Mansourian et al. (2015): The effect of "curcuma Longa" topical gel on radiation -induced oral mucositis in patients with head and neck cancer

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Title	The effect of "curcuma Longa" topical gel on radiation -induced oral mucositis in patients with head and neck cancer
Topic	Curcumin
Author	Mansourian, A, Amanlou, M, Shirazian, S, Moosavian Jahromi, Z, Amirian, A
Year	2015
Journal	International Journal of Radiation Research
DOI	https://doi.org/10.7508/ijrr.2015.03.011

Brief summary

In this study, patients with head and neck tumors were examined during radiotherapy. The patients were instructed to apply a gel to the entire oral cavity 3 times a day, with half receiving a curcumin gel and the other half a placebo gel. There were more cases of severe mucositis (an inflammation of the mucous membrane, a common adverse side effect of radiotherapy) in the curcumin arm than in the placebo arm. In addition, patients in the curcumin arm reported less burning in the mouth and had less redness of the oral mucosa and minor mouth ulcers. There are some criticisms of this study. Only a very small sample was examined and it cannot be ruled out that the two arms differed at the beginning of the study because very few characteristics of the patients were reported at the beginning of the study. In addition, the quality of reporting in the study was generally poor; for example, there was no information on the extent to which the patients used the gels as instructed.

In dieser Studie wurden Patienten mit Kopf-Hals-Tumor während der Radiotherapie untersucht. Die Patienten bekamen die Anweisung 3 Mal täglich den gesamten Mundraum mit einem Gel zu bestreichen, wobei die eine Hälfte ein Curcumin-Gel bekam und die andere Hälfte ein Placebo-Gel. In der Curcumin-Gruppe gab es mehr Fälle von schwerer Mukositis (eine Entzündung der Schleimhaut, eine häufige unerwünschte Nebenwirkung von Radiotherapie) als in der Placebo-Gruppe. Zudem berichteten die Patienten der Curcumin-Gruppe geringeres Brennen im Mund und hatten kleinere Hautrötungen der Mundschleimhaut und kleinere Geschwüre im Mund. An dieser Studie gibt es einige Kritikpunkte. Es wurde nur eine sehr kleine Stichprobe untersucht und es ist nicht ausgeschlossen, dass sich die beiden Gruppen zur Beginn der Studie unterschieden haben, weil nur sehr wenige Charakteristiken der Patienten zu Beginn der Studie berichtet wurden. Zudem hat die Studie allgemein eine schlechte Berichtqualität, es fehlt zum Beispiel die Angabe, inwiefern die Patienten die Gels so verwendet haben, wie es vorgegeben war.

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	Minimum age of 18 years, presence of head and neck cancer, minimum radiation dose of 50 Gy (the least dose resulting in mucositis), the ability of patient to use topical gel (by his/her or examiner’s report), minimally 50% of patient’s oral cavity in radiation field (according to the radiotherapist’s opinion)
Exclusion criteria	History of radiation therapy or chemotherapy in previous year, chemotherapy protocol in addition to radiotherapy, any allergy to condiments, especially "Turmeric root", any complications due to the use of topical gel during the study, suffering from any kind of oral disease such as active oral infection, ulcer, having any systemic disease or taking any medication
N randomized	37
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	ITT not specified, but no drop-out reported.
Countries of data collection	Iran
LoE Level of evidence	2b Oxford 2009
Outcome timeline Data collection times	T0: Baseline T1-T3: Tag 7, 14, 21

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	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	Radiation therapy
Specifications on cancer therapies	NI
Previous cancer therapies	NI
Gender	Mixed
Gender specifications	16% female
Age groups	Adults (18+)
Age groups specification	Mean (SD): 51.34 (12.08) 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	19
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	Curcumin
Dosage and regime	Topical turmeric gel (0.5%); Coat entire mouth with gel 3 times a day Start: day 0 radiotherapy Duration: entire radiotherapy (21 days)
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.	21
Side effects / Interactions	NI

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	18
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 Gel
Dosage and regime	Coat entire mouth with gel 3 times a day Start: day 0 radiotherapy Duration: entire radiotherapy (21 days)
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.	21
Side effects / Interactions	NI

Outcomes

Mucositis

Outcome type As specificed by the authors	Primary
Outcome specification	Max. degree of mucositis
Type of measurement	Observation, WHO-Scale (World Health Organisation)
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".	Max. degree of mucositis (number (%) of patients): Grade 1: Intervention arm: 15 (78.9%), Placebo arm: 3 (16.7%) Grade 2: Intervention arm: 4 (21.1%), Placebo arm: 8 (44.4%) Grade 3: Intervention arm: 0 (0%), Placebo arm: 7 (38.9%) Grade 4: Intervention arm and Placebo arm: 0 Difference between arms in distribution of grades: p < 0.001 Time between T0 and onset of max. mucositis: no numbers given; p = 0.315 Incidence of max. mucositis (number (%)): 7 days: Intervention arm: 4 (21.1%), Placebo arm: 8 (44.4%) 14 days: Intervention arm: 6 (31.6%), Placebo arm: 4 (22.2%) 21 days: Intervention arm: 9 (47.4%), Placebo arm: 6 (33.3%)
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	some concerns
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	some concerns
Overall RoB judgment	some concerns

Mucositis

Outcome type As specificed by the authors	Primary
Outcome specification	Burning Sensation in the mouth
Type of measurement	VAS (Visual Analogue 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".	Significant difference between intervention vs. placebo arm in mean (SD): intervention 3.7 (2.1) vs. placebo 7.9 (2.0); p < 0.001
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	some concerns
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	some concerns
Overall RoB judgment	some concerns

Erythema

Outcome type As specificed by the authors	Primary
Outcome specification	Oral mucosal erythema
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".	Significant difference between intervention vs. placebo arm for max. size in mm (mean (SD)): intervention 4.9 (2.2) vs. placebo 8.9 (2.7); p < 0.001
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	some concerns
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	some concerns
Overall RoB judgment	some concerns

Oral ulcus

Outcome type As specificed by the authors	Primary
Outcome specification	NA
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".	Significant difference between intervention vs. placebo arm for max. size in mm (mean (SD)): intervention 1.3 (2.7) vs. placebo 6.4 (4.2); p < 0.001
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	some concerns
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	some concerns
Overall RoB judgment	some concerns

Funding and Conflicts of Interest

Funding	NI
Conflicts of Interest	According to authors no conflict of interest.

Further points for assessing the study

Sample

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

Alternative Explanation

Other explanations for an effect besides the investigated intervention	Yes
- Possibility of attention effects	NA
- Possibility of placebo effects	NA
- Other reasons	Possible baseline differences cannot be excluded, hardly any information on baseline characteristics (only gender, age and radiotherapy dose) Poor report quality (e.g. no information on how cancer types are distributed between the arms, no information on dropout and compliance)

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	Yes
Correction for multiple testing	NA
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	NA
Side effects considered in result interpretation	NA
Ethics votum	Yes

Additional Notes

PRO:

• Ethics approval obtained
• Double-blinding

CONTRA:

• Small sample size
• No power analysis
• Possible baseline differences cannot be ruled out
• Limited information on baseline characteristics (only gender, age, and radiotherapy dose)
• Poor reporting quality (e.g., no information on cancer types distribution between arms, no data on dropout and compliance)