Hoopfer et al. (2015): Three-arm randomized phase III trial: Quality aloe and placebo cream versus powder as skin treatment during breast cancer radiation therapy

Reference ↗
Title	Three-arm randomized phase III trial: Quality aloe and placebo cream versus powder as skin treatment during breast cancer radiation therapy
Topic	Aloe vera
Author	Hoopfer, D, Holloway, C, Gabos, Z, Alidrisi, M, Chafe, S, Krause, B, Lees, A, Mehta, N, Tankel, K, Strickland, F, Hanson, J, King, C, Ghosh, S, Severin, D
Year	2015
Journal	Clinical Breast Cancer
DOI	https://doi.org/10.1016/j.clbc.2014.12.006

Brief summary

In this study, the researchers tested the use of a skin cream containing aloe vera extract on the severity of radiation-induced skin reactions. Women with breast cancer were randomised into one of three arms. Arm 1 used either baby powder or corn starch on the skin during radiotherapy, followed by a Glaxal base cream for one month after therapy. Arm 2 used a skin cream containing aloe vera extract on their skin during radiotherapy and for one month afterwards. Arm 3 used the same skin cream without aloe vera extract during radiotherapy and for one month afterwards. After radiotherapy, patients who used the cream either with aloe vera extract or without aloe vera had stronger skin reactions than patients who used a powder (baby powder or corn starch). A cream with aloe vera extract had no effect on the severity of radiation-induced skin reactions.

In dieser Studie testeten die Forscher die Verwendung einer Hautcreme mit Aloe Vera Extrakt auf den Schweregrad der strahleninduzierten Hautreaktionen. Frauen mit Mammakarzinom wurden in einen von drei Armen randomisiert. Arm 1 verwendete während der Strahlentherapie entweder Babypulver oder Maisstärke auf der Haut, gefolgt von einer Glaxal-Basiscreme für einen Monat nach der Therapie. Arm 2 verwendete eine Hautcreme, die Aloe Vera Extrakt enthielt, auf ihrer Haut während der Strahlentherapie und für einen Monat danach. Arm 3 verwendete die gleiche Hautcreme ohne Aloe Vera Extrakt während der Strahlentherapie und einen Monat danach. Nach der Strahlentherapie hatten Patientinnen, die die Creme entweder mit Aloe Vera Extrakt oder ohne Aloe Vera verwendet hatten, stärkere Hautreaktionen als Patientinnen, die ein Pulver (Babypuder oder Maisstärke) verwendeten. Eine Creme mit Aloe Vera Extrakt hatte keine Wirkung auf die Schwere der strahleninduzierten Hautreaktionen.

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	3

Study characteristics

Inclusion criteria	>18 years; nonmetastatic breast cancer; previous mastectomy or segmental resection; agreement to comply with the study protocol; signed informed consent
Exclusion criteria	Uncontrolled diabetes; uncontrolled eating disorders; acquired immunodeficiency syndrome, active lupus or scleroderma; known allergy to pure aloe; inability to complete the screening and informed consent procedures before receiving a total of 10 Gy of radiation
N randomized	248
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	All analyses were by intention-to-treat.
Countries of data collection	Canada
LoE Level of evidence	1b Oxford 2009
Outcome timeline Data collection times	T0: baseline T1: weekly until end of radiation T2: week 1, 2, and 4 after end of radiation

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
Types of cancer "Other Cancers" means that only a subpopulation was specified, but further unspecified cancer types were included	Breast Cancer
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	Body-Mass-Index of all subjects BMI<25 = 60; BMI 25-29 = 78; BMI>30 = 99 BMI per arm Powder arm: BMI<25 = 14 (17.72%); BMI 25-29 = 28 (35.4%); BMI>30 = 37 (46.84%) Aloe arm: BMI <25 = 23 (28.40%); BMI 25-29 = 26 (32.10%); BMI >30 = 32 (39.51%) Placebo arm: BMI <25 = 23 (29.87%); BMI 25-29 = 24 (31.17%); BMI >30 = 30 (38.96%)
Current cancer therapies	Radiation therapy
Specifications on cancer therapies	Chemotherapy before radiotherapy per arm Powder arm: No = 47 (59.5%); Yes = 32 (40.5%) Aloe arm: No = 31 (38.3%); Yes = 50 (61.7%) Placebo arm: No = 36 (46.8%); Yes = 41 (53.3%) Surgery per arm: Powder arm: Mastectomy = 32 (40.5%); Segmental resection = 47 (59.5%) Aloe arm: Mastectomy = 34 (42%); Segmental resection = 47 (58%) Placebo arm: Mastectomy = 23 (29.9%); Segmental resection = 54 (70.1%)
Previous cancer therapies	Chemotherapy, Surgery
Gender	Female
Gender specifications	100% female
Age groups	Adults (18+)
Age groups specification	Mean age (SD) per arm: Powder arm = 79 (33.3) years Aloe arm = 81 (34.2) years Placebo arm = 77 (32.5) 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	81
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	Not arm specified: 11
Drop-out reasons	Not arm specified: 10 patients withdrew immediately after randomization, 1 patient was withdrawn because of a selection error
Intervention	Aloe vera cream
Dosage and regime	Apply approx. 2.5 ml of cream 3 times a day to irradiated skin during radiotherapy and for one month afterwards.
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.	60
Side effects / Interactions	Skin rash occurred in all 3 arms, with the highest reported incidence in aloe cream (aloe cream 30.9%; placebo cream 15.6%; powder 5.1%).

Arm type Active control: group receives active treatment; </br>Passive control: for example treatment as usual, waiting control, no treatment	Active control
Number of participants (arm) N randomized	79
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	Not arm specified: 11
Drop-out reasons	Not arm specified: 10 patients withdrew immediately after randomization, 1 patient was withdrawn because of a selection error
Intervention	Powder
Dosage and regime	Non-metallic baby powder or corn starch on the irradiated, intact skin 2x daily during radiotherapy. This was followed by one month of Glaxal base cream (WellSpring Pharmaceutical), 2x daily.
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.	60
Side effects / Interactions	Skin rash occurred in all 3 arms, with the highest reported incidence in aloe cream (aloe cream 30.9%; placebo cream 15.6%; powder 5.1%).

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	77
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	Not arm specified: 11
Drop-out reasons	Not arm specified: 10 patients withdrew immediately after randomization, 1 patient was withdrawn because of a selection error
Intervention	Placebo cream
Dosage and regime	Apply approx. 2.5 ml of placebo cream 3 times a day to irradiated skin during radiotherapy and for one month afterwards.
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.	60
Side effects / Interactions	Skin rash occurred in all 3 arms, with the highest reported incidence in aloe cream (aloe cream 30.9%; placebo cream 15.6%; powder 5.1%).

Outcomes

"Catterall Skin Scoring Profile" is not in the list (AQoL-8D (Assessment of Quality of Life), ASAT (Auditory Sustained Attention Test), BIA (Bioelectrical impedance analysis), BPI-SF (Brief Pain Inventory - Short Form), CTCAE (Common Terminology Criteria of Adverse Events), ESAS (Edmonton Symptom Assessment Scale), FAACT (Functional Assessment of Anorexia-Cachexia Therapy), FACIT (Functional Assessment of Chronic Illness Therapy), FLIE (Functional Living Index for Emesis), Genitourinary atrophy self-assessment tool, ...) of allowed values for the "Type of measurement" property.

Toxicity

Outcome type As specificed by the authors	Primary
Outcome specification	Acute skin reactions Were scored using a modified 10-point Catterall skin scoring profile. 1 no visible reaction 2 light erythema 3 moderate erythema 4 severe erythema 5 dry desquamation < 50% of irradiated area 6 dry desquamation > 50% of irradiated area 7 blistering present 8 moist desquamation < 50% of the irradiated area 9 moist desquamation > 50% of irradiated field 10 ulceration present
Type of measurement	CSSP (Catterall Skin Scoring Profile)
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".	The severity followed the same sequence trajectory in all 3 arms with a peak effect commonly occurring within the first week after end of radiation, although for 10 patients, the peak reaction occurred at 2 weeks after radiation (7 in the aloe cream, 1 in the placebo cream, and 2 in the powder arm) Erythema as the maximum reaction (CSSP score 1-4) occurred in 16.5% of the powder, 8.6% of the aloe cream, and 6.6% of the placebo cream arms. Dry desquamation as a maximum reaction (CSSP score 5-6) occurred in 35.4% of the powder, 28.4% of the aloe cream, and 29% of the placebo cream arms. Moist desquamation in < 50% of the field as the maximum reaction (CSSP score 7-8) occurred in 44.3% of the powder, 49.4% of the aloe cream, and 56.6% of the placebo cream arms. Moist desquamation in > 50% of the field as a maximum reaction (CSSP score 9-10) occurred in 3.8% of the powder, 13.6% of the aloe cream, and 7.9% of the placebo cream 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".	The univariate analysis according to treatment arm at 1 week after radiation showed placebo cream had an increased CSSP effect of 0.61 (p=0.0845) greater than that for powder. Also, aloe cream had an increased CSSP effect of 0.80 greater than that for powder (p=0.0283).

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	?

Toxicity

Outcome type As specificed by the authors	Primary
Outcome specification	Perceived Symptoms The participants scored the severity of dryness, itchiness, burning, and pain using a 6-point Likert tool Patient symptom inventory: 0=none/not present; 1=mild; 2=discomfort; 3=distressing; 4=horrible; 5=excruciating
Type of measurement	VNS (Verbal Numerical 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".	No statistically significant differences were found in the symptoms of dryness, itching, or burning among the 3 arms at 1 week after radiotherapy. A statistically significant difference was found in the pain scores, with 9 of the 67 powder arm patients rating pain as high compared with 21 of 72 in the aloe arm and 25 of the 74 in the placebo arm (p=0.0163).

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	?

Toxicity

Outcome type As specificed by the authors	Primary
Outcome specification	Changes The changes in skin dryness, itchiness, burning sensation, and pain relative to the previous follow-up point were also scored using a 6-point Likert tool. The response options possible relative to the changes in symptoms were: 0=none; 1=unchanged; 2=slightly improved; 3=much improved; 4=slightly worse; 5=much worse.
Type of measurement	VNS (Verbal Numerical 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".	No difference between the treatment arms was found among the arms in the Likert scales measuring the change in the symptoms comparedwith the previous week.

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	Canadian Breast Cancer Foundation Alberta/Northwest Territories chapter
Conflicts of Interest	Pangea Phytoceuticals provided aloe extract and creams

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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