line 42: | ||
{{Characteristics of participants | {{Characteristics of participants | ||
|Setting= | |Setting=Curative, Palliative | ||
|Types of cancer=Breast Cancer, Colorectal Cancer, Gastrointestinal Cancers, Gastrointestinal Cancers - Pancreatic Cancer, Genitourinary Cancers - Testicular Cancer, Gynecologic Cancers, Hematologic Cancers, Lung Cancer, Other Cancers | |Types of cancer=Breast Cancer, Colorectal Cancer, Gastrointestinal Cancers, Gastrointestinal Cancers - Pancreatic Cancer, Genitourinary Cancers - Testicular Cancer, Gynecologic Cancers, Hematologic Cancers, Lung Cancer, Other Cancers | ||
|Stage cancer=NI | |Stage cancer=NI | ||
| Line 47: | Line 49: | ||
|Current cancer therapy=Chemotherapy | |Current cancer therapy=Chemotherapy | ||
|Specifications on cancer therapies=Moderate-to-high emetogenic intravenous chemotherapy | |Specifications on cancer therapies=Moderate-to-high emetogenic intravenous chemotherapy | ||
Chemotherapy regimen, n(%): | Chemotherapy regimen, n(%): | ||
Doxorubicin + cyclophosphamide 20 (26) | |||
FOLFOX ± biological 13 (17) | Doxorubicin + cyclophosphamide = 20 (26) | ||
Cisplatin based 12 (15) | |||
FOLFIRINOX 6 (8) | FOLFOX ± biological = 13 (17) | ||
Other 27 (35) | |||
Cisplatin based = 12 (15) | |||
FOLFIRINOX = 6 (8) | |||
Other = 27 (35) | |||
|Previous cancer therapies=NI | |Previous cancer therapies=NI | ||
|Gender=Mixed | |Gender=Mixed | ||
|Gender specifications=Female | |Gender specifications=Female : 61 (78%) | ||
Male | Male: 17 (22%) | ||
|Age groups=Adults (18+) | |Age groups=Adults (18+) | ||
|Age groups specification= | |Age groups specification=Median age (range): 55 (29-80) years | ||
}} | }} | ||
=Arms= | =Arms= | ||
| Line 69: | Line 77: | ||
Death (n = 1); failure to comply (n = 1); chemotherapy stopped (n = 1); patient preference (n = 1) | Death (n = 1); failure to comply (n = 1); chemotherapy stopped (n = 1); patient preference (n = 1) | ||
|Intervention=THC:CBD | |Intervention=THC:CBD | ||
|Dosage and regime=1-4 capsules THC 2.5mg/CBD 2.5mg | |Dosage and regime=1-4 capsules (each THC 2.5mg/CBD 2.5mg) 3x daily from one day before chemotherapy to day 5; median (SD) number of capsules: 2 (1-3) | ||
|One-time application=No | |One-time application=No | ||
|Duration in days=-999 | |Duration in days=-999 | ||
|Side Effects / Interactions=Moderate or severe cannabinoid-related side effects in | |Side Effects / Interactions=Moderate or severe cannabinoid-related side effects in intervention arm and placebo arm (31% vs. 7%, p=0.002): | ||
* Significant differences for sedation (19% vs. 4%, p=0.002) and dizziness (10% vs. 1%, p=0.03) | |||
* No differences for disorientation (p=0.5) and anxiety (p=1.00) | |||
* No cannabinoid-related serious adverse events reported | |||
83% of participants preferred cannabis over placebo and 15% | 83% of the participants preferred cannabis over placebo and 15% had a preference for placebo (p<0.001) | ||
|Order number=1 | |Order number=1 | ||
|Arm topic=Cannabinoids | |||
}} | }} | ||
{{Arm | {{Arm | ||
|Arm type=Placebo | |Arm type=Placebo | ||
|Number of participants (arm)=41 | |Number of participants (arm)=41 | ||
|Drop-out= | |Drop-out=2 | ||
|Drop-out reasons=Discontinued after placebo (n = 2): | |Drop-out reasons=Discontinued after placebo (n = 2): | ||
chemotherapy stopped (n = 1); patient preference (n = 1) | chemotherapy stopped (n = 1); patient preference (n = 1) | ||
|Intervention=Placebo | |Intervention=Placebo | ||
|Dosage and regime=Median number of capsules 3 (2-4) | |Dosage and regime=Median (SD) number of capsules = 3 (2-4) | ||
|One-time application=No | |One-time application=No | ||
|Duration in days=-999 | |Duration in days=-999 | ||
|Side Effects / Interactions=Moderate or severe cannabinoid-related side effects in | |Side Effects / Interactions=Moderate or severe cannabinoid-related side effects in intervention arm and placebo arm (31% vs. 7%, p=0.002): | ||
* Significant differences for sedation (19% vs. 4%, p=0.002) and dizziness (10% vs. 1%, p=0.03) | |||
* No differences for disorientation (p=0.5) and anxiety (p=1.00) | |||
* No cannabinoid-related serious adverse events reported | |||
83% of participants preferred cannabis over placebo and 15% | 83% of the participants preferred cannabis over placebo and 15% had a preference for placebo (p<0.001) | ||
|Order number=2 | |Order number=2 | ||
|Arm topic=Cannabinoids | |||
}} | }} | ||
{{Arm Overview}} | {{Arm Overview}} | ||
| Line 102: | Line 119: | ||
|Type of measurement=Observation | |Type of measurement=Observation | ||
|Results during intervention=Results after 2 cycles, after switching to the other arm: | |Results during intervention=Results after 2 cycles, after switching to the other arm: | ||
* Significant advantage for intervention arm (25%) compared to placebo arm (14%): RR=1.77; 90% CI=1.12,2.79; p=0.041. | |||
|Results after intervention= | |Results after intervention=NA | ||
|Bias arising from the randomization process= | |Bias arising from the randomization process=low risk | ||
|Bias due to deviation from intended intervention (assignment to intervention)= | |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 deviation from intended intervention (adhering to intervention)=NA | ||
|Bias due to missing outcome data= | |Bias due to missing outcome data=low risk | ||
|Bias in measurement of the outcome= | |Bias in measurement of the outcome=some concerns | ||
|Bias in selection of the reported result= | |Bias in selection of the reported result=low risk | ||
|Other sources of bias= | |Other sources of bias=NA | ||
|Overall RoB judgment= | |Overall RoB judgment=high risk | ||
|Order number=1 | |Order number=1 | ||
|Outcome topic=Cannabinoids | |||
}} | }} | ||
{{Outcome | {{Outcome | ||
| Line 120: | Line 138: | ||
|Type of measurement=NRS (Numeric Rating Scale) | |Type of measurement=NRS (Numeric Rating Scale) | ||
|Results during intervention=Results after 2 cycles, after switching to the other arm: | |Results during intervention=Results after 2 cycles, after switching to the other arm: | ||
Advantage for intervention | * Advantage for intervention arm for percentage for CR (p=0.04), for scales "no vomiting" (p=0.05), "no emergency medication" p=0.04), "no significant nausea" (p=0.03), mean and maximum number of vomiting per day (p=0.003, p=0.001), mean/maximum nausea values (p's<0.001). | ||
|Results after intervention= | * No difference for complete response and "no significant nausea" (p=0.12) | ||
|Bias arising from the randomization process= | |Results after intervention=NA | ||
|Bias due to deviation from intended intervention (assignment to intervention)= | |Bias arising from the randomization process=low risk | ||
|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 deviation from intended intervention (adhering to intervention)=NA | ||
|Bias due to missing outcome data= | |Bias due to missing outcome data=low risk | ||
|Bias in measurement of the outcome= | |Bias in measurement of the outcome=high risk | ||
|Bias in selection of the reported result= | |Bias in selection of the reported result=low risk | ||
|Other sources of bias= | |Other sources of bias=NA | ||
|Overall RoB judgment= | |Overall RoB judgment=high risk | ||
|Order number=2 | |Order number=2 | ||
|Outcome topic=Cannabinoids | |||
}} | }} | ||
{{Outcome | {{Outcome | ||
| Line 137: | Line 157: | ||
|Outcome specification=Quality of life (nausea & vomiting scales) at baseline, day -1, end of treatment | |Outcome specification=Quality of life (nausea & vomiting scales) at baseline, day -1, end of treatment | ||
|Type of measurement=AQoL-8D (Assessment of Quality of Life), FLIE (Functional Living Index for Emesis) | |Type of measurement=AQoL-8D (Assessment of Quality of Life), FLIE (Functional Living Index for Emesis) | ||
|Results during intervention=FLIE: significant advantage for intervention | |Results during intervention=FLIE: | ||
* significant advantage for intervention arm for nausea scale (mean difference: 20.9 on 100-point scale, p < 0.001) and vomiting scale (mean difference: 11.9, p < 0.001) | |||
AQOL-8D | |||
|Results after intervention= | AQOL-8D: | ||
|Bias arising from the randomization process= | * significant advantage for intervention arm in use-related QoL (mean difference: 0.04, 95% CI 0.01,0.07; p=0.019) | ||
|Bias due to deviation from intended intervention (assignment to intervention)= | * physical health (mean difference: 0.06, 95% CI 0.03-0.09, p < 0.001) | ||
* mental health (mean difference: 0.04, 95% CI 0.01, 0.06, p=0.004) | |||
* pain (mean difference: 0.08, 95% CI 0.03, 0.13, p=0.003) | |||
|Results after intervention=NA | |||
|Bias arising from the randomization process=low risk | |||
|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 deviation from intended intervention (adhering to intervention)=NA | ||
|Bias due to missing outcome data= | |Bias due to missing outcome data=low risk | ||
|Bias in measurement of the outcome= | |Bias in measurement of the outcome=high risk | ||
|Bias in selection of the reported result= | |Bias in selection of the reported result=low risk | ||
|Other sources of bias= | |Other sources of bias=NA | ||
|Overall RoB judgment= | |Overall RoB judgment=high risk | ||
|Order number=3 | |Order number=3 | ||
|Outcome topic=Cannabinoids | |||
}} | }} | ||
{{Outcome | {{Outcome | ||
|Outcome type=Secondary | |Outcome type=Secondary | ||
|Outcome name=Toxicity | |Outcome name=Toxicity | ||
|Outcome specification= | |Outcome specification=Self-developed measurement instrument: structured checklist of cannabinoid-specific adverse events | ||
|Type of measurement=CTCAE (Common Terminology Criteria of Adverse Events) | |Type of measurement=CTCAE (Common Terminology Criteria of Adverse Events), Self-developed measurement instrument | ||
|Results during intervention=Moderate or severe cannabinoid-related side effects in intervention | |Results during intervention=Moderate or severe cannabinoid-related side effects in intervention arm (31%) and placebo arm (7%) (p=0.002): | ||
* Significant differences for sedation (19% vs. 4%, p=0.002), dizziness (10% vs. 1%, p=0.03) | |||
* No differences for disorientation (3% vs. 0%, p=0.5), anxiety (1% vs. 1%, p=1.00) | |||
* No cannabinoid-related serious adverse events were reported. | |||
83% of participants preferred cannabis over placebo and 15% | 83% of the participants preferred cannabis over placebo and 15% had a preference for placebo (p<0.001). | ||
|Results after intervention= | |Results after intervention=NA | ||
|Bias arising from the randomization process= | |Bias arising from the randomization process=low risk | ||
|Bias due to deviation from intended intervention (assignment to intervention)= | |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 deviation from intended intervention (adhering to intervention)=NA | ||
|Bias due to missing outcome data= | |Bias due to missing outcome data=low risk | ||
|Bias in measurement of the outcome= | |Bias in measurement of the outcome=high risk | ||
|Bias in selection of the reported result= | |Bias in selection of the reported result=low risk | ||
|Other sources of bias= | |Other sources of bias=NA | ||
|Overall RoB judgment= | |Overall RoB judgment=high risk | ||
|Order number=4 | |Order number=4 | ||
|Outcome topic=Cannabinoids | |||
}} | }} | ||
{{Outcome Overview}} | {{Outcome Overview}} | ||
| Line 175: | Line 206: | ||
{{Funding and Conflicts of Interest | {{Funding and Conflicts of Interest | ||
|Funding=This work was supported by the Department of Health, NSW Government, Australia. Tilray supplied and covered the cost of study treatments and were given the opportunity to review the study protocol and manuscript, but had no role in data analysis. | |Funding=This work was supported by the Department of Health, NSW Government, Australia. Tilray supplied and covered the cost of study treatments and were given the opportunity to review the study protocol and manuscript, but had no role in data analysis. | ||
|Conflicts of Interest=Conflict of interest can be seen in the article, many contacts to pharmaceutical industries | |Conflicts of Interest=Conflict of interest can be seen in the article, many contacts to pharmaceutical industries. | ||
}} | }} | ||
=Further points for assessing the study= | =Further points for assessing the study= | ||
{{Further points for assessing the study | {{Further points for assessing the study | ||
|Samples sufficiently large= | |power analysis performed=Yes | ||
| | |Sample size corresponds to power analysis=Yes | ||
|Reasons given for samples being too small according to power analysis=NA | |||
|Samples sufficiently large=NA | |||
|Ethnicity mentioned=No | |||
|Other explanations for an effect besides the investigated intervention=Yes | |||
|Possibility of attention effects=NA | |||
|Possibility of placebo effects=NA | |||
|Other reasons=Knowledge of assignment and believe in positive influence in outcomes assessed with self-report-questionnaires | |||
|Correct use of parametric and non-parametric tests=NI | |||
|Correction for multiple testing=Yes | |||
|Measurement of compliance=Yes | |||
|Consistent reporting in numbers=No | |||
|Comprehensive and coherent reporting=No | |||
|Cross-over=Yes | |||
|sufficient washout period=NA | |||
|Tested for carry-over effects=NA | |||
|Were sequence effects tested=NA | |||
|Effect sizes reported=No | |||
|Were side effects systematically recorded=Yes | |||
|Side effects taken into account in the interpretation of the results=Yes | |||
|Ethics / CoI / Funding=Yes | |||
|Blinding reliable=No | |||
|Check whether blinding was successful=No | |||
|reasons given for samples being too small according to power analysis=? | |reasons given for samples being too small according to power analysis=? | ||
|Testing for normal distribution=? | |Testing for normal distribution=? | ||
|Correct application of statistical tests=? | |Correct application of statistical tests=? | ||
|mono- or multicentric=? | |mono- or multicentric=? | ||
}} | }} | ||
{{Additional Notes | {{Additional Notes | ||
|Additional Notes= | |Additional Notes=PRO: | ||
* Ethical approval | |||
* Power analysis | |||
* Daily contact with staff on days of administration | |||
* Structured assessment of side effects using a checklist | |||
* Adherence monitored through diary entries and capsule counts | |||
* McNemar’s test used to control for within-patient correlation | |||
* Control for order effects (p=0.29) | |||
* Comparability at baseline ensured by study design | |||
CONTRA: | |||
* Correction for multiple testing only for primary endpoints | |||
* 90% confidence interval (CI) (p=0.1) used for primary endpoints and 95% CI for secondary endpoints due to pilot study design (primary endpoint was also significant at 95%) | |||
* No differentiation of primary endpoint into acute or delayed responses, despite being listed in the methodology | |||
* Unclear presentation of when and how each endpoint is measured | |||
* Numerous interactions with pharmaceutical companies | |||
* Capsule dosing individualized, with no subgroup analyses for high vs. low doses | |||
}} | }} | ||
Latest revision as of 17:10, 26 November 2024
| Reference ↗ | |
|---|---|
| Title | Oral THC:CBD cannabis extract for refractory chemotherapy-induced nausea and vomiting: a randomised, placebo-controlled, phase II crossover trial |
| Topic | Cannabinoids |
| Author | Grimison, P, Mersiades, A, Kirby, A, Lintzeris, N, Morton, R, Haber, P, Olver, I, Walsh, A, McGregor, I, Cheung, Y, Tognela, A, Hahn, C, Briscoe, K, Aghmesheh, M, Fox, P, Abdi, E, Clarke, S, Della-Fiorentina, S, Shannon, J, Gedye, C, Begbie, S, Simes, J, Stockler, M |
| Year | 2020 |
| Journal | Annals of Oncology |
| DOI | https://doi.org/10.1016/j.annonc.2020.07.020 |
Brief summary
The study included 81 patients with different types of cancer and a history of nausea and vomiting due to chemotherapy. They were randomly divided into two arms, one arm received THC and CBD daily and the other arm a placebo. After one cycle of chemotherapy, the arms were switched. At the end of two cycles (so that everyone was in each arm), there was overall less and less severe nausea and vomiting in the THC/CBD arm and an improvement on some quality of life measurement scales. However, the patients receiving THC/CBD had more side effects, such as dizziness and sedation, which were tolerable, according to the authors. The study has an elaborate study design. The statistics seem well thought out and take many factors into account, but a few methodological decisions remain unexplained. It should be noted in particular that many of the people involved in the article have direct contacts with the pharmaceutical industry.
In der Studie wurden 81 Patienten mit verschiedenen Krebsarten und Vorgeschichte von Übelkeit und Erbrechen durch Chemotherapie eingeschlossen. Diese wurden zufällig in zwei Gruppen eingeteilt, eine Gruppe bekam täglich THC und CBD und die andere Gruppe ein Placebo. Nach einem Zyklus Chemotherapie wurden die Gruppen getauscht. Am Ende von zwei Zyklen (sodass jeder in jeder Gruppe war) zeigte sich insgesamt weniger und weniger schwere Übelkeit und Erbrechen in der Gruppe mit THC/CBD und eine Verbesserung auf einigen Skalen der Messung der Lebensqualität. Jedoch hatten die Patienten die THC/CBD bekamen mehr Nebenwirkungen, wie Schwindel und Sedierung, die laut den Autoren jedoch tolerierbar waren. Die Studie hat ein aufwändiges Studiendesign. Die Statistik wirkt gut durchdacht und bezieht viele Faktoren mit ein, jedoch bleiben ein paar methodische Entscheidungen unerklärt. Besonders anzumerken ist, dass viele beteiligten Personen in dem Artikel direkte Kontakte zu Pharmaindustrien aufweisen.
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 | Yes |
| Number of arms | 2 |
Study characteristics
| Inclusion criteria | Aged ≥18 years; any malignancy of any stage; receiving intravenous
chemotherapy of moderate or high emetogenic risk; receive at least two more consecutive cycles; refractory CINV (defined as emesis, and/or nausea of moderate severity on a 5-point rating scale, and/or requiring use of rescue medications) in earlier chemotherapy cycles despite guideline-consistent antiemetic prophylaxis consisting of corticosteroids, a 5-HT3 antagonist, and an NK-1 antagonist with or without olanzapine where indicated |
|---|---|
| Exclusion criteria | Eastern Cooperative Oncology Group (ECOG) performance status of >2; a contraindication to medicinal cannabis such as unstable cardiovascular disease, substance use disorder, or significant mental health disorder; experiencing disease-related nausea and vomiting; receiving concomitant oral chemotherapy; had received/were planned to receive radiotherapy to the brain or gastrointestinal tract during the study period |
| N randomized | 81 |
| 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. | PP Analysis |
| Specifications on analyses | Only participants who have received both interventions have been included in the efficacy analyses. Data on safety were sourced from the safety population (all participants who received ≥1 dose of study drug). The primary analysis was a comparison of the proportion of participants with complete response between the two treatment arms during two overall phases of treatment (0-120 h) of cycles A and B, using McNemar’s test to account for the within-patient correlation. Continuous outcomes were analysed with a linear model, and accounted for the correlation within a participant. All tests used a two-sided significance level of 10%. Secondary analyses have not been adjusted for multiple comparisons. |
| Countries of data collection | Australia |
| LoE Level of evidence | Level 2 Oxford 2011 |
| Outcome timeline Data collection times | T0: baseline
T1: one day before chemotherapy T2: day 8 of each cycle T3: between 30-42 days after end of intervention |
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. | Curative, Palliative |
|---|---|
| Types of cancer "Other Cancers" means that only a subpopulation was specified, but further unspecified cancer types were included | Breast Cancer, Colorectal Cancer, Gastrointestinal Cancers, Gastrointestinal Cancers - Pancreatic Cancer, Genitourinary Cancers - Testicular Cancer, Gynecologic Cancers, Hematologic 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 | NI |
| Specifications on cancer stages | Any malignancy of any stage |
| Comorbidities | NI |
| Current cancer therapies | Chemotherapy |
| Specifications on cancer therapies | Moderate-to-high emetogenic intravenous chemotherapy
Chemotherapy regimen, n(%): Doxorubicin + cyclophosphamide = 20 (26) FOLFOX ± biological = 13 (17) Cisplatin based = 12 (15) FOLFIRINOX = 6 (8) Other = 27 (35) |
| Previous cancer therapies | NI |
| Gender | Mixed |
| Gender specifications | Female : 61 (78%)
Male: 17 (22%) |
| Age groups | Adults (18+) |
| Age groups specification | Median age (range): 55 (29-80) 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 | 40 |
| Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date | 4 |
| Drop-out reasons | Discontinued after THC:CBD (n = 4):
Death (n = 1); failure to comply (n = 1); chemotherapy stopped (n = 1); patient preference (n = 1) |
| Intervention | THC:CBD |
| Dosage and regime | 1-4 capsules (each THC 2.5mg/CBD 2.5mg) 3x daily from one day before chemotherapy to day 5; median (SD) number of capsules: 2 (1-3) |
| 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. | -999 |
| Side effects / Interactions | Moderate or severe cannabinoid-related side effects in intervention arm and placebo arm (31% vs. 7%, p=0.002):
|
| Arm type Active control: group receives active treatment; </br>Passive control: for example treatment as usual, waiting control, no treatment | Placebo |
|---|---|
| Number of participants (arm) N randomized | 41 |
| Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date | 2 |
| Drop-out reasons | Discontinued after placebo (n = 2):
chemotherapy stopped (n = 1); patient preference (n = 1) |
| Intervention | Placebo |
| Dosage and regime | Median (SD) number of capsules = 3 (2-4) |
| 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. | -999 |
| Side effects / Interactions | Moderate or severe cannabinoid-related side effects in intervention arm and placebo arm (31% vs. 7%, p=0.002):
|
Outcomes
CINV (Chemotherapy-Induced Nausea and Vomiting)
| Outcome type As specificed by the authors | Primary |
|---|---|
| Outcome specification | Complete response, no vomiting or emergency medication 0-120h of chemotherapy |
| 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". | Results after 2 cycles, after switching to the other 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 | low risk |
| 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 | low risk |
| Bias in measurement of the outcome | some concerns |
| Bias in selection of the reported result | low risk |
| Other sources of bias | NA |
| Overall RoB judgment | high risk |
CINV (Chemotherapy-Induced Nausea and Vomiting)
| Outcome type As specificed by the authors | Secondary |
|---|---|
| Outcome specification | Self-reported "complete response" ("no vomiting", "no clinically significant nausea", defined as nausea <2 on a 10-point scale, and "no use of emergency medication") during the acute (0-24 h), delayed (24-120 h) and general phase (0-120 h) of chemotherapy with diary day -1 to 6 of each cycle) |
| Type of measurement | NRS (Numeric Rating 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". | Results after 2 cycles, after switching to the other 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 | low risk |
| 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 | low risk |
| Bias in measurement of the outcome | high risk |
| Bias in selection of the reported result | low risk |
| Other sources of bias | NA |
| Overall RoB judgment | high risk |
Quality of life
| Outcome type As specificed by the authors | Secondary |
|---|---|
| Outcome specification | Quality of life (nausea & vomiting scales) at baseline, day -1, end of treatment |
| Type of measurement | AQoL-8D (Assessment of Quality of Life), FLIE (Functional Living Index for Emesis) |
| 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". | FLIE:
|
| 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 | low risk |
| 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 | low risk |
| Bias in measurement of the outcome | high risk |
| Bias in selection of the reported result | low risk |
| Other sources of bias | NA |
| Overall RoB judgment | high risk |
Toxicity
| Outcome type As specificed by the authors | Secondary |
|---|---|
| Outcome specification | Self-developed measurement instrument: structured checklist of cannabinoid-specific adverse events |
| Type of measurement | CTCAE (Common Terminology Criteria of Adverse Events), Self-developed measurement instrument |
| 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". | Moderate or severe cannabinoid-related side effects in intervention arm (31%) and placebo arm (7%) (p=0.002):
83% of the participants preferred cannabis over placebo and 15% had a preference for placebo (p<0.001). |
| 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 | low risk |
| 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 | low risk |
| Bias in measurement of the outcome | high risk |
| Bias in selection of the reported result | low risk |
| Other sources of bias | NA |
| Overall RoB judgment | high risk |
Funding and Conflicts of Interest
| Funding | This work was supported by the Department of Health, NSW Government, Australia. Tilray supplied and covered the cost of study treatments and were given the opportunity to review the study protocol and manuscript, but had no role in data analysis. |
|---|---|
| Conflicts of Interest | Conflict of interest can be seen in the article, many contacts to pharmaceutical industries. |
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 | No |
Alternative Explanation
| Other explanations for an effect besides the investigated intervention | Yes |
|---|---|
| - Possibility of attention effects | NA |
| - Possibility of placebo effects | NA |
| - Other reasons | Knowledge of assignment and believe in positive influence in outcomes assessed with self-report-questionnaires |
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 | NI |
|---|---|
| Correction for multiple testing | Yes |
| Measurement of compliance | Yes |
| Consistent reporting in numbers (figures, flowchart, abstract, results) | No |
| Comprehensive and coherent reporting | No |
| Cross-over | Yes |
| - 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 | Yes |
| Side effects considered in result interpretation | Yes |
| Ethics votum | Yes |
Additional Notes
PRO:
- Ethical approval
- Power analysis
- Daily contact with staff on days of administration
- Structured assessment of side effects using a checklist
- Adherence monitored through diary entries and capsule counts
- McNemar’s test used to control for within-patient correlation
- Control for order effects (p=0.29)
- Comparability at baseline ensured by study design
CONTRA:
- Correction for multiple testing only for primary endpoints
- 90% confidence interval (CI) (p=0.1) used for primary endpoints and 95% CI for secondary endpoints due to pilot study design (primary endpoint was also significant at 95%)
- No differentiation of primary endpoint into acute or delayed responses, despite being listed in the methodology
- Unclear presentation of when and how each endpoint is measured
- Numerous interactions with pharmaceutical companies
- Capsule dosing individualized, with no subgroup analyses for high vs. low doses