Puataweepong et. al (2009): The efficacy of oral Aloe vera juice for radiation induced mucositis in head and neck cancer patients: a double-blind placebo-controlled study

Reference ↗
Title	The efficacy of oral Aloe vera juice for radiation induced mucositis in head and neck cancer patients: a double-blind placebo-controlled study
Topic	Aloe vera
Author	Puataweepong, P, Dhanachai, M, Dangprasert, S, Sithatani, C, Sawangsilp, T, Narkwong, L, Puttikaran, P, Intragumtornchai, T
Year	2009
Journal	Asian Biomedicine
DOI	https://mahidol.elsevierpure.com/en/publications/the-efficacy-of-oral-aloe-vera-juice-for-radiation-induced-mucosi

Brief summary

In this study, a juice containing 80% aloe was tested for the treatment of radiation-induced oral mucositis. Patients undergoing radiotherapy for the treatment of head and neck cancer were divided into two arms. One arm received the juice with aloe, the other arm received a comparable juice without aloe. All patients were asked to drink 15 ml of their assigned juice three times a day from the start of radiotherapy until eight weeks after the end of treatment. Fewer patients in this study had severe oral mucosal inflammation when they drank the aloe juice compared to the placebo juice. The researchers concluded that aloe juice can be recommended as an alternative therapy for the prevention of severe oral mucositis in patients undergoing radiotherapy.

In dieser Studie wurde einen Saft mit 80% Aloe zur Behandlung einer strahlungsinduzierten Mundschleimhautentzündung getestet. Patienten, die sich einer Strahlentherapie zur Behandlung von Kopf- und Halskrebs unterziehen, wurden in zwei Arme eingeteilt. Eine Arm erhielt den Saft mit Aloe, der andere Arm erhielt einen vergleichbaren Saft ohne Aloe. Alle Patienten wurden gebeten, 15 ml ihres zugordneten Saftes dreimal täglich vom Beginn der Strahlentherapie bis acht Wochen nach Beendigung der Therapie zu trinken. Weniger Patienten wiesen in dieser Studie eine schwere Mundschleimhautentzündung auf, wenn sie den Aloe-Saft im Vergleich zum Placebo-Saft tranken. Die Forscher kamen zu dem Schluss, dass der Aloe-Saft als alternative Therapie zur Vorbeugung schwerer Mundschleimhautentzündung bei Patienten in der Strahlentherapie empfohlen werden kann.

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	Stage II-IVMO cancer of the head and neck; radiotherapy in adjuvant or definitive setting; Karnofsky performance > 70.
Exclusion criteria	Previous radiotherapy; allergies to aloe; diabetes mellitus; HIV
N randomized	61
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	According to authors ITT analysis but 1 drop-out (non-compliance); Chi-square/t-test; logistic regression analysis; Kaplan-Meier test; log-rank test; multivariate analysis was performed using the Cox proportional hazard model
Countries of data collection	Thailand
LoE Level of evidence	2b Oxford 2009
Outcome timeline Data collection times	T0: Baseline = 10 days prior to the first day of radiation therapy T1: weekly for 3-4 weeks Follow-up: 8th week

Characteristics of participants

Patients were stratified on the basis of concurrent chemotherapy because concurrent chemotherapy might worsen the degree of radiation-induced mucositis.

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, 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	Early Stage, Advanced Stage
Specifications on cancer stages	Tumor staging Aloe arm: T1 = 3 (10%); T2 = 8 (28%); T3 = 6 (21%); T4 = 12 (41%) Placebo arm: T1 = 5 (16%); T2 = 8 (26%); T3 = 6 (19%); T4 = 11 (36%); Unknown = 1 (3%)
Comorbidities	NI
Current cancer therapies	Radiation therapy
Specifications on cancer therapies	Previous surgery Aloe arm: 4 (13%) Placebo arm: 12 (38%) Chemotherapy Aloe arm: yes = 17 (57%); no = 13 (43%) Placebo arm: yes = 18 (58%); no = 13 (42%)
Previous cancer therapies	Surgery, Chemotherapy
Gender	Mixed
Gender specifications	Gender per arm: Aloe arm: male = 27 (90%); female = 3 (10%) Placebo arm: male = 20 (65%); female 11 (35%)
Age groups	Adults (18+)
Age groups specification	Mean age (min-max) per year: Aloe arm: 60 (38-91) years Placebo arm: 54 (31-84) 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	30
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	0
Drop-out reasons	NA
Intervention	Aloe
Dosage and regime	Patients were instructed to take 15ml of the solution 3x daily, beginning on the first day of radiation and continuing throughout the three-four weeks of the radiation course and continuing until the end of the 8th week follow-up. + all patients: received the usual recommendations of daily rinsing with water, saline solution, if necessary rinsing with viscous lidocaine, or use of analgesics and antibiotics + all patients: radiation therapy
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.	56
Side effects / Interactions	No adverse events were reported by the patients.

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	31
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	One patient in the placebo arm discontinued the test solution due to unfavorable taste and was reported as a non-compliance.
Intervention	Placebo
Dosage and regime	Patients were instructed to take 15ml of the solution 3x daily, beginning on the first day of radiation and continuing throughout the three-four weeks of the radiation course and continuing until the end of the 8th week follow-up. + all patients: received the usual recommendations of daily rinsing with water, saline solution, if necessary rinsing with viscous lidocaine, or use of analgesics and antibiotics + all patients: radiation therapy
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.	56
Side effects / Interactions	One patient in the placebo arm discontinued the test solution due to unfavorable taste and was reported as a non-compliance.

Outcomes

Mucositis

Outcome type As specificed by the authors	Primary
Outcome specification	Incidence of severe mucositis Severe mucositis was defined as the Radiation Therapy Oncology Group (RTOG) mucositis grade 2, 3, and 4. During radiation treatment, visual signs of mucositis were assessed two times per week by two radiation oncologists. After the complete course of radiation, the patients were assessed at the last radiation day and were asked to come for OPD visits for mucosal assessment at week 2 and 4 post-radiation Grade: 0 = no change over baseline 1 = injection, might experience mild pain not requiring analgesic 2 = patchy mucositis that produces an inflammatory serosanguinous discharge, might experience moderate pain requiring analgesic. 3 = confluent fibrinous mucositis; might include severe pain requiring narcotics 4 = ulceration, hemorrhage, necrosis.
Type of measurement	RTOG Acute Radiation Morbidity Scoring Criteria (Radiation Therapy Oncology Group)
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 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".	Apparently, patients in the aloe arm had a lower incidence of severe mucositis than patients in the placebo arm. This was statistically significant (53% vs. 87%, p=0.004).

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	?

Mucositis

Outcome type As specificed by the authors	Primary
Outcome specification	Onset of severe mucositis Was defined as the time-duration from the first day of radiation to the day when the observer recorded the most severe mucositis.
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".	The median onset of severe mucositis was 32 and 33 days for patients taking Aloe vera and patients assigned to take placebo, respectively (p= 0.609).

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	?

Mucositis

Outcome type As specificed by the authors	Primary
Outcome specification	radiation breaks
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".	Radiotherapy break due to mucositis: Aloe arm = 1 (3%) Placebo arm = 4 (13%)
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".	The patients in the aloe arm had a lower percentage of radiation breaks due to mucositis than patients in the placebo arm but the difference was not statistically significant (p=0.35).

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	NI; Verum appears to have been donated by the Faculty of Pharmacy, based on a thank you note to the faculty.
Conflicts of Interest	NI

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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