Côté et al. (2016): Improving Quality of Life With Nabilone During Radiotherapy Treatments for Head and Neck Cancers: A Randomized Double-Blind Placebo-Controlled Trial

Reference ↗
Title	Improving Quality of Life With Nabilone During Radiotherapy Treatments for Head and Neck Cancers: A Randomized Double-Blind Placebo-Controlled Trial
Topic	Cannabinoids
Author	Côté, M, Trudel, M, Wang, C, Fortin, A
Year	2016
Journal	Annals of Otology, Rhinology & Laryngology
DOI	https://doi.org/10.1177/0003489415612801

Brief summary

In the study, 56 patients with head and neck tumors were randomly divided into two arms, one received nabilone (synthetic THC) every day and the other a placebo. All patients received radiotherapy or a combination of radiotherapy and chemotherapy for seven weeks. At the end of the study, the authors found no differences between the arms for quality of life in general, as well as the symptoms of pain, weight fluctuations, appetite, nausea, mood and sleep. The study sample was small and 24 patients dropped out over the course of the study. The presentation of the results is superficial and inadequate. Without statistical values (mean values), the analysis is not transparent. Further methodological deficiencies in the analysis do not allow any conclusions to be drawn about the results.

In der Studie wurden 56 Patienten mit Kopf-Hals Tumoren zufällig in zwei Gruppen eingeteilt, wovon eine Gruppe jeden Tag Nabilon (synthetisches THC) bekam und die andere ein Placebo. Alle Patienten bekamen für sieben Wochen Radiotherapie oder eine Kombination aus Radio- und Chemotherapie. Am Ende der Studie fanden die Autoren keine Unterschiede zwischen den Gruppen für Lebensqualität allgemein, als auch für die Symptome Schmerz, Gewichtsschwankungen, Appetit, Übelkeit, Stimmung und Schlaf. Die Stichprobe der Studie war klein und es sind über den Verlauf der Studie noch 24 Patienten ausgestiegen. Die Darstellung der Ergebnisse ist oberflächlich und unzureichend. Ohne Angabe von statistischen Werten (Mittelwerte) ist eine Transparenz der Analyse nicht gegeben. Weitere methodische Mängel in der Analyse lassen keine Aussagen zu den Ergebnissen zu.

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	Monocentric
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	2

Study characteristics

Inclusion criteria	Histological diagnosis of squamous cell carcinoma of the oral cavity, the oropharynx, the hypopharynx, and/or the larynx; treated by radiotherapy alone, postoperative radiotherapy, radiochemotherapy alone, or postoperative radiochemotherapy; aged 18 to 80 years; no other cancer diagnosis in the past 5 years, except for basal cell and squamous cell carcinoma of the skin
Exclusion criteria	Metastatic disease; history of radiotherapy in the head and neck region; Karnofsky score <60; cognitive impairment; hepatic insufficiency; pregnant or breastfeeding woman; history of hypersensitivity or adverse reactions to marijuana or other cannabinoids; history of schizophrenia or any other form of psychosis
N randomized	56
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	Repeated measures analyses of variance (ANOVA), estimated with a linear mixed model, enable us to test the effect of time and treatment on continuous outcomes, while a generalized linear mixed model is used as a logistic regression for dichotomous outcomes. The P-values that are presented are for the interaction term of these models. All the analyses were also carried out while adjusting for site, treatment, and tumor size.
Countries of data collection	Canada
LoE Level of evidence	Level 2 Oxford 2011
Outcome timeline Data collection times	T0: baseline before radiotherapy T1: first week T2: second week until T3: 7th week Follow-up: between 9th - 11th week

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, Neo-adjuvant, Adjuvant
Types of cancer "Other Cancers" means that only a subpopulation was specified, but further unspecified cancer types were included	Head and Neck 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	NI
Comorbidities	NI
Current cancer therapies	Chemotherapy, Radiation therapy
Specifications on cancer therapies	Radiotherapy only: intervention arm = 13; placebo arm = 10 Radiotherapy postoperative: intervention arm = 7; placebo arm = 2 Radiochemotherapy: intervention arm = 7; placebo arm = 15 Radiochemotherapy postoperative: intervention arm = 1, placebo arm = 1
Previous cancer therapies	Surgery, No therapy
Gender	Mixed
Gender specifications	Female n = 10 (17.86%); male n = 46 (82.14%)
Age groups	Adults (18+)
Age groups specification	Mean age per arm: intervention arm = 63.5 years placebo arm = 63.8 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	28
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	9
Drop-out reasons	Not arm specified: severe nausea (n = 5); difficulty swallowing (n = 4); hospitalization (n = 4), pneumonia (n = 1); discontinued RT (n = 1); without reason (n = 9)
Intervention	Nabilon + all patients: additional administration of antiemetics (metoclopramide) and painkillers (acetaminophen (paracetamol), codeine, hydromorphone or transdermal fentanyl) possible
Dosage and regime	0.5 mg nabilone tablets (from Valeant Canada) once a day before radiotherapy in the first week twice a day in the second week third week until end of radiotherapy: adjusted by radiation oncologist up to maximal 4 tablets
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.	49
Side effects / Interactions	No differences for sleepiness (p=0.32), anxiety (p=0.92) and xerostomia (p=0.83)

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	28
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	15
Drop-out reasons	Not arm specified: severe nausea (n = 5); difficulty swallowing (n = 4); hospitalization (n = 4), pneumonia (n = 1); discontinued RT (n = 1); without reason (n = 9)
Intervention	Placebo + all patients: additional administration of antiemetics (metoclopramide) and painkillers (acetaminophen (paracetamol), codeine, hydromorphone or transdermal fentanyl) possible
Dosage and regime	Placebo tablets once a day before radiotherapy in the first week twice a day in the second week third week until end of radiotherapy: adjusted by radiation oncologist up to maximal 4 tablets
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.	49
Side effects / Interactions	No differences for sleepiness (p=0.32), anxiety (p=0.92) and xerostomia (p=0.83)

Outcomes

Quality of life

Outcome type As specificed by the authors	Primary
Outcome specification	Quality of life (target improvement of 15 points at week 7)
Type of measurement	EORTC QLQ (European Organisation for Research and Treatment of Cancer Core/ Quality of Life questionnaire)
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".	No difference between arms (p=0.4270), even after controlling for tumor site, treatment method and cancer stage at week 7 or the entire study period
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 difference between arms (p=0.4270), even after controlling for tumor site, treatment method and cancer stage at week 7 or the entire study period

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)	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	NA
Overall RoB judgment	some concerns

Pain

Outcome type As specificed by the authors	Secondary
Outcome specification	Pain with VAS + number of other analgesics used
Type of measurement	VAS (Visual Analogue Scale), 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".	Over the course of the intervention and after: no differences for pain (p=0.6048), analgesic use (p=0.6671), no delay in time to 20% pain increase (p=0.4614) between arms
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".	Over the course of the intervention and after: no differences for pain (p=0.6048), analgesic use (p=0.6671), no delay in time to 20% pain increase (p=0.4614) between arms

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)	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	NA
Overall RoB judgment	some concerns

Weight

Outcome type As specificed by the authors	Secondary
Outcome specification	Weight fluctuations, total days without feeding tube or gastrostomy
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".	Over the course of the intervention and after: no difference for weight fluctuations (p=0.1454) or need for a feeding tube (no p-value) between arms.
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".	Over the course of the intervention and after: no difference for weight fluctuations (p=0.1454) or need for a feeding tube (no p-value) between arms.

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)	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	NA
Overall RoB judgment	some concerns

Appetite

Outcome type As specificed by the authors	Secondary
Outcome specification	Appetite with questionnaire (no further information)
Type of measurement	Unspecified questionnaire
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".	Over the course of the intervention and after: no difference (p=0.3295) between arms
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".	Over the course of the intervention and after: no difference (p=0.3295) between arms

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)	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	NA
Overall RoB judgment	some concerns

Nausea

Outcome type As specificed by the authors	Secondary
Outcome specification	Nausea with questionnaire (no further information) + number of antiemetic drugs used
Type of measurement	Unspecified questionnaire
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".	Over the course of the intervention and after: no difference for nausea (p=0.7105) or antiemetic consumption (p=0.6124) between arms
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".	Over the course of the intervention and after: no difference for nausea (p=0.7105) or antiemetic consumption (p=0.6124) between arms

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)	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	NA
Overall RoB judgment	some concerns

Unspecified effects

Outcome type As specificed by the authors	Secondary
Outcome specification	Sleep quality and mood (no information on survey)
Type of measurement	NI
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".	Over the course of the intervention and after: no differences for mood (p=0.3214) and sleep quality (p=0.4438) between arms
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".	Over the course of the intervention and after: no differences for mood (p=0.3214) and sleep quality (p=0.4438) between arms

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)	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	NA
Overall RoB judgment	some concerns

Toxicity

Outcome type As specificed by the authors	Secondary
Outcome specification	Toxicity of nabilone
Type of measurement	NI
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".	No differences for sleepiness (p=0.3166), anxiety (p=0.9163) and xerostomia (p=0.8341)
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)	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	NA
Overall RoB judgment	some concerns

Funding and Conflicts of Interest

Funding	The authors received research grants from the Canadian Institutes of Health Research and the Fonds de recherche en santé du Québec. ICN Valeant Pharmaceuticals provided the nabilone and the placebo pills during the trial.
Conflicts of Interest	According to authors no conflict of interest.

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	No
- Possibility of attention effects	NA
- Possibility of placebo effects	NA
- Other reasons	NA

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	No
Measurement of compliance	NI
Consistent reporting in numbers (figures, flowchart, abstract, results)	Yes
Comprehensive and coherent reporting	No
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	Yes
Side effects considered in result interpretation	Yes
Ethics votum	Yes

Additional Notes

PRO:

• Ethical approval
• Power analysis
• Intent-to-treat analysis
• Baseline comparability
• Mention of drop-out comparison in the discussion, though no statistical values are provided

CONTRA:

• Lack of blinding control
• No correction for multiple testing
• Superficial and inadequate presentation of results: results are only shown graphically, with no mean/SD values available, lacking transparency
• Very high drop-out rate, with 12 out of 15 participants in placebo arm who dropped out receiving Radiochemotherapy
• Exact dosing from week 3 onward may vary for each participant
• Apart from the primary endpoint, no specific timing provided for final comparisons