Reference ↗
Title	Double-blind randomized phase III study comparing a mixture of natural agents versus placebo in the prevention of acute mucositis during chemoradiotherapy for head and neck cancer
Topic	Aloe vera
Author	Marucci, L, Farneti, A, Di Ridolfi, P, Pinnaro, P, Pellini, R, Giannarelli, D, Vici, P, Conte, M, Landoni, V, Sanguineti, G
Year	2017
Journal	Head & Neck
DOI	https://doi.org/10.1002/hed.24832

Study Note

Most patients who receive radiotherapy to the head and neck suffer from inflammation of the oral mucosa during the course of radiotherapy. In this study, the researchers investigated the effect of a commercial herbal mouthwash made from propolis, aloe, camomile and marigold on the development of oral mucosal inflammation. Half of the patients used the herbal mouthwash and the other half used a mouthwash without these herbal substances, which was similar in appearance, flavour and density. All patients were asked to rinse their mouths four times a day on weekdays and three times a day at weekends. There was no difference in the severity of oral mucosal inflammation between the two arms. The researchers concluded that the herbal mouthwash containing propolis, aloe, camomile and calendula had no effect on the oral mucosal inflammation in these patients.

Die meisten Patienten, die eine Strahlentherapie im Kopf- und Halsbereich erhalten, leiden im Verlauf der Bestrahlung unter Mundschleimhautentzündungen. In dieser Studie untersuchten die Forscher die Wirkung einer kommerziellen pflanzlichen Mundspülung aus Propolis, Aloe, Kamille und Ringelblume auf die Entwicklung der Mundschleimhautentzündung. Die Hälfte der Patienten benutzte die pflanzliche Mundspülung und die andere Hälfte eine Mundspülung ohne diese pflanzlichen Stoffe, die in Aussehen, Geschmack und Dichte ähnlich war. Alle Patienten wurden gebeten, ihren Mund viermal täglich an Werktagen und dreimal täglich an Wochenenden zu spülen. Es gab keinen Unterschied in der Schwere der Mundschleimhautentzündung zwischen den beiden Armen. Die Forscher kamen zu dem Schluss, dass die pflanzliche Mundspülung aus Propolis, Aloe, Kamille und Ringelblume bei diesen Patienten keinen Effekt auf die Mundschleimhautentzündung hat.

Brief summary

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	?
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	Age > 18 years; squamous cell carcinoma of the mouth, pharynx or larynx; ability to eat an adequate oral diet
Exclusion criteria	Previous radiotherapy in the head or neck area; functional disorders of the bone marrow, liver or kidneys; allergy to aloe
N randomized	107
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.	?
Specifications on analyses	?
Countries of data collection	Italy
LoE Level of evidence	1b Oxford 2009
Outcome timeline Data collection times	?

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.	?
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	?
Specifications on cancer stages	?
Comorbidities	?
Current cancer therapies	?
Specifications on cancer therapies	?
Previous cancer therapies	?
Gender	Mixed
Gender specifications	?
Age groups	Adults (18+)
Age groups specification	?

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	53
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	1
Drop-out reasons	Not arm-specified: 2 patients never started chemoradiotherapy because of early systemic progression or early death from intercurrent disease; 1 patient died during the first week of treatment from intercurrent disease
Intervention	Herbal mouthwash
Dosage and regime	Faringel Herbal mouthwash (propolis, aloe, calendula, camomile) Rinse with 7mL of mouthwash 4 times per day (before each main meal and radiotherapy session) during week days, and 3 times per day (before each main meal) during weekend +all patients: concomitant chemoradiotherapy (daily treatment, 5 times per week, for 6-6.5 weeks) + dental and nutritional evaluation before treatment
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.	42
Side effects / Interactions	3 patients complained of its taste or consistency

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	51
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	Not arm-specified: 2 patients never started chemoradiotherapy because of early systemic progression or early death from intercurrent disease; 1 patient died during the first week of treatment from intercurrent disease
Intervention	Placebo
Dosage and regime	Placebo mouthwash with the same colour, taste and density in identical 200mL bottles, with honey. Rinsing with 7ml of mouthwash 4 times per day (before each main meal and radiotherapy session) during week days, and 3 times per day (before each main meal) during weekends +all patients: concomitant chemoradiotherapy (daily treatment, 5 times per week, for 6-6.5 weeks) + dental and nutritional evaluation before treatment
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.	42
Side effects / Interactions	1 patient complained of its taste or consistency

Outcomes

Toxicity

Outcome type As specificed by the authors	Primary
Outcome specification	During weekly visits patients underwent a structured interview and physical examination by both a nurse and a radiation oncologist. At each visit, the following items were scored: objective mucositis (CTCAE), functional mucositis (CTCAE) and dysphagia (CTCAE).
Type of measurement	CTCAE (Common Terminology Criteria of Adverse Events)
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".	NI
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".	61 patients (58.6%) developed peak grade 3 objective mucositis during treatment, with no difference between arms (p=0.665). 57 patients (54.8%) developed peak grade 3 functional mucositis during treatment with no differences between arms (p=0.442). 67 patients (64.4%) developed peak grade 3 dysphagia during treatment, with no differences between arms (p = 0.132).

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

Pain

Outcome type As specificed by the authors	Secondary
Outcome specification	During weekly visits patients underwent a structured interview and physical examination by both a nurse and a radiation oncologist. At each visit, the following items were scored: pain control (Verbal descriptor scale). Peak pain: (0) None (1) Slight (2) Moderate (3) Severe (4) Extreme (5) As bad as it can be
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".	NI
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".	There was no difference in the extent of pain between the groups (p=0.886)

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

Funding and Conflicts of Interest

Funding	?
Conflicts of Interest	?

Further points for assessing the study

Sample

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

Alternative Explanation

Other explanations for an effect besides the investigated intervention	?
- Possibility of attention effects	?
- Possibility of placebo effects	?
- Other reasons	?

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	?
Correction for multiple testing	?
Measurement of compliance	?
Consistent reporting in numbers (figures, flowchart, abstract, results)	?
Comprehensive and coherent reporting	?
Cross-over	?
- Sufficient washout period	?
- Tested for carry-over effects	?
- Tested for sequence effects	?

Interpretation of results

Effect sizes reported (clinical vs. statistical significance)	?
Side effects systematically recorded	?
Side effects considered in result interpretation	?
Ethics votum	?

Additional Notes

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