Revision as of 11:18, 14 October 2024

Reference ↗
Title	Phase II double-blind randomized study comparing oral aloe vera versus placebo to prevent radiation-related mucositis in patients with head-and-neck neoplasms
Topic	Aloe vera
Author	Su, CK, Mehta, V, Ravikumar, L, Shah, R, Pinto, H, Halpern, J, Koong, A, Goffinet, D, Le, QT
Year	2004
Journal	International Journal of Radiation Oncology, Biology, Physics
DOI	https://doi.org/10.1016/j.ijrobp.2004.02.012

Study Note

Brief summary

In this study, researchers investigated the effect of an aloe juice on oral mucosal inflammation in patients treated with radiotherapy to the head and neck area. The patients were divided into two arms: one arm drank the aloe juice and the orther arm a placebo juice in which the aloe was replaced with water (otherwise the juices had the same ingredients). At the end of the study, the patients who used the aloe juice were just as likely to suffer from severe oral mucosal inflammation as those who used the placebo juice, and there were no differences in quality of life.

In dieser Studie untersuchten Forscher die Wirkung eines Aloe Saftes auf die Mundschleimhautentzündung bei Patienten, die mit Strahlentherapie im Kopf- und Halsbereich behandelt wurden. Die Patienten wurden in zwei Gruppen eingeteilt: eine trank den Aloe-Saft und die andere einen Placebo-Saft, bei dem die Aloe durch Wasser ersetzt wurde (sonst hatten die Säfte die gleichen Inhaltsstoffe). Nach Abschluss der Studie litten die Patienten, die den Aloe-Saft verwendeten, genauso häufig an schweren Mundschleimhautentzündungen wie diejenigen, die den Placebo-Saft verwendet hatten, auch bezüglich der Lebensqualität gab es keine Unterschiede.

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-IVM0 carcinoma in the head-neck-area; radiotherapy (at least 50 Gy); Karnofsky power > 60; both primary radical radiotherapy and postoperative radiotherapy patients were eligible
Exclusion criteria	Patients who are unable to complete the study questionnaires.
N randomized	58
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	chi-square tests; Kaplan-Meier analyses; Cox proportional hazard models
Countries of data collection	United States
LoE Level of evidence	2b Oxford 2009
Outcome timeline Data collection times	T0: Baseline before radiation T1: first week of radiation T2: third week of radiation T3: sixth week of radiation

Characteristics of participants

Stratification by primary tumour site and chemotherapy treatment (yes/no).

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
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
Specifications on cancer stages	Histologically confirmed Stage II-IVM0 carcinoma of the head and neck Primary tumor site (n): Oral cavity: Aloe = 1 (4%); Placebo = 8 (27%) Oropharynx: Aloe = 9 (32%); Placebo = 2 (7%) Larynx: Aloe = 6 (21%); Placebo =7 (23%) Hypopharynx: Aloe = 2 (7%); Placebo = 1 (3%) Nasopharynx: Aloe = 4 (14%); Placebo = 6 (20%) Unknown primary: Aloe = 4 (14%); Placebo = 1 (3%) Other: Aloe = 2 (7%); Placebo = 5 (17%)
Comorbidities	NI
Current cancer therapies	Radiation therapy, Chemotherapy
Specifications on cancer therapies	Of the 58 patients, 41% underwent primary surgical resection with adjuvant radiotherapy, and 59% received definitive radiotherapy; 41% of patients also received concurrent chemotherapy. Chemotherapy per arm: Aloe arm: 36% Placebo arm: 47%
Previous cancer therapies	Surgery
Gender	Mixed
Gender specifications	Gender per arm: Aloe arm: male = 82%; female = 17.9% Placebo arm: male = 77%; female = 23.3%
Age groups	Adults (18+)
Age groups specification	Mean age per arm: Aloe arm = 57 years Placebo arm = 55 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	1
Drop-out reasons	Withdrawing from the study because of difficulty in adhering to the four times daily oral care regimen
Intervention	Aloe vera solution
Dosage and regime	The aloe vera solution consisted of 94.5% aloe juice, 5.0% pear juice concentrate, 0.4% lemon-lime flavor, and 0.1% citric acid. Patients were instructed to take a 20ml swish and swallow 4x daily, beginning on the first day and continuing throughout the RT course. + all patients were instructed to alleviate oral discomfort by rinsing daily with a baking soda mouth rinse, and swishing and swallowing Benadryl and nystatin combination mouthwashes and viscous lidocaine, as needed + all patients: radiation dose 50-70 Gy at 1.8-2 Gy per day
One-time application	No
Duration in days For long-term interventions, the number of days is an estimation.</br>A value of -999 indicates that the exact duration cannot be extracted from the study due to ambiguous or incomplete information. See Outcome timeline or Dosage and regime for further information.	42
Side effects / Interactions	No patients reported adverse effects, and none withdrew from the study because of side effects.

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	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	Placebo solution
Dosage and regime	The aloe vera solution consisted of 94.5% water, 5.0% pear juice concentrate, 0.4% lemon-lime flavor, and 0.1% citric acid. Patients were instructed to take a 20ml swish and swallow 4x daily, beginning on the first day and continuing throughout the RT course. + all patients were instructed to alleviate oral discomfort by rinsing daily with a baking soda mouth rinse, and swishing and swallowing Benadryl and nystatin combination mouthwashes and viscous lidocaine, as needed + all patients: radiation dose 50-70 Gy at 1.8-2 Gy per day
One-time application	No
Duration in days For long-term interventions, the number of days is an estimation.</br>A value of -999 indicates that the exact duration cannot be extracted from the study due to ambiguous or incomplete information. See Outcome timeline or Dosage and regime for further information.	42
Side effects / Interactions	No patients reported adverse effects, and none withdrew from the study because of side effects.

Outcomes

Mucositis

Outcome type As specificed by the authors	Primary
Outcome specification	Incidence of severe mucositis Severe mucositis = grade 2, 3 or 4 mucositis of RTOG Biweekly, treating physicians evaluated patients for mucositis at 15 head-and-neck subsites using a 4-point grading scale. These subsites included the upper lip, lower lip, anterior oral cavity, posterior oral cavity, anterior tongue, posterior tongue, hard palate, oropharynx, nasopharynx, hypopharynx, skin, ear, salivary glands, and esophagus.
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".	Patients in the aloe arm had a lower maximal mucositis severity grade than patients in the placebo arm, but the difference was not statistically significant.
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	?
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	Duration of mucositus Biweekly, treating physicians evaluated patients for mucositis at 15 head-and-neck subsites using a 4-point grading scale. These subsites included the upper lip, lower lip, anterior oral cavity, posterior oral cavity, anterior tongue, posterior tongue, hard palate, oropharynx, nasopharynx, hypopharynx, skin, ear, salivary glands, and esophagus.
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".	Patients in the two arms did not have statistically significant differences in the duration of Grade 2 or worse mucositis during the radiation course.
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	?
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	Secondary
Outcome specification	Treatment interruptions Radiation interruptions because of 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".	Patients in the two arms had the same outcomes along prolonged radiation breaks and overall treatment time.
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	?
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	?

Quality of life

Outcome type As specificed by the authors	Secondary
Outcome specification	On the biweekly examination days, patients filled out a quality of life questionnaire scoring their overall health, soreness, and the effect of soreness on daily activity (including brushing teeth, swallowing, and eating). A Scale of 1–10, with 10 best for health score and 0 worst for soreness score
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".	Although the quality of life values favoured the aloe group, the differences between the arms were not statistically significantly different. Compared with placebo patients, aloe patients had a lower probability of a 3 point or greater drop in their overall health quality of life score during radiation, although this difference between the arms was not statistically significant.
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	?
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
Conflicts of Interest	Verum was donated by a commercial company

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

PRO/CONTRA ?