Rao et al. (2014): The Indian Spice Turmeric Delays and Mitigates Radiation-Induced Oral Mucositis in Patients Undergoing Treatment for Head and Neck Cancer: An Investigational Study

Reference ↗
Title	The Indian Spice Turmeric Delays and Mitigates Radiation-Induced Oral Mucositis in Patients Undergoing Treatment for Head and Neck Cancer: An Investigational Study
Topic	Curcumin
Author	Rao, S, Dinkar, C, Vaishnav, LK, Rao, P, Rai, MP, Fayad, R, Baliga, MS
Year	2014
Journal	Integrative Cancer Therapies
DOI	https://doi.org/10.1177/1534735413503549

Brief summary

This study investigated the efficacy of a curcumin mouth rinse compared to a povidone-iodine mouth rinse in patients with head and neck cancer during radiotherapy. Throughout radiotherapy, mucositis (an inflammation of the mucosa, a common adverse side effect of radiotherapy) was less severe in the curcumin arm than in the other arm. There were also fewer overall cases of intolerable mucositis in the curcumin arm. In addition, curcumin patients lost less weight on average than the others. No differences were found with regard to the number of patients who had to interrupt treatment and the average duration of the interruption.

In dieser Studie wurden die Wirksamkeit einer Curcumin-Mundspülung im Vergleich zu einer Povidon-Iod-Mundspülung bei Patienten mit Kopf-Hals-Tumor während der Radiotherapie untersucht. Über die gesamte Radiotherapie hinweg war Mukositis (eine Entzündung der Schleimhaut, eine häufige unerwünschte Nebenwirkung von Radiotherapie) in der Curcumin-Gruppe weniger schwerwiegend als in der anderen Gruppe. In der Curcumin-Gruppe gab es auch insgesamt weniger Fälle von unerträglicher Mukositis. Zudem verloren Curcumin-Patienten im Durchschnitt weniger Gewicht als die anderen. Keine Gruppenunterschiede fanden sich hinsichtlich der Anzahl an Patienten, bei denen eine Therapieunterbrechung nötig war und hinsichtlich der durchschnittlichen Dauer der Unterbrechung.

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	Single
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	NI
Exclusion criteria	Infected tooth, ulcers, or mucositis of the oral cavity
N randomized	80
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	NA
Countries of data collection	India
LoE Level of evidence	1b Oxford 2009
Outcome timeline Data collection times	Mucositis was assessed before the start of the radiation treatment and at weekly intervals

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	Early Stage
Specifications on cancer stages	T1-TX, N0-NX, M0-MX
Comorbidities	NI
Current cancer therapies	Surgery, Chemotherapy, Radiation therapy
Specifications on cancer therapies	Only radiation therapy, radiation therapy + chemotherapy or radiation therapy + chemotherapy + surgery
Previous cancer therapies	NI
Gender	Mixed
Gender specifications	20% female
Age groups	Adults (18+)
Age groups specification	Mean (SD, range) = 55.96 (12.25, 26-85) 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	40
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	Personal reasons
Intervention	Curcumin solution + Standard oral, dental, medical, and supportive care was provided to all subjects of both cohorts by a qualified dental physician. The patients were also instructed to clean their teeth with a soft toothbrush 4 times a day
Dosage and regime	Curcumin solution; 1 capsule with 400g curcumin powder dissolved in approximately 80ml water (prepared by the nurse), 10ml as a mouthwash (4 times for 2 minutes each) Start: Day 1 radiotherapy, 6 times daily Duration: 7 weeks
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.	49
Side effects / Interactions	NI

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	40
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	Povidone-iodine solution + Standard oral, dental, medical, and supportive care was provided to all subjects of both cohorts by a qualified dental physician. The patients were also instructed to clean their teeth with a soft toothbrush 4 times a day
Dosage and regime	Povidone-iodine solution (diluted 1:100; 1ml Betadine, 100ml water), Mouthwash, 10ml twice daily Duration: 6 weeks
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.	49
Side effects / Interactions	NI

Outcomes

Mucositis

Outcome type As specificed by the authors	Primary
Outcome specification	Oral Mucositis
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".	Weeks 1-7: Curcumin arm < Povidone-iodine arm; p < 0.001 (derived from graph only, no values provided) Cases of intolerable mucositis: Curcumin arm: 14/39 vs. Povidone-iodine arm: 34/40; p < 0.0001
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)	some concerns
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

Toxicity

Outcome type As specificed by the authors	Secondary
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".	Number (%) of patients requiring therapy interruption: Curcumin arm: 7 (17.95%), Povidone-iodine arm: 9 (24%) ns. Number of days lost: mean (SD) Curcumin arm: 7 (0), Povidone-iodine arm: 7.25 (0.56) ns. Weight loss: mean (SD) Curcumin arm: 3.92 (2.13), Povidone-iodine arm: 4.45 (2.15); 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)	some concerns
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	According to information none.
Conflicts of Interest	According to authors no conflict of interest.

Further points for assessing the study

Sample

Power analysis performed	Yes
- Sample size corresponds to power analysis	Yes
- Reasons for insufficient sample size based on power analysis	NA
If no power analysis performed: at least moderate sample size (n >= 30 per arm)	NA
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	Intervention arm has to rinse its mouth much more often than comparison arm, and this increased rinsing frequency could potentially affect the results

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	NI
Correction for multiple testing	NA
Measurement of compliance	Yes
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
• Active control
• Large sample size according to power analysis calculation
• Low dropout (Curcumin arm: 2.5%, Povidone-iodine arm: 0%)

CONTRA:

• Curcumin arm must rinse mouth much more frequently than Povidone-iodine arm
• Poor reporting quality (e.g., some numbers can only be derived from graphs)