A Randomized Double-Blind Placebo-Controlled Phase IIB Trial of Curcumin in Oral Leukoplakia

Oral leukoplakia is the most common and well-defined potentially malignant lesion (1, 2) of the oral cavity. The reported annual malignant transformation rate is 1% with a total lifetime risk of 42% (2–4). It is a predominantly white lesion of oral mucosa that cannot be compared with other lesions without malignant transformation potential such as candidiasis, lichen planus, frictional keratosis, leukodema, and lupus erythematosis (5). Several novel technologies have been introduced in the recent past that can detect oral malignant lesions at the preneoplastic stage (6, 7).However, there exists no effective strategies to treat oral leukoplakia.

Surgical excision of leukoplakia has significant morbidity with a relapse rate of 26% to 35% (8, 9). Although chemoprevention by retinoids has a clinical response rate of up to 67% (10, 11), high toxicities and relapse following cessation of therapy have prevented its clinical use (12). All subsequent chemoprevention trials, with various agents so far, have been ineffective (13).

Concordance of several preclinical and observational clinical studies of curcumin, a polyphenol extracted from the plant Curcumin longa, has established antiproliferative, proapoptotic, and prodifferentiation properties of the drug, in diverse epithelial malignancies including that of the oral cavity (14–17). A prior phase I clinical trial has demonstrated that curcumin is well tolerated at a dosage as high as 8 g/day for 3 months (18). In this study, we investigated the efficacy and safety of curcumin in treatment of oral leukoplakia.

Curcumin Chemoprevention in Oral Potentially Malignant Lesion (OPML) trial (CCP-OPML-06) was a multicenter, double-blind, randomized, placebo-controlled trial to test whether curcumin can, effectively and safely, treat oral leukoplakia. This trial was funded by the Department of Biotechnology (DBT), Government of India. The study was carried out in accordance with the International Conference on Harmonization recommendation on Good Clinical Practice. The study protocol was approved by Institutional Research Review Boards and registered with Drugs Controller General of India (F.No.4-129/06-DC) and the clinical trial registry of Indian Council of Medical Research (CTRI/091/000113). The safety and efficacy data were reviewed by an Independent Data and Safety Monitoring Board (IDSMB). The clinical trial schema, eligibility criteria (19), and patient disposition are given in Fig. 1. The principal inclusion criteria were the presence of clinical and histologically confirmed oral leukoplakia of size more than 15 mm² in area and with any linear dimension more than 1 cm, no previous biopsy or treatment for head and neck cancer and no chemopreventive treatment prior to 3 months of accrual, Zubrod performance of 0 to 2, normal hematologic and biochemical parameters, and ability to participate in the trial and sign informed consent. The main criteria was the presence of oral submucous fibrosis.

The trial was led by a steering committee consisting of the lead principal investigator, the principal investigators of the three participating clinical sites and the central laboratory. This steering committee directed all aspects of the study, including design, data gathering, analyses, and article preparation. A clinical research organization (Manipal-Acunova, India) had the responsibilities for medical monitoring, data management, and statistical analysis.

The subjects with clinical evidence of oral leukoplakia, as per the World Health Organization (WHO) consensus criteria (5), were recruited from the outpatient clinics of head and neck oncology services of three academic medical centers in India. These were Regional Cancer Center, Trivandrum, Amrita Institute of Medical Science, Kochi, and Chennai Dental Research Foundation, Chennai. The recruitment period was from June 2007 to December 2011. Subjects stratified by study sites were randomly assigned in a 1:1 ratio to receive curcumin or placebo. The randomization was done centrally at the CCP-OPML study center located at Manipal-Acunova, Bangalore (with no external input) by telephone or fax to each of the three recruitment centers located in Trivandrum, Kochi, and Chennai. The study was conducted in a double-blind fashion without revealing the treatment assignments to patients or investigators except the study statistician and pharmacists.

The investigational product was curcumin, reconstituted with turmeric oil and dispensed in capsules (BCM95–Biocurcumax). Preclinical pharmacokinetic studies have demonstrated that its bioavailability was, approximately, 6 times more than curcumin alone (20). Curcumin was dispensed in calendar packs of three 600 mg capsules in a twice-daily regimen consumed orally after food (3.6 g/day) for 6 months. The placebo capsules containing cellulose were identical in physical characteristics and dispensed similar to the curcumin. The curcumin and placebo were procured from Arjuna Natural Extracts, India.

After determining the eligibility and baseline clinical evaluation, all the subjects underwent incision biopsy of the lesion using a 5 mm punch biopsy. The subjects who meet the clinical and histologic diagnosis of leukoplakia and other inclusion/exclusion criteria were randomized to receive either curcumin or placebo, in a twice-daily regimen, for 6 months. At the end of 6 months of intervention, the lesion was measured to determine the primary endpoint of clinical response, and biopsy was performed for histologic response. Those subjects demonstrating clinical partial response (PR) were continued on their respective treatment (either curcumin or placebo) for 6 additional months to determine the effect of long-term treatment. The remaining subjects with complete response (CR) and stable disease (SD) were observed for 6 months, without intervention, to determine durability of response. Clinical and histopathologic assessments of the subjects were repeated at the end of 12 months. The patient disposition and clinical follow-up results are given in Supplementary Fig. S1.

Physical examination and laboratory tests, including complete blood count, serum biochemistry, and urine analysis, were performed at baseline, 6, and 12 months after randomization. In addition, patients were reviewed once a month to evaluate concomitant medication, lesion(s) size measurement, compliance, and adverse events (AE). The risk habits were defined by the presence of tobacco (smoking/chewing) and/or alcohol habits. Smoking habit was defined by usage of either cigarettes or “beedi,” a local form of cigar, wherein tobacco is rolled inside tobacco leaves, and some patients used both. The risk habits were evaluated and the subjects were counseled on risk–habit cessation prior to enrollment and during the monthly reviews. The counseling was carried out by a medically trained study coordinator.

The lesions were measured using disposable paper rulers during monthly follow-up visits. The area of a lesion was obtained by multiplying the longest diameter by the greatest perpendicular diameter. In case of multiple lesions, the largest lesion was considered as the index lesion. Total area was obtained from the sum of areas of all the lesions. On appearance of new lesions or clinical progression, the lesion was rebiopsied. Any subject with histologic progressive disease (hPD) was terminated from the study, and appropriate treatment was offered. The histopathology diagnosis and grading of dysplasia were determined by the pathologist at each of the clinical sites using the WHO oral dysplasia criteria for inclusion in the study (21). Prior to initiation of the trial, three pathologists involved in the study reviewed and agreed upon the diagnostic criteria. The panel of three pathologists reviewed the slides independently at the central laboratory and reported consensus of observations to determine histologic response.

Primary Efficacy Endpoint: The primary efficacy endpoint of this study was the clinical response based on the comparison of the lesion size at baseline and at 6 months. A standard treatment response criteria (22) were used: CR, disappearance of the lesion; PR, 50% or greater decrease in the sum of products of diameters of all measured lesions; SD, neither sufficient shrinkage to qualify for PR or sufficient increase to qualify for PD; and PD any increase of more than 25% in the sum of products of diameters of all measured lesions.

Secondary endpoints: The secondary endpoints of this study included the following:

1. Histologic response: The histologic response criteria at follow-up in comparison with baseline result of the index lesion are defined as follows: histologic CR (hCR), complete reversal of dysplasia/hyperplasia to normal epithelium; histologic PR (hPR), regression of the degree of dysplasia; histologic SD (hSD), no change in the degree of dysplasia; and hPD, any increase in severity grade.

2. Combined response: A previously described oral leukoplakia staging system that integrates both clinical and histologic criteria was utilized to determine the combined response criteria (23). The definition of combined response criteria is as follows: complete response, clinical CR and histologic CR; partial response, clinical PR and histologic PR or SD; stable disease: clinical SD and histologic PR or SD; progressive disease, clinical PD and/or histologic PD.

3. Durability of response: Additional 6-month clinical follow-up was done for those subjects who showed clinical CR or SD at 6-month evaluation to determine the durability of response. The response evaluation at 6 months (clinical, histologic, and combined response) was correlated with that at 12 months.

4. Effect of continued intervention: The patients with clinical PR were continued on the intervention (either curcumin or placebo) for additional 6 months to determine effect of long-term intervention. The responses were evaluated with the same response criteria as carried out at the 6-month evaluation.

5. Compliance: The compliance to medication was reviewed on a monthly basis. Compliance is calculated based on the formula given below:

   

   The subject was deemed to be compliant if the average monthly pill count is ≥ 80% (i.e., ≤20% capsules remained at end of each month). The unblinded pharmacist counted the pills at each monthly review, and the results were recorded on the Drug Compliance Form. The average compliance of each treatment group was calculated separately.

6. Safety evaluation: AEs were classified according to criteria from Medical Dictionary for Regulatory Activities (MedDRA), version 8.1 (21). The total number of AE(s), based on their frequency, causality, as well as severity, were compared between treatment and control arms. AE(s) were described as unrelated, unlikely, possibly related, probably related, and definitely related to the study medication.

The trial was designed with a statistical power of 90%. Therefore, a sample size of 223 subjects was required to detect 25% more clinical response in the treatment arm when compared with the placebo arm. The power calculation assumed a dropout rate of 30%. All the efficacy analyses were performed on the intent-to-treat (ITT) population, with primary efficacy end points determined for all patients by follow-up clinical examination at 6 months. For those subjects whose 6-month endpoint measurements were not available, the ITT analysis utilized the most recent measurements to determine the clinical response outcome. In addition, the analysis of the clinical outcomes was also conducted after excluding the patients whose 6-month endpoint measurements were not available. For both the approaches, the proportions of patients with CR or PR were grouped together as responders, and proportions of patients with SD or PD were grouped together as nonresponders. Separate descriptive analyses were carried out with histologic response and combined clinical and histologic response as endpoints. The response rates were presented as percentage and 95% confidence intervals (CI). Comparison between responses in curcumin and placebo groups was carried out using χ² and Fisher exact tests. Statistical significance was defined as P value <0.05. In addition, the clinical response to curcumin therapy versus placebo at 6 months was compared individually in subgroups stratified by demographic and clinical factors using binomial logistic regression analysis. The results were presented as ORs and P values.

For safety evaluation, the proportions of subjects with AEs were classified by MedDRA SOCs and Preferred Terms and summarized by treatment arm as treatment-emergent AEs (24). An AE was considered to be treatment-emergent, if the onset of the AE was subsequent to the administration of the study medication. The safety population consisted of all those who have received at least one dose of study medication. AEs were also summarized by severity as mild, moderate, severe, life threatening, and death related and by relationship to study medication as unrelated, unlikely, possibly related, probably related, and definitely related to study medication.

The funding agency had no role in study design, collection of data, data analysis, and interpretation of the results or writing the report. All authors have access to the entire raw data. The authors confirm the completeness and veracity of the data and analysis. The corresponding authors had the final responsibility on the decision to submit for publication.

Of the 280 subjects screened, 223 subjects met all the inclusion and exclusion criteria and were enrolled in the study and formed the ITT population. Disposition of these subjects is outlined in COSORT Flow Chart in Fig. 1. One hundred and eleven patients were randomized into the curcumin arm and 112 patients in the placebo arm. The demographic, risk profile, and clinical characteristics were comparable in the two groups (Table 1). Ninety-four subjects in each arm had endpoint measurement completed at 6 months. The reasons for withdrawal from the trial are given in Supplementary Data (Supplementary Fig. S1). Eleven patients in curcumin arm and 14 patients in placebo arm had at least one post baseline evaluation, which was used for the ITT analysis for clinical response. Therefore, 105 subjects in the treatment arm and 108 subjects in the placebo arm were available at the end of 6 months for evaluation of primary endpoints. Sixty-eight and 67 evaluable patients were available for follow-up till 12 months in the treatment and placebo arm, respectively.

Compliance was evaluated at 6 months of intervention in 105 patients from the curcumin arm and 108 patients from the placebo arm. The drug compliance at 6 months was 83.8% (n = 88; 95% CI, 75.6 – 89.6) in curcumin arm and 83.3% (n = 90; 95% CI, 77.1–90.6) in placebo arm. The drug compliance in PR subjects at 12 months was 79% in curcumin arm and 84% in placebo arm.

In the ITT population of 105 subjects in curcumin arm and 108 patients in placebo arm, a clinical response (CR + PR) was observed in 75 subjects (67.5%; 95% CI, 58.4–75.6) in curcumin arm and in 62 subjects (55.3%; 95% CI, 46.1–64.2) in placebo arm. Thirty (27.0%; 95% CI, 19.6–36.0) subjects in curcumin arm and 46 (41.1%; 95% CI, 32.4–50.3) subjects in placebo arm were nonresponders (SD + PD). Statistically significant difference in clinical response rate was observed between the curcumin and the placebo arms (P = 0.03; Figs. 2 and 3A and B; Supplementary Table ST1). When the analysis was repeated with the subjects who had completed 6-month endpoint evaluation (94 subjects in each arm), the results were consistent with the ITT analysis (Supplementary Table ST2). Clinical response (CR + PR) rate was 74.5% in curcumin arm versus 57.4% in placebo arm. The difference in clinical response rate observed between the curcumin and the placebo arms was statistically significant (P = 0.02).

Histologic response (hCR + hPR) was observed in 25 (22.5%; 95% CI, 15.7–31.3) subjects in the curcumin arm and in 23 (20.5%; 95% CI, 14.1–28.9) subjects in the placebo arm. No response (hSD + hPD) was noted in 60 (54.1%; 95% CI, 44.8–63.0) and 63 (56.3%; 95% CI, 47.0–65.1) subjects in the curcumin and placebo arms, respectively. Data of 26 subjects in both the curcumin and placebo arms were not available. The difference in histologic response rates between curcumin arm and the placebo arm was not statistically significant (P = 0.71; Fig. 2; Supplementary Table ST1).

Combined response (CR + PR) was noticed in 65 (58.6%; 95% CI, 49.3–67.3) subjects in the curcumin arm and 50 (44.6%; 95% CI, 35.8–53.9) subjects in the placebo arm. No response (SD+PD) was noticed in 28 (25.2%; 95% CI, 18.1–34.1) and 43 (38.4%; 95% CI, 29.9–47.6) subjects in the curcumin and placebo arm, respectively. Data of 18 and 19 subjects in the curcumin and placebo arms, respectively, were not available. The difference in combined response rates between the curcumin and placebo arms was statistically significant (P = 0.03; Fig. 2; Supplementary Table ST1).

Of the 67 subjects in the curcumin arm with clinical response, only 23 (34.3%) showed histologic response, whereas 14 of 16 clinical nonresponders were histologic nonresponders. The result is summarized in Supplementary Table ST3. The Kappa correlation coefficient was 0.13 (P = 0.06) for the curcumin group and 0.27 (P = 0.001) for placebo group (data not provided).

Univariate and multivariate logistic regression analyses were conducted comparing risk of nonresponse (SD/PD) in curcumin arm to the placebo arm. The univariate analysis showed a significantly lower odds of SD/PD in curcumin arm compared with placebo arm (OR, 0.54; 95% CI, 0.31–0.95; P, 0.03). Similarly, significantly lower odds of SD/PD in curcumin arm were noticed after adjusting individually for significant factors such as presence of dysplasia, lesion type (homogenous vs. nonhomogenous), smoking tobacco use, smokeless tobacco use, alcohol use, and habit cessation through trial period. On multivariate analysis, adjusting for the key factors of habit cessation, presence of dysplasia, and lesion type (homogenous vs. nonhomogenous), curcumin showed a significantly lower odds of SD/PD compared with placebo (OR, 0.40; 95% CI, 0.21–0.76; P, 0.005).

The clinical response to curcumin therapy versus placebo at 6 months was also evaluated individually in all the subgroups stratified by demographic, clinical, and pathologic variables such as age, gender, subsite, morphology of lesion (homogenous and nonhomogenous leukoplakia, erythroplakia; Supplementary Fig. S2), histology of lesion, type of habits, abstinence, or continuation of habits. The ratio of responders to nonresponders in each arm and the risk odds ratio based on logistic regression analysis are presented separately for each of these variables in Fig. 4. A significant reduction in risk of SD/PD with curcumin versus placebo was noted with homogenous leukoplakia lesions (P = 0.03), nondysplastic lesions (P = 0.003), smokeless tobacco use (P = 0.03), alcohol use (P = 0.04), either tobacco/alcohol use (P = 0.01) and in subjects who continued to use tobacco/alcohol through the trial period (P = 0.009).

To evaluate durability of response, subjects with CR and SD at 6 months were followed up for an additional 6 months after completion of the intervention. The results are summarized in Table 2. Among 22 subjects with CR at 6 months in the curcumin arm, 4 were lost to follow-up. Of the 18 subjects available at follow-up, 16 (88.9%) continue to have CR at 12 months (95% CI, 67.2–96.9). In the placebo group, out of 12 subjects with CR, 4 subjects were lost to follow-up, whereas 7 (87.5%; 95% CI, 52.9–97.8) remain to have CR at 12-month follow-up, P = 0.99. Among the subjects with SD at 6 month evaluation, durable response (CR/PR/SD) at 12 months was noted in 7 (70%; 95% CI, 39.7–89.2) and 14 (82.4%; 95% CI, 59.0–93.8) in the curcumin and placebo arms, respectively (P = 0.64). Thirteen in the curcumin arm and 15 in the placebo arm, who were lost to follow-up, were not included in the analysis. Similarly, when histologic and combined response criteria were evaluated, no statistically significant difference in durability of response was noted between the two study arms (data not shown).

A total of 103 subjects with clinical PR at 6 months were allowed to continue on curcumin (n = 53) or placebo (n = 50) for additional 6 months to determine any additional benefit on longer-term curcumin therapy (Supplementary Table ST4). At the end of 12 months, CR or PR was seen in 29 (54.7%; 95% CI, 41.5–67.4) subjects in curcumin arm and 30 (60.0%; 95% CI, 46.2–72.4) subjects in placebo arm. SD or PD was seen in 7 (13.2%; 95% CI, 6.6–24.8) subjects in curcumin arm and 10 (20.0%; 95% CI, 11.2–33.0) subjects in placebo arm. No statistically significant difference was observed between the two groups, suggesting that treatment longer than 6 months may not have additional benefit.

IDSMB that monitored the study did not identify any safety concerns. The safety study population consisted of 223 subjects (111 in the curcumin arm and 112 in the placebo arm). Daily dose of 3.6 g of curcumin was well tolerated by the study population during the study period. A total of 61 (27.4%) subjects experienced at least one AE during the study period, 26 (23.4%) in curcumin arm, and 35 (31.3%) in placebo arm. There is no statistically significant difference in major AEs between the curcumin and placebo arms (Supplementary Table ST5).

Moderate/severe AEs were recorded in 4 patients in the curcumin and included anaemia, skin/subcutaneous tissue disorders, and hypertension. The placebo group recorded 18 patients with moderate/severe AEs, which included epistaxis and pleural effusion, anaemia, hypertension, increase in levels of creatinine/lactate dehydrogenase, and infections (leptospirosis, urinary, and respiratory tract infections). Four subjects from curcumin arm and 1 from placebo arm withdrew from the study due to Adverse Events (AEs)/Serious Adverse Events (SAEs). One subject in each arm experienced severe AE (n = 1), whereas all other AEs reported in study were mild or moderate. Three subjects with AEs were assessed to be possibly related to treatment in the curcumin arm. Three subjects with AEs were assessed to be possibly related and one to be probably related to treatment in the placebo arm. No death was reported among the study population during the study period. The details of AEs are provided in Supplementary Table ST5.

Since the first description of chemoprevention of oral leukoplakia about 25 years ago (11), there have been several attempts to develop a safe and clinically effective chemopreventive agent. Clinical use of chemoprevention strategies for oral leukoplakia has been hampered by the high rate of relapse and occurrence of AEs with the interventions (12). This was highlighted in a recent meta-analysis and in the Cochrane review, which are summarized in Supplementary Table ST6 (25–27). In the present study, we report curcumin to be a clinically effective and safe agent to treat oral leukoplakia, suggesting its chemopreventive potential in oral cancer.

Though in chemoprevention trials incidence of cancer may be used as the primary endpoint, all, but two, of the 26 reported trials have employed clinical response as a surrogate primary endpoint, as was adopted in the present study. This is primarily due to the need for longer follow-up period and larger sample size if cancer incidence is considered as the endpoint. The reported clinical response of previous oral leukoplakia chemoprevention trials ranges from 4% to 67% (25). Vitamin A or retinoid has been the most investigated chemopreventive agent for oral leukoplakia, with a reported response rate of 45% to 67% (26–28). In the present study, we observed 67.5% clinical response rate (complete or partial) and 20.7% SD after 6 months of intervention. This response rate is better than most of the previously reported oral leukoplakia chemoprevention trials (Supplementary Table S6). It is to be noted that the validity of clinical response, as a surrogate endpoint for cancer development in oral leukoplakia, has not been established.

Histologic response as an endpoint is used infrequently in oral chemoprevention trials and has yielded inconsistent results (25–27). Subjective nature of oral dysplasia diagnostic criteria and high inter-observer variability has been attributed as the primary reason. In the present study, we did not observe significant improvement in histologic response despite improvement in clinical response. We have attempted to overcome the frequently reported inter-observer variability encountered in oral dysplasia grading by using well-defined oral dysplasia diagnostic criteria and obtaining a consensus report of three pathologists for histologic response evaluation. The possibility of technical artifacts during biopsy cannot be ruled out in the study. It has been reported that incisional biopsy under diagnosed 73.3% of the patients, in comparison with pathologic examination of excised oral leukoplakia lesions (29). There is a possibility that the biopsy may have geographically missed the worst histologic region. In addition, after chemoprevention intervention, the persistent lesion may represent histologically higher-grade lesion that may be sampled during the follow-up biopsy. These inherent methodological challenges for using histologic outcomes as endpoint in oral chemoprevention studies need to be considered while interpreting the results.

One of the consistent findings of all previous chemoprevention trials in oral leukoplakia to date has been relapse of lesions after cessation of therapy. It ranged from 50% with topical Bleomycin (30), 54% to 64% with vitamin A and beta carotene (31), and 56% with retinoid (11). In the present study, we observed clinical and histologic relapse only in 7.7% and 7.3% respectively in the curcumin arm after 6 months of follow-up.

An interesting observation, in the current study, was the relatively high response and the low relapse rates in the placebo arm compared with previous reports. It has been shown that tobacco cessation alone can result in clinical response in 43.2% to 58.3% of subjects with leukoplakia (32, 33). This study employed a structured habit cessation counseling program. This was carried out by medically trained study coordinators prior to enrollment of subjects to the study and during each monthly review. This resulted in high rates of habit cessation (28% in the curcumin and 29% in the placebo), which might have contributed to the better response and lower relapse rate in both arms. This argument is further supported by the subgroup analyses that showed the response rate in the placebo arm to be relatively higher (67.9%) in subjects who quit tobacco/alcohol, compared with the subjects who continued using tobacco/alcohol (51.5%). Whereas, in the curcumin arm, the response rates were similar between subjects who quit (74.1%) and who did not quit (73.2%) risk habits. Furthermore, logistic regression analysis showed a lack of difference in risk between the curcumin arm versus placebo among subjects who quit habits (P = 0.61).

Subgroup analyses of the data showed that curcumin has a significantly better chemopreventive potential than placebo in smokeless tobacco users, alcohol users, and in subjects who continued to use tobacco or alcohol during the trial. These results seem to support the previous studies that have hypothesized that curcumin may prevent alcohol and tobacco-induced carcinogenesis by regulating pathways involving NF-kB, COX-2 and AKT/MTOR (34). However, it must be noted that these results were based on our post-hoc subgroup analyses. Therefore, additional studies may be needed to further confirm the efficacy of curcumin in tobacco and alcohol users.

Chemoprevention trials have used varying durations of intervention ranging from 14 days to 12 months. In the current study, we did not observe improvement in response rate following continued therapy after 6 months in subjects with PR. This implies an absence of additional benefit in treating subjects with curcumin for periods more than 6 months. Further studies are required to understand the mechanism of resistance in order to optimize the curcumin therapy.

One of the major hurdles in chemoprevention clinical trials has been the toxicity associated with medical interventions (12). Because only one third of all oral leukoplakia undergo malignant transformation, it is essential that the interventions should be less toxic. In this study, daily dose of 3.6 g of curcumin is found to be well tolerated. Though compliance to 3.6 g dispensed in six capsules per day was satisfactory in a study setting, one concern may be its feasibility in clinical practice. It is to be noted that the 3.6 g dose was used in this study based on the previously established tolerance dose (15) and not the efficacy dose. Thus, if the compliance in clinical practice proves to be an issue, it could be of value to determine efficacy of a lower dose of curcumin.

Low durable response rate and high toxicity were encountered in most of the oral leukoplakia chemoprevention intervention trials during the past three decades. Findings from this study suggest that curcumin may serve as an effective treatment for oral leukoplakia, with good tolerance and durable clinical response. It is to be noted that there was no statistically significant difference in the durability of response between the placebo and curcumin arms. Further long-term studies are required to determine whether the clinical response in oral leukoplakia can be translated to a decrease in oral cancer development. In addition, molecular biomarkers, rather than a reliance on dysplasia, and molecular marker–based-targeted interventions are required for risk stratification, response evaluation, and to improve effectiveness of chemoprevention (35, 36).

V. Jayaprakash is a medical scientist (permanent employee) at AstraZeneca Pharmaceuticals LP. No potential conflicts of interest were disclosed by the other authors.

Conception and design: M.A. Kuriakose, K. Ramdas, B. Dey, S. Iyer, G. Thomas, M.R. Pillai

Development of methodology: M.A. Kuriakose, K. Ramdas, S. Iyer, S. Ramachandran, N.A. Kumar, G. Thomas, K. Ranganathan, M.R. Pillai

Acquisition of data (provided animals, acquired and managed patients, provided facilities, etc.): M.A. Kuriakose, K. Ramdas, S. Iyer, G. Rajan, K.K. Elango, A. Suresh, R.R. Kumar, R. Prathiba, N.A. Kumar, G. Thomas, T. Somanathan, H.K. Ravindran, K. Ranganathan

Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis): M.A. Kuriakose, K. Ramdas, S. Iyer, A. Suresh, R.R. Kumar, N.A. Kumar, S.B. Katakam, S. Parashuram, V. Jayaprakash, M.R. Pillai

Writing, review, and/or revision of the manuscript: M.A. Kuriakose, K. Ramdas, B. Dey, S. Iyer, K.K. Elango, A. Suresh, S. Ramachandran, N.A. Kumar, G. Thomas, K. Ranganathan, S. Parashuram, V. Jayaprakash, M.R. Pillai

Administrative, technical, or material support (i.e., reporting or organizing data, constructing databases): M.A. Kuriakose, B. Dey, G. Rajan, R.R. Kumar, N.A. Kumar

Study supervision: M.A. Kuriakose, K. Ramdas, B. Dey, S. Iyer, S. Ramachandran, N.A. Kumar, G. Thomas, M.R. Pillai

Other (principal investigator from Regional Cancer Centre, Trivandrum): K. Ramdas, B. Dey

Other (contributed the support by way of interpreting all the pathologic slides): T. Somanathan

The authors thank Dr. Benny Antony, Technical Director, Arjuna Natural Products Ltd, India, for providing curcumin and placebo capsules. The investigators thank members of the IDSMB—Drs. B. Mathew, Sundaram, Vijaykumar, Pavithran, Manjula Datta, and Saraswathi. The study was coordinated by Manipal Acunova. The authors are grateful to Dr. Surinder Kher, Manigandan Easaran, and Kumar Gautham.

This article is dedicated to the memory of Dr. Divya Ravindran, a coinvestigator of the study who tragically passed away during the course of this project.

This study was supported by Department of Biotechnology, Government of India (No.BT/PR6068/Med/14/739/2005).

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.