TABLE 7.

Clinical studies in chemopreventive phytochemicals/herbal derivatives against HNC.

Phyto-chemical/herbal extract/	Type of study	Study participants	Dosage, treatment duration, and follow-up	Criteria (inclusion/exclusion)	Clinical outcome	Adverse effects reported	Ref
13-cis-Retinoic acid	Randomized double-blind trial	• n = 44	1–2 mg/(kg of body weight)/day (oral)3 months (6 months)	Inclusion	• decrease in size of lesions in 67% of drug recipients as compared to 10% in placebo recipients	• Toxic effects acceptable except in 2 cases	Hong et al. (1986)
		• Retinoic acid Placebo::24:20		• Patients with histologically confirmed oral premalignant lesions
					Histologic response in 56% of drug recipients with clinical response	• Cheilitis, facial erythema, peeling of the skin in 79% drug recipients
		• Age- <50: 6 50-69: 29 > 70: 6		Exclusion
				• Fertile women
		• Gender M:F::31:13	Evaluation: every 2–3 weeks (4–6 weeks)	• People taking >25,000 USP/day units of vitamin A	• Dysplasia reversed in 54% of the drug recipients as compared to 10% of placebo recipients	• Conjunctivitis in 54%
		Risk factors:
		o Alcohol and tobacco: 20/44		• People diagnosed with oral cancer 2 years before the study
		o Alcohol only: 11/44			• Histological improvement in 50% of drug recipients	• Hypertriglyceridemia in 71%
		o Tobacco only: 9/44
		o Neither: 4/44
Vitamin A	Randomized double-blind Trial	• n = 65	200,000IU of vitamin A/week administered in the form of capsules administered twice weekly (0.14 mg/kg body weight per day)	Inclusion	• Complete remission in 57% in VitA as compared to 3% in placebo	• No adverse effects	Stich et al. (1988a)
		Vitamin A:Placebo::30:35		Betel quid chewers with well-established leukoplakias
		• Completed study = 54			• No new leukoplakias in all chewers receiving vitamin A, as compared to 21% in the placebo
		Vitamin A: Placebo::21:33
		Risk factors:			• Number of layers of spinous cells decreased in 85%
		o Betel quid chewing and alcohol drinking: 37%	Duration of trial- 6 months
		o Chewing, drinking and smoking of bidis:28%			• Loss of polarity of basal cells was reduced from 72 to 22%
		o Chewing and smoking of bidis: 2%	Evaluation		• Subepidermal lymphocytic infiltration diminished from 66.7 to 5.5%
		• Betel quid chewing without any additional oral habit: 16%	Every 3 months		• Nuclei with condensed chromatin disappeared from the epidermal layer (72.2% before to 0% at the trial end)
Beta-carotene and beta-carotene plus vitamin A	Randomized double-blind Trial	• n = 130	Group I: 180 mg beta-carotene/week	Inclusion	Frequency (%) of micronucleated cells was reduced in leukoplakia of betel quid chewers	• No adverse effects	Stich et al. (1988b)
		Three groups receiving:		Betel quid chewers with well-established leukoplakias
		o Beta-carotene: Group I, 35 people
		o Beta-carotene and vitamin A: Group II, 60 people			% micronucleated cells placebo, leukoplakia
		o Placebo-group III, 35 people			o Before: 3.69 ± 1.22
		• Completed study: Groups I, II, III are: 30, 54, 26	Group II: 180 mg beta-carotene + 100,000 IU vitamin A/week		o After: 4.00 ± 1.32
		• Age: 48.8 ± 12.9			• % micronucleated cells beta carotrene, leukoplakia
		Risk factors:			o Before: 4.09 ± 1.10
		o Betel quid chewing and alcohol drinking: 37%			o After: 1.18 ± 0.77
		o Chewing, drinking and smoking of bidis: 28%	Group III: Placebo For 6 months		% micronucleated cells beta-carotene + vitamin A, leukoplakia
		o Chewing and smoking of bidis: 2%			o Before: 4.01 ± 1.05
		• Betel quid chewing without any additional oral habit: 16%			o After: 1.16 ± 0.94
					• Well-established leukoplakias regressed. Remission of leukoplakias in
					o Group I: 14.8%
					o Group II: 27.5%
					o Group III: 3%
					• The development of new leukoplakias was inhibited new leukoplakia occurrence:
					o Group I: 14.8%
					o Group II: 7.8%
					o Group III: 21.2%
Beta-carotene		• n = 25	30 mg/day for 3 months	Inclusion	• 17 had major responses (two complete, 15 partial), a response rate of 71%	• No significant toxicity attributable to beta-carotene was encountered in this trial	Garewal et al. (1990)
		• completed study = 24		• Adult patients diagnosed as having clinically measurable oral leukoplakia while undergoing routine dental examinations
		• Gender Bias- M:F::21:3	Responding patients: 3 more months (rest were taken off the therapy)
		• Age (years)
		o < 50: 9		Exclusion	• Relapses after discontinuation of treatment: 8/11 responders within 3 months of cessation of drug
		o 50-69: 9		Patients taking high daily doses of vitamin A
		o > 70: 6
		Risk factors	Evaluation: 2–3 months intervals
		o Alcohol and tobacco: 9
		o Alcohol only: 7
		o Tobacco only: 4
Isotretinoin	Randomized placebo-controlled study	• n = 103	50–100 mg per square meter of body-surface area per day	Inclusion	• No significant differences between the two groups in the number of local, regional, or distant recurrences of the primary cancers	• Mild or moderate	Hong et al. (1990)
		• Completed study = 100		• Clinically free of disease after having undergone surgery or radiation therapy (or both) for histologically confirmed primary OSCC, OPSCC, HPSCC, or LSCC
		• Drug:Placebo::49:51	For 12 months and follow-up for 32 months	Exclusion	• The isotretinoin group had significantly fewer second primary tumors	• Severe skin dryness, cheilitis, hypertriglyceridemia, and conjunctivitis, occurred in 12, 2, 6, and 8%, respectively, of isotretinoin recipients
		• Gender bias: M:F::78:32		• Abnormal renal or hepatic function
		• Age- 31–73 years		• Distant metastasis or a Karnofsky performance score <60%
		Risk factors –		• Previous chemotherapy, within the 2 years	• Only 2 patients (4 percent) in the isotretinoin group had second primary tumors, as compared with 12 (24%) in the placebo group
		• Smoker:	Evaluation:	• A diagnosis of any cancer except in situ or T1 HNSCC or skin cancer other than melanoma
		o Current:Former::33:57	Monthly during treatment and once in three months during follow-up	• Women of reproductive capacity	• Multiple second primary tumors occurred in four patients, all of whom were in the placebo group
		• Alcohol		• Patients taking large doses of vitamin a (>25,000 USP units per day)
		o Yes:No::55:45
Alpha-tocopherol	A single-arm phase II study	• n = 43	400 IU twice daily for 24 weeks	Inclusion	• Clinical response (complete or partial) in 20/43 patients was observed	• No grade 3 or 4 toxic effects were reported	Benner et al. (1993)
		• Gender bias- M:F::24:19		Patients with bi-dimensionally measurable symptomatic leukoplakia (i.e., lesions associated with discomfort such as burning or pain) or leukoplakia with dysplasia
		• Mean age: 55.6 years
		Tobacco use				• Observed side effects were grade 1: Vertigo, extremity aches, nausea, diarrhea, intestinal cramps, breast enlargement, fatigue, and fluid retention
		o Current: 48.8%
		o Past: 30.3%			• Histological response was observable in 9 patients
		o Never 20.9%	Evaluation: At 6, 12, and 24 weeks
		• Alcohol use
		o Current: 55.8%
		o Past: 18.6%
		• Never: 25.6%
Isotretinoin Beta-carotene	Uncontrolled open trial conducted in two phases	Phase I (induction therapy with high dose isotretinoin) n = 70	Phase I: isotretinoin: 1.5 mg/kg body weight/day	Inclusion	Phase I	Phase I: Substantial side effects. 23 patients with grade 3 or 4 toxic reactions. Dry skin, cheilitis, conjunctivitis, Triglycerdemia	Lippman et al. (1993)
				• Oral lesions that were histologically confirmed as pre-malignant and could be measured in two dimensions	• Partial or complete response was observed in 55% of the patients and stable disease maintained in 35% of the patients
		Completed/evaluated: 66	Phase II: Low dose isotretinoin: 0.5 mg/kg body weight/day	• Normal hepatic and renal functions acceptable	Phase II
		Phase II: (Maintenance therapy with low dose isotretinoin OR beta-carotene with patients who responded to induction therapy) n = 59	Beta-carotene: 30 mg/day	• Acceptable fasting triglyceride levels at entry	• Positive outcome (improved/stable lesions) was observed in 92 percent (22) patients on low dose isotretinoin therapy
		Completed/evaluated: 53	Phase I: 3 months	Exclusion		Phase II: Relatively mild, favoring the beta-carotene group. Hypertriglycerdemia, mild and reversible skin yellowing, dry skin, cheilitis, conjunctivitis
		• Beta-	Phase II: 9 months	• High current vitamin A intake (>25,000 USP units per day)	• 45 percent (13) patients on beta carotene therapy showed a positive response
		Carotene:isotretinoin::33:26	Evaluation: Every 4 weeks	• High beta-carotene intake
				• History of oral cancer within two years before study
Riboflavin, retinol vitamin E, and beta-carotene	Randomized double blind trial	• n = 532	Riboflavin (R): 80 mg/week	Inclusion:	• Significant decrease in the prevalence odds ratio (OR) of oral leukoplakia was observed after 6 months of treatment	Nausea, vomiting, and itching	Zaridze et al. (1993)
		• Completed study 487 at 6 months 471 at 20 months	Retinol (VA): 100,000 IU/week	Only men who had a diagnosis of chronic esophagitis and/or oral leukoplakia
			Beta-carotene (BC): 40 g/day
		• Gender bias: All men	Vitamin E (VE): 80 mg/week
		• Age: 50–69 years	In 4 groups with placebo (p)
		• 191 with leukoplakia	1: p,p,p
			2: R,p,p
			3: p,VA,VE,BC
			4: R,VA,VE,BC
			For 20 Months Evaluation: At 6th and 20th month
Beta-carotene, ascorbic acid, and alpha-tocopherol	Open Trial	• n = 7	Beta-carotene: 30 mg/day	Inclusion	• Clinical improvement of the oral lesion was noted in 55.7% of patients	No side effects were reported	Kaugars et al. (1994)
		• Gender bias M:F::45:34	Ascorbic acid: 1,000 mg/day	• Patients with clinically apparent oral leukoplakic lesions that had been histologically verified as either hyperkeratosis or epithelial dysplasia with hyperkeratosis	• 22 (48.8%) of 45 patients who continued their pre-study levels of risk-factor exposure had clinical improvement
		• Age 25–85 years	Alpha-tocopherol: 800 IU/day	Exclusion:
		• Risk factors (smoking, smokeless tobacco, alcohol): 65/79	For 9 months Evaluation: At 1st, 3rd, 6th, 9th month	Cases that were either consistent with lichen planus or were suggestive of lichenoid change	• 4 out of 9 patients who had never used either tobacco or alcohol showed clinical improvement
		• Risk factor reduction or cessation during the course of the study: 20/65
Spirulina fusiformis (lyophilized powder)	Blind Placebo Controlled trial	• n = 115 SF:Placebo::60:55	Lyophilized: Spirulina fusiformis 1 g/da for 12 months with a 2 years follow-up evaluation: Every 2 months during supplementation	Inclusion:	• 20/44 subjects in the SF group showed a complete response as compared to 3/43 subjects in the placebo group	Headache, muscular pain	Mathew et al. (1995)
		• Completed study = 87 SF:Placebo::44:43		Subjects with oral leukoplakia	• 5 subjects in SF group showed a partial response as compared to 0 in the placebo
		• Mean age: 47.1 years			• The CR rates were 46% (17 of 37) for lesions 2 cm in diameter • After 1 year of stopping supplementation
		• Smokers-Yes:No::28:59
		• Alcohol-Yes::No::52:35			9 of 20 (45%) subjects with CR in the SF arm reported with recurrence of lesions
		• Chewers-Yes:No::84:87			• 2 years follow-up: malignant transformations were observed in 10% of subjects in the placebo group and 5% of subjects in SF group
Retinyl palmitate	Randomized Blind Trial	• n = 106	200,000 IU per week (administered orally) for 1 year with 2 years follow-up	Inclusion	• No second primaries were observed in subjects in the vitamin a group	No clinically obvious side effects (dryness of the tongue in two subjects)	Jyothirmayi et al. (1996)
		• Drug:Placebo::56:50		• Patients with HNC with complete clinical regression of lesions on follow-up after therapy
		• Gender bias: M:F::73:33		• Have had either radical radiotherapy or surgery or both
		• Completed study = 93
		• RP:Placebo::50:43	Evaluation: Every 2 months during supplementation	Exclusion	• 2 subjects developed primaries (1 case of tongue cancer and 1 of floor of mouth cancer) in the placebo group
		Risk factors		• Patients with clinical evidence of disease, abnormal kidney and liver function
		o Chewing tobacco:65
		o Smoking: 61
Retinyl palmitate	Open trial conducted in two phases	• n = 20	Phase I	Inclusion	• Complete remission rate observed in 75% (15 of 20 patients)	None of the patients had more than grade 2 reactions; grade 3 and 4 reactions or a withdrawal because of intolerable toxic effects were not observed	Issing et al. (1996)
		• Gender bias-M:F::17:3	300,000 IU/day to 1,500,000 IU/day in patients showing resistant lesions in the fifth week	• Presence of larynx leukoplakia which could be measured in two dimensions
		• Age range: 46-80		• Normal renal and hepatic function
		• Risk factors:		• Acceptable fasting triglyceride levels upon entry
		o Alcohol and tobacco: 7	Phase II	Exclusion	Partial response was observed in 5 patients. Among the 5 patients with partial response, 3 relapsed.
		o Alcohol only: 8; tobacco only: 1	150,000 IU/day for patients who responded to therapy	• Possibility of pregnancy
		• Neither: 4	Median duration of treatment and follow-up: 18 months	A current intake of large doses of vitamin a (>25,000 USP units per day) or betacarotene
			Evaluation: Every 4 weeks during study and 3 months during follow-up
Vitamin a and beta-carotene	Randomized double blind trial	• n = 160	Vitamin A: 300,000 IU/week	NIL	• Vitamin a group: Complete regression in 22 of 42 (52%) subjects	Headache, muscular pain, dry mouth	Sankaranarayanan et al. (1997)
		• Completed study = 131
		• Vitamin A:Beta-Carotene:Placebo::50:55:55	Beta-carotene:360 mg/week		• Beta-carotene group: 15/46 (32%) of subjects showed complete regression
		• Completed study: vitamin A: Beta-carotene:: 42:46:43	For 12 months and 1 year follow-up
		• Gender bias-M:F::1.79:1	Evaluation: Every 2 months during supplementation		• Homogeneous leukoplakias and smaller lesions responded better than non-homogeneous and larger lesions
		• Chewing tobacco-Yes:No::127:4			• 1 year after stopping treatment:
		• Smokers-Yes:No::41:70			o 64% complete responders with vitamin a and 53% complete responders with beta carotene developed recurrent lesions and
		• Alcohol-Yes:No::72:59			• 10% subjects in the placebo group and 5% in the beta carotene group developed malignancy at the site of leukoplakia
Tea	Double-blind intervention trial	n = 64	3 g, 4:1:1 mixture of green tea, green tea polyphenols and tea pigment administered orally and applied topically	Inclusion:	• 37.9% showed decrease in the lesions among 29 treated patients; 3.4% showed an increase		Li et al. (1999)
		Tea:Placebo::32:32		Patients suffering from oral leukoplakia
		Age-23–28 years			• 10% of patients in the placebo group showed an decrease in lesions; 6.7% showed an increase
		Gender bias-M:F::40:24
		Smokers	For 6 months Evaluation: Every 2 months		• Micronucleated exfoliated oral mucosa cells in treated group was lower in placebo group
		Yes:No::46:18
		Evaluated/completed trial: 59
Interferon-alfa, 13- cis -retinoic acid, and alpha-tocopherol	Phase II single-arm trial	• n = 45	Dose modifications based on monthly evaluated toleration of therapy	Inclusion	At median 24-months of follow-up, the clinical end point rates were	Mild to moderate mucocutaneous side effects, flu-like symptoms, anorexia, and weight loss, fatigue, peripheral neuropath optic neuritis, mild to moderate hypertriglyceridemia	Shin et al. (2001), Seixas-Silva et al. (2005)
		• Gender bias-M:F::36:9	Interferon-alfa: (1-3)X106 IU/m2 subcutaneous injection, three times a week	• Confirmed diagnosis of squamous cell carcinoma of the oral cavity, oropharynx, larynx, or hypopharynx	Among 45
		• Age	13-cRA: 20–50 mg/m2/day	• Locally advanced stage III or IV disease	• 9% for local/regional recurrence (four patients)
		o Median: 52 years	Alpha-tocopherol: 1,200 IU/day	• Enrolled a minimum of 3 weeks and maximum of 24 weeks after definitive local therapy with surgery, radiotherapy, or both	• 5% for local/regional recurrence and distant metastases (two patients)
		o Range: 43–70 years		• Should not have received chemotherapy, immunotherapy, or hormonal therapy before entry onto the study	• 2% for SPT (one patient), which was acute promyelocytic leukemia
		• Initial stage	For 12 months	• Must have recovered from the acute toxic effects of surgery, radiotherapy, or both	• Median 1- and 2-years rates of overall survival were 98 and 91%, respectively, and of disease-free survival were 91 and 84%, respectively
		o Stage III: 11		• Must be able to swallow the pills without breaking them	At median 49.4-months of follow-up
		o Stage IV: 34	Evaluation: Every 3 months (monthly check ups for dose modification)	• Life expectancy of >12 weeks	• 9 (20%) of 44 patients experienced progressive disease, 3 since the last report
		• Prior treatment		• Karnofsky performance status rating of >80%	• Two patients had local recurrences
		o Surgery: 3		• Adequate bone marrow function and adequate renal and hepatic functions	• 1 had local and distant relapse. The progression-free survival percentages at 1 year, 3 years, and 5 years were 88.9, 82.2 and 80% respectively
		o Radiotherapy:15	Follow up: median 24 months and median 49.4 months	Exclusion	• The overall survival percentages at 1 year, 3 years, and 5 years were 97.8, 88.9 and 81.3% respectively
		• Surgery and radiotherapy: 27		• If taking megadoses of vitamin a (>25,000 IU)
				• If they were women of child-bearing potential who were not practicing adequate birth control
				If they had a baseline triglyceride level > twice the normal range
ZengShengPing (Sophra tonkinensis, Polygonum bistorta, Prunella vulgaris, Sonchus brachyotus, Dictamnus dasycarpus, and Dioscorea bulbifer)	Randomized placebo-controlled trial	n = 120	3.6 g per day for 8–12 months	Inclusion	Positive response was observed in 67.8% (40/59) patients of ZSP group, and in 17% (9/53) patients of placebo group		Sun et al. (2010)
		Completed/evaluated = 112		• 20 patients with oral leukoplakia i.e white patch or plaque that cannot be characterized clinically or pathologically as any other disease
		ZSP:Placebo::59:53
		Mean age: (ZSP:Placebo)- 52.9:44.4
		Gender bias-M:F::69:43		Exclusion
		Risk factors-		• Those with a previous diagnosis of head and neck or oral cancer
		smokers		• Those currently treated by other drugs or having drug hypersensitivity
		Yes:No::53:59		• Those requiring extensive dental procedures
		Drinkers		Those with a history of social or psychiatric situations interfering with study compliance
		Yes:No::10:102
Lycopene	Randomized placebo-controlled trial	n = 58	Group B: 4 mg/day	Inclusion	• Clinically the patients in groups A, B, C had a mean response of 80, 66.25 and 12.5% respectively		Singh et al. (2004)
		Gender bias-M:F::44:14	Group C: Placebo	• Patients suffering from oral leukoplakia	• Group A:
		Age: 10–70 years (70% between 31 and 70 years)	For 3 months		o Complete response-11
			Follow-up: 2 months		o Partial response-7
			Evaluation: Every 7–10 days during treatment and 15 days during follow-up		o Stable response-2
					• Group B:
					o Complete response -5
					o Partial response-7
					o Stable response-2
					• Group C:
					o Complete response-0
					o Partial response-3
					o Stable response-15
Green tea extract	Phase II, randomized double-blinded placebo-controlled trial	n = 41	Group 1	Inclusion	• The clinical response rate was higher in the three combined GTE arms (50%) vs. placebo (18.2%)	Treatment-related adverse events reported by 28 of the 30 (93.3%) patients who received GTE	Tsao et al. (2009)
		Placebo:Group1:Group2:Group3::1:11:9:10	GTE: 500 mg/m2	• Presence of one or more histologically confirmed, bidimensionally measurable OPLs that could be sampled by biopsy and had at least one of the following high-risk features of malignant transformation
		Gender bias-M:F::19:22	Group 2	• Harboring at least mild dysplasia	• Histologic response rate 21.4% (GTE arms) vs. 9.1% (placebo)	There were only three grade 3 adverse events and no grade 4 or 5 adverse events
		Smoker	GTE: 750 mg/m2	• Located in a high-risk area (i.e., floor of mouth, ventrolateral tongue, and soft palate)
		Never: 15	Group 3	• Significant extent of OPL tissue involvement
		Former: 22	GTE: 1,000 mg/m2	• Presence of symptoms (pain or substantial discomfort)
		Current: 4	Group 4: Placebo	• Age between ≥18 and ≤75 years	• The clinical response rate was dose dependent—58% in the combined higher-dose GTE arms (group 2 and 3) vs. 36.4% group 1 and 18.2% (placebo)	Common grade 1 and 2 events: Headaches, insomnia, nausea, nervousness, flatulence, gastric reflux, back pain
		Cigar	For 12 weeks	• Zubrod performance status of <2
		Former 1	Follow up: 27.5 (median time)	• Adequate hematologic, liver, and renal function
		Current 3	Evaluation: After 4 weeks	• Adequate cardiac function
		Smokeless tobacco		• Negative pregnancy test in females of childbearing potential within 7 days before first dose of study medication; use of effective contraceptive method while on the trial
		Former: 1		Exclusion	• Dose dependency was not seen in histologic response
		Current: 0		• Known hypersensitivity to oral GTE or its analogs
		Alcohol		• Use of prior investigational agents within 30 days
		Never: 8		• Any serious intercurrent illness	• With a median follow-up time of 27.5 months, 15 patients subsequently developed oral cancer with a median time to oral cancer development of 46.4 months
		Former: 9		• History of prior malignancy with less than a 1-year disease-free interval before study entry
		Current: 24		• Lactating females patients who were not able to abstain from the consumption of methylxanthine-containing products (including coffee, tea, chocolate, caffeinated soft drinks, and theophylline) and decaffeinated tea
Black raspberries		n = 40	10% w/w	Inclusion criteria	• 16 of the 21 BRB treated lesions decreased in size for an average overall size decrease of 26%	No adverse effects	Mallery et al. (2014)
		BRB:Placebo::22:18	For 12 weeks	• Microscopically confirmed premalignant oral epithelial lesions
		Gender Bias-M:F::14:24	Follow-up: 3 months	• No use of tobacco products for six weeks prior and during the three-month study	• 17 of the 19 placebo gel treated lesions increased in clinical lesional size with an average increase of 18%
		Age-32–78 years	Long-term follow-up: 3–31 months	• No previous history of cancer	• 2 BRB gel patients had 100% lesional resolution
		Smoker		Exclusion criteria	• Statistical decrease in histopathologic grade while placebo gel application did not significantly impact histopathologic grade
		Y:N::16:24		• Previous or current history of non-basal cell cancer
				• Use of tobacco products	• After 3 months 6 of 22 BRB and 7 of 17 placebo patients had visible evidence of lesional recurrence at the former treatment sites
				Either a microscopic diagnosis of no premalignant change or oral squamous cell carcinoma (OSCC) in the pretrial biopsy
Curcumin	Randomized double blind phase IIB trial	• n = 223	Three 600 mg capsules taken twice daily; orally and after food (3.6 g/day) for six months	Inclusion	• Statistically significant difference observed	Moderate/severe AEs were recorded in 4 patients in the curcumin arm including anemia skin/subcutaneous tissue disorders, and hypertension	Kuriakose et al. (2016)
		Drug:Placebo::111:112		• The presence of clinical and histologically confirmed oral leukoplakia >15 mm2 in area	• Clinical response: 75 subjects (67.5%) in curcumin arm and in 62 subjects (55.3%) in placebo arm
		• Gender Bias-M:F::161:62		• 1 cm linearly	• Thirty (27%) subjects in curcumin arm and 46 (41.1%) subjects in placebo arm were non-responders
		• Smoking-	103 subjects for 6 more months. (Drug:Placebo::53:50)	• No previous biopsy or treatment for head and neck cancer prior to 3 months of accrual	• Histologic response was observed in 25 (22.5%) subjects in the curcumin arm and in 23 (20.5%) subjects in the placebo arm
		current(C)/Former(F)		• No chemopreventive treatment prior to 3 months of accrual	• Combined (clinical and histological) response was noticed in 65 (58.6%) subjects in the curcumin arm and 50 (44.6%) subjects in the placebo arm
		Yes:No::112:111 (C:F::61:27)		• Zubrod performance of 0–2	• Curcumin group: Of the 18 subjects available at follow-up, 16 (88.9%) continue to have CR at 12 months
		• Alcohol- Daily/Non-Daily (D/ND)		• Normal hematological and biochemical parameters
		Yes:No::93:130 (D:ND::16::51)	Evaluation: Monthly during supplementation	Exclusion:	• Placebo arm: 7 of 8 subjects (87.5%) demonstrating no relapse after 6 months follow-up
		• Chewing Tobacco-Current(C)/Former(F)		The presence of oral submucous fibrosis
		Yes:No::158:63 (C:F::95:63)
Calendula officinalis and lycopene	Double-blinded comparative study	n = 60	Calendula officinalis gel (group 1): 2 mg by weight/g	Inclusion	• Group 1		Singh and Bagewadi, (2017)
		CO:Lycopene::30:30	Lycopene gel (group 2): 2 mg by weight/g	• Patients with clinically and histopathologically confirmed cases of homogeneous leukoplakia	° Average size of leukoplakia before treatment: 4.14 cm2 (standard deviation [SD] = 2.07)
		Gender bias-M:F::50:10	Administered topically thrice a day		o Average size treatment: 2.09 cm2 (SD = 2.59)
		Age	For 1 month		Group 2
		26–75 years (maximum in 56–65 years)	Follow-up: 3 months		° The average size of leukoplakia before treatment: 4.46 cm2 (SD = 2.41)
					o Average size after treatment: 2.89 cm2 (SD = 3.07)
					• The mean difference in the reduction in size before and after treatment for group I was 2.0 ± 1.0 cm while for the group II, it was 1.57 ± 0.87 cm