Phytochemicals are non-nutritive substances found in plants that contribute significantly to the flavor and color of the plants, as well as the beverages derived from them. They are also being studied for their potential health benefits ^[1][2][1,2]. Some of the potential mechanisms underlying phytochemical health benefits include their role as substrates for biochemical reactions, cofactors of enzymatic reactions, inhibitors of enzymatic reactions, absorbents/sequestrants that bind to and eliminate undesirable constituents in the intestine, ligands that agonize or antagonize cell surface or intracellular receptors, scavengers of reactive or toxic chemicals, compounds that enhance the absorption and or stability of essential nutrients, selective growth factors for beneficial gastrointestinal bacteria, fermentation substrates for beneficial oral, gastric, or intestinal bacteria, and selective inhibitors of deleterious intestinal bacteria ^{[3][4][5][6][7][8][9]}[3,4,5,6,7,8,9]. There is a large body of evidence supporting phytochemicals’ effectiveness in the prevention of various diseases, including cardiovascular disease, diabetes, osteoporosis, cataracts, menopausal conditions, gastrointestinal disorders, atopic eczema, hyperactivity, gynecological, neurological, and immunological disorders and even cancer ^[10][11][12][10,11,12]. According to the data, more than 19.3 million new cancer cases were recently diagnosed and reported, resulting in approximately 10 million deaths by 2020 [13]. Cancer incidences are constantly increasing around the world, resulting in millions of deaths each year, indicating that new approaches to cancer control are urgently needed. An alternative approach to this problem could be to focus on carcinogenesis control rather than attempting to cure the end-stage disease of cancer [14]. Chemoprevention—the use of natural, synthetic, or biologic chemical agents to reverse, suppress, or prevent carcinogenic progression to an invasive cancer—is a possible way to achieve this assumption [15]. It is estimated that an appropriate lifestyle modification could prevent more than two-thirds of human cancers, and diet is responsible for 10–70% (on average, 35%) of the human cancer mortality. Population and laboratory studies are accumulating evidence that phytochemicals have significant anticarcinogenic and antimutagenic properties [16]. Numerous studies on cell lines and animal models have found phytochemicals to be effective in both the treatment and the prevention of cancer, and the results appear to be very promising. It has been demonstrated that phytochemicals extracted from medicinal plants can reduce cell proliferation, cause apoptosis, delay metastasis, and inhibit angiogenesis. Garlic has inhibitory effects on the growth of the Hep-2 human larynx carcinoma cell line, according to the research by Hadjzadeh et al. [17]. Studies on the effect of the Hibiscus sabdariffa leaf extract on human cell and xenograft models revealed that it induces autophagic cell death in human melanoma, inhibits the growth of LNCaP in xenograft tumor studies and human cell models, and induces apoptosis in human leukemia and gastric carcinoma cells ^{[18][19][20][21]}[18,19,20,21]. Purushothaman et al. discovered in their study using a rat model that Shemamruthaa has a significant anti-cancer effect due to its role in reducing LPO, preventing membrane damage, and restoring membrane integrity [22]. It was demonstrated by Mortazavian et al. that the ethyl acetate and n-butanol fractions of Viola tricolor have significant antitumor effects against the neuroblastoma N2a cells in their study on a human cell line [23]. The ethyl acetate fraction of Viola tricolor has potential cytotoxic properties by reducing tumor cell proliferation, inducing apoptosis, and inhibiting angiogenesis on CAM, according to the research by Sadeghnia et al. [24] Berrington et al. discovered that rosemary species have possible chemopreventive properties because of their high antioxidant content in their research on the anticancer activity of specific herbs and spices [25]. 

One of the early case-control studies on the association between phyto-estrogen intake and the risk of breast cancer by Ingram D. et al. showed a substantial reduction in breast cancer risk among women with a high intake of the phyto-estrogens—particularly the isoflavonic phyto-estrogen equol and the lignan enterolactone. Phyto-estrogen intake was measured based on urinary excretion, and 144 samples were included for the analysis. The findings were claimed to have potential for the prevention of breast cancer ^[26][52]. Another study, investigating 250 urine samples collected from Chinese women in Shanghai, revealed a reduction of the risk of breast cancer with increasing excretion of total isoflavonoids and total lignans. The adjusted odds ratio was 0.28 (95% confidence interval, 0.15–0.50) for women who had a high excretion rate of both total lignans and isoflavonoids compared with those with low excretion of both groups of phytoestrogens. The results further confirm that the high intake of certain phytoestrogens may reduce the risk of breast cancer ^[27][53]. The association between flavonoid intake and the reduced breast cancer risk was also suggested in a case-control study conducted among women who resided in Nassau and Suffolk counties in Long Island, New York. Cases (n = 1434) and controls (n = 1440) were interviewed about the known and suspected risk factors and asked to complete a food frequency questionnaire regarding their average intake in the prior 12 months. The decrease was most pronounced among postmenopausal women for flavonols, flavones, flavan-3-ols, and lignans ^[28][54]. J Peterson et al. found a strong, statistically significant inverse association of flavone intake with breast cancer in a large case-control study of 820 women with breast cancer and 1548 control women, conducted in Greece. The inverse association of flavones implies a 13% reduction in the breast cancer risk per 1 s.d. (0.5 mg day⁻¹) of an increase in the intake of the respective compounds. Inverse associations with breast cancer risk were also found for flavonols, flavan-3-ols, and anthocyanidins ^[29][55]. Ying Wang et al. examined the associations between seven subclasses of dietary flavonoids and the invasive postmenopausal breast cancer risk overall and by ER status in a U.S. prospective cohort of 56,630 postmenopausal women, among whom 2116 invasive breast cancers were verified during a follow-up. There was a modest inverse association between flavone intake and the overall breast cancer risk and between flavan-3-ol intake and risk of ER− breast cancer but not for ER+ breast cancer risk. Those results also seem to be consistent with the above-mentioned studies indicating a beneficial role of plant-based diets in breast cancer risk ^[30][56].

Several meta-analyses show an association between soy isoflavone intake and the reduction of breast cancer risk ^[31][32][33][57,58,59]. Hui et al.’s study, involving 9513 cases and 181,906 controls, six of which were prospective cohort studies and six were case-control studies, implies that the intake of flavonols and flavones, but not other flavonoid subclasses or total flavonoids, is associated with a decreased risk of a breast cancer, especially among post-menopausal women ^[34][60]. Moreover, a meta-analysis including five cohort studies (11,206 patients) revealed that soy food intake might be associated with reduced mortality and recurrence, especially for ER-negative, ER+/PR+, and postmenopausal patients ^[35][61].

The case control study by Lee MM et al. in China based on 133 cases and 265 age- and residential community-matched controls evaluated the effect of the soy isoflavone intake on the risk of prostate cancer with the result suggesting a reduction of this risk associated with the consumption of soy products ^[36][62]. A population-based prospective study on 43,509 Japanese men showed similar findings ^[37][63]. Milan S. Geybels et al. investigated the associations among flavonoid intake, black tea consumption, and prostate cancer risk in the Netherlands Cohort study, which included 58,279 men. From 1986 to 2003, 3362 prostate cancers were identified, including 1164 advanced (stage III/IV) cancers. Results implied an association between dietary flavonoid intake and a decreased risk of advanced-stage prostate cancer ^[38][64]. A case control study nested in the European Prospective Investigation into Cancer and Nutrition indicates that higher plasma concentrations of the isoflavone genistein, but not other isoflavones, were associated with a lower risk of prostate cancer ^[39][65]. The University of Hohenheim a conducting the randomized controlled double-blind crossover trial (NCT01538316), which aimed to compare the effects of the flavonoid quercetin and isoflavone genistein with those of a placebo on the rate of increase in prostate-specific antigen (PSA). At the beginning of the study in March 2012, 60 participants were recruited. Over a period of 18 months, the primary outcome was determined by the increase in PSA every three months. The study’s completion date was projected to be April 2014, but the recruitment process unfortunately has not been updated since 15 May 2012. Meta-analyses of the two studies, including men with an identified risk of PCa, found a significant reduction in the PCa diagnosis after the administration of soy/soy isoflavones, and therefore, there may be support for the epidemiological findings of a potential role for soy/soy isoflavones in PCa risk reduction ^[40][66].

The European Prospective Investigation into Cancer and Nutrition (EPIC) study looked at the link between dietary flavonoids, lignans, and gastric cancer incidence (GC). The study by Zamora-Ros et al. included 477,312 subjects (29.8% men) aged 35–70 years from ten European countries, with 683 incident GC cases confirmed over an 11-year period. Total flavonoid intake was found to have a significant inverse relationship with GC risk in women but not in men ^[41][67]. Similar results were obtained by Woo, H.D. et al. in their case-control study on the association between GC and flavonoid intake in the Korean population. The study conducted with 334 cases and 334 matched controls aged 35–75 years suggested a significant inverse association between the gastric cancer risk and dietary flavonoids and their subclasses, with the exception of anthocyanidins and isoflavones. Also in this case, the above-mentioned effects were observed in women, but not in men. Moreover, no significantly different effects were observed in the subgroup analysis of H. pylori and smoking status ^[42][68]. Petrick J. et al. investigated the relationship between flavonoid intake and the incidence and the survival of esophageal and gastric cancer in a multicenter, population-based study in the United States. Case participants with the esophageal adenocarcinoma (n = 2740), gastric cardia adenocarcinoma (n = 248), esophageal squamous cell carcinoma (n = 191), and other gastric adenocarcinomas (n = 341) were followed until 2000 for vital status, and 662 frequency-matched controls were included in the study. The total flavonoid intake had little or no consistent association, but the anthocyanin intake was associated with a 57% reduction in the risk of incident esophageal adenocarcinoma and a lower risk of mortality from gastric cardia adenocarcinoma ^[43][69]. Zamora-Ros et al. looked at the link between dietary flavonoid and lignan intake and the risk of colorectal cancer in a Spanish population. The study included 424 colorectal cancer cases and 401 hospital-based controls. The findings indicated an inverse relationship among total flavonoids, lignans, some individual flavonoid subgroups, and the risk of colorectal cancer ^[44][70].

In a series of studies conducted in Uruguay, the protective effect of plant sterol intake on breast and ovarian carcinogenesis was reported ^[45][92]. Two investigations conducted in New York supported an association between reduced ovarian and endometrial cancer risks and a diet high in plant foods, which included phytosterols ^[46][93]. Similarly, the naturally occurring dietary intake of phytosterols in a Spanish free-living population has been also estimated to be higher than that in people living in other non-Mediterranean European countries, suggesting that this could be a part of the Mediterranean diet phenomenon. A randomized, clinical trial conducted in 2015 in Spain involving a Mediterranean diet intervention showed a reduction in the breast cancer risk in the intervention group ^[47][94]. The hospital-based case-control study conducted in Mexico City between 1994 and 1996 supports a protective role of specific dietary phytochemicals in breast cancer risk by menopausal status, independent of other reproductive factors ^[48][95].

A clinical trial, conducted in 2020 by the University of Leeds, aimed to establish the influence of LDL-C-lowering dietary intervention on the ability of non-cancer cells (adipocytes, fibroblasts, and macrophages) to change the chemotherapy response and the metastatic process in breast cancer cells. The main intervention of this involved supplementation with phytosterols in the form of an enriched yoghurt to the volunteers with high LDL-C levels over the course of 8 weeks. To evaluate the effectiveness of the supplementation, volunteers’ blood, white blood cells (macrophages), and fat tissue cells were examined with the purpose of measuring oxysterol, LDL-C, and phytosterol concentrations and to measure alterations in the behavior of cancer cells mediated by the host cells in the laboratory examination. The status of the study remains as recruiting, and the last update was posted on 20 May 2021 ^[49][96].

A study by Fraser in 1999 showed that vegetarians have a lower risk of prostate cancer—54% greater in vegetarians (p ≈ 0.03) than in the nonvegetarians. A multivariate evaluation revealed an association of chemoprevention with higher dried fruit intake (p < 0.05) ^[50][83].

Despite the chemoprotective model of dietary phytosterols in animal studies ^[51][52][53][77,78,79], a high dietary intake of the plant sterols was not associated with a lower risk of colon and rectal cancers in the Netherlands Cohort Study on Diet and Cancer ^[54][97]. Chinese research by Jing Huang et al. in 2017 indicated that the consumption of total phytosterols, β-sitosterol, campesterol, and campestanol is inversely associated with colorectal cancer risk in a Chinese population ^[55][98]. A study conducted by Fraser from 1999 on the Seventh-day Adventists population claimed that the risk of a colon cancer was increased by 88% in nonvegetarians compared with that in vegetarians (p < 0.003). Increased legume consumption over three times a week was associated with a much lower relative risk of colon cancer (0.33; 95% CI: 0.13, 0.83), but only in the red meat-eating nonvegetarians ^[50][83].

In a case-control study conducted in Uruguay in 1993–1996 and including 463 cases of lung cancer and 465 hospitalized controls, the influence of phytosterols on a neoplasm was evaluated. Total phytosterol intake was inversely correlated with lung cancer risk (OR 0.50, 95% CI 0.31–0.79) and the dose–response effect was statistically significant (p = 0.002). The relationships between beta-sitosterol, campesterol, and stigmasterol and the lung cancer risk were similar. This protective effect was distinctly evident for adenocarcinoma of the lung ^[56][99]. Fraser established a strong inverse association between fruit consumption and the risk of lung cancer in the Seventh-day Adventists population for both main histologic subtypes ^[57][100].

Between 1997 and 1999, a case-control study involving 120 cases of stomach cancer and 360 controls was conducted in Uruguay. Total phytosterols were associated with a strong inverse relationship with stomach cancer. Combined exposure to the high intake of total phytosterols and alpha-carotene was also inversely associated with the gastric cancer risk ^[58][101].

Mills et al.’s research implies a significant negative association between the consumption of dried fruits (p < 0.05), legumes (p = 0.01), and also vegetarian meat analogues (p = 0.03) and pancreatic cancer risk in the Seventh-day Adventists population ^[59][102].

Results from a population-based case-control study from January 2015 to December 2016 in a single institution of the municipality of Catania, southern Italy, in which 340 patients took part, suggested that high intake of caffeic acid and ferulic acid may be associated with a reduced risk of prostate cancer (PCa) and may have beneficial effects in reducing the PCa incidence ^[60][112].

In a multipurpose, prospective cohort study of 10,812 middle-aged women who were university graduates conducted by the Seguimiento Universidad de Navarra, findings suggested that the phenolic acid content of the diet, particularly dietary hydroxycinnamic and the chlorogenic acids present in coffee, fruits, and vegetables, was associated with a lower breast cancer risk among the postmenopausal women in this Mediterranean cohort ^[61][113].

An open-label, randomized controlled trial conducted by Guangzhou University of Chinese Medicine evaluated the efficacy and safety of traditional Chinese medicine (TCM) in advanced non-small cell lung cancer (NSCLC) patients who underwent chemotherapy. One of the types of medicine administered was ZhenqiFuzheng (ZQFZ) capsules consisting of sinapinic acid, ferulic acid, asiatic acid, pratensein, and glycitein. The results from this study showed that TCM treatment could improve the quality of life of NSCLC patients and alleviate their symptoms with good safety ^[62][114]. Another Chinese study conducted in 2020 by Yanqing Zhou and Chenxi Wu indicated that ZQFZ granules could treat NSCLC through multitargets and multipathways ^[63][115].

The study conducted by Duke University Medical Center showed that the use of a stable topical formulation of 15% L-ascorbic acid, 1% alpha-tocopherol, and 0.5% ferulic acid was particularly effective for reducing the thymine dimer mutations known to be associated with a skin cancer.

The First Affiliated Hospital of Henan University of Science and Technology registered two clinical trials aiming to investigate the efficiency and safety of caffeic acid for Chinese advanced esophageal squamous cell cancer (ESCC). Unfortunately both studies (2017, 2020) were last updated in 2020, with their status remaining as unknown. The first study involved 240 patients with an advanced ESCC diagnosis split into control and experimental groups, which was to receive 300 mg of the caffeic acid orally until the occurrence of the progression of disease, death, or unacceptable adverse effects. Results were to be assessed after a 1-year follow-up period. The 2020 study aimed to investigate the efficacy of the oral administration of 100–200 mg of caffeic acid, depending on body mass, to 80 advanced ESCC patients who failed chemotherapy or chemoradiotherapy. Treatment was to be administered in a two-week period followed by a one-week black interval. Similarly, the follow-up period was supposed to last 1 year. No results of both studies are available ^[64][65][117,118].

The Wnt signaling pathway is often activated in colon cancers, and resveratrol has been shown to modulate this pathway ^[66][145]. To further understand the actions of resveratrol on the Wnt signaling pathway, a clinical trial was conducted with colon cancer patients receiving treatment with resveratrol, while laboratory studies examined its effects on colon cancer and the normal colonic mucosa ^[67][146]. In a study from 2009, eleven patients were treated with resveratrol in a two-week course in the form of pills (20 mg) or freeze-dried grape extract before undergoing standard surgical resection of the tumor. The dose of resveratrol was gradually increased for each patient (for the first and second patient—a dose of 20 mg/day, the third and fourth—80 mg/day, for the fifth and sixth—160 mg/day plus grape extract at a dose of 125 mg/day mixed with an 8 oz glass of water), and no dose adjustments were made during the trial. Gene expression analysis of the colon cancer tissue showed that some genes (myc and cyclinD1) increased following exposure to resveratrol or the grape extract, but the mechanism behind these increases is unclear and requires further investigation.

Resveratrol can activate a protein called Notch-1, which has been shown to prevent tumor cell growth. A study conducted by the University of Wisconsin, aimed to investigate the effects of resveratrol and Notch-1 on neuroendocrine tumor tissue patients with neuroendocrine tumors, assessed how well they tolerated the product when taken for up to three months. Resveratrol was administered at a dose of 5 gm/day orally, in two divided doses of 2.5 mg each, without stopping for a total of three cycles. The researchers’ primary goal was to demonstrate that resveratrol treatment in patients with low-grade GI neuroendocrine tumors will significantly increase Notch1 activation in post-treatment tumor biopsy specimens when compared to pretreatment levels. The primary endpoint will be the level of expression of full-length Notch1, cleaved Notch1, HES-1, and ASCL-1, as measured by Western blotting using quantitative densitometry ^[68][148].

Loma Linda University has been conducting a study since 2019 ^[69][149], which involves 50 participants and aims to investigate the impact of resveratrol on IGF-II levels in healthy African American women. Preclinical studies have demonstrated that resveratrol inhibits IGF-II and promotes apoptosis in the breast cancer cell lines ^[69][149]. The researchers intend to assess the baseline IGF-II levels in healthy African American women, who are at a higher risk of mortality and worse outcomes when treated with the standard adjuvant therapies for the breast cancer. The study will monitor the IGF-II levels of participants receiving the resveratrol therapy for 6 weeks. ResVida^® is the oral preparation used in the study, which contains pure trans-resveratrol with a purity of over 99% and is manufactured by DSM nutritional products. Healthy African American women will receive a daily dosage of 150 mg in the form of one capsule. The study involves four visits, including an initial visit and three additional visits at two-week intervals. The study coordinator will provide each participant with a two-week supply of a RSV and a medication calendar during visits 2–4. The blood samples will be collected by a trained phlebotomist during each visit and handed to the research laboratory to measure the IGF2 levels and other biomarkers.

Paller et al. ^[70][150] conducted two studies to assess the effectiveness of low microgram doses of pulverized muscadine grape extract (MPX) capsules as a treatment option for patients with biochemically recurrent prostate cancer. The first study, which lasted for 28 days, evaluated the safety of both: a low dose (500 mg) and a high dose (4000 mg) of MPX. The second study lasted for 12 months ^[71][151], and despite treatment with microgram doses, the prostate-specific antigen doubling time (PSADT), which indicates disease progression, remained unchanged, indicating that the doses used were below the therapeutic threshold. Van Die et al. ^[72][152] also tested a blend containing a higher dose of resveratrol (30 mg) in a similar group of patients and reported an insignificant increase in PSADT. However, it should be noted that low doses were used in the studies, which may explain the lack of effect, and that much higher doses may be necessary for therapeutic efficacy. Additionally, the impact of the other constituents in the formulation on the pharmacokinetic profile of resveratrol is currently unknown. Further studies that use pure resveratrol at higher doses in a similar group of patients would be beneficial.

Popat et al. in 2009 conducted a clinical trial on the safety and activity of SRT501 (resveratrol) alone or in the combination with bortezomib in patients with multiple myeloma (MM). Unfortunately, the study has been terminated due to the extensive adverse effects (AEs) experienced by all of the 24 participants, including nausea (79%), diarrhea (71%), vomiting (54%), fatigue (46%), and anemia (38%). Adverse effects above or equal to grade 3 were reported by over half of the participants. Out of 24 patients treated with SRT501, 15 were withdrawn from the treatment. Eleven patients discontinued before the first response assessment and were not evaluable. The median time to progression was 2.8 months, and the overall survival was not reached. During the study, two deaths were reported—one possibly treatment-related and other one due to progressive disease. None of the patients treated with resveratrol monotherapy achieved a minor, partial, or complete response ^[73][153].

The most examined carotenoids in terms of their importance in protection from prostate carcinogenesis and its progression are lycopene, β-carotene, and α-carotene ^[74][171]. Results in the most updated meta-analyses show that higher lycopene consumption and circulating blood concentrations are associated with a decreased risk of prostate cancer. In a meta-analysis of 42 studies that involved almost 700,000 participants, it was found that the risk of prostate cancer decreased by 1% for every additional 2 mg of lycopene consumed in the diet and by 4% for every additional 10 μg dL⁻¹ of circulating lycopene ^[75][172]. Another meta-analysis from 2015 ^[76][173] showed that higher intake of α-carotene was associated with a 13% lower relative risk of prostate cancer, and each additional 0.2 mg of α-carotene consumed reduced the prostate cancer risk by 2%. However, there was no association found between the β-carotene and prostate cancer risk. Chemoprevention in prostate cancer has also been evaluated in the clinical trial by the National Taiwan University Hospital examining the effects of multi-carotenoid (MCS) supplementation, although no results has been posted and the study was last updated in October, 2015. The study was set to evaluate the effectiveness of the administration of 30, 15, or 0 mg of MSC orally daily in a group of 300 high-risk patients. Outcome measures include a comparison of the cumulative prostate cancer incidence among the groups and the change from baseline in the serum carotenoid levels. Previous Phase II and III clinical trials by the investigators reported no MCS-related serious adverse events (SAEs), although there is no information available on the AEs in this study ^[77][174].

Only β-carotene, blood α-carotene, and blood lutein showed an association with a decrease in breast cancer risk. In a dose-response analysis, dietary β-carotene was associated with a 5% decrease in breast cancer for each additional 5 mg consumed, while blood α-carotene and β-carotene had a significant linear dose-response—breast cancer risk decreased by 26% for each additional 50 μg of β-carotene dL⁻¹ or 18% for each additional 10 μg α-carotene dL⁻¹. Additionally, breast cancer risk decreased by 32% for each additional 25 μg lutein dL^{−1 [78]}[175]. The Cancer Prevention Study II (CPS-II) Nutrition Cohort evaluated associations between plasma carotenoids and invasive breast cancer in post-menopausal women ^[79][176]—only plasma α-carotene was associated with invasive breast cancer, especially for estrogen receptor-positive breast cancer. The pre-diagnostic consumption of β-carotene was associated with a 30% decrease in all-cause mortality for the highest quantile and a 7% decrease in risk for 1.2 g per day for all-cause fatalities. No associations between lycopene, α-carotene, β-cryptoxanthin, or lutein consumption and all-cause mortality or breast-cancer specific survival have been found ^[80][177]. Rock et al.’s analysis of 3043 Women’s Healthy Eating and Living Study participants diagnosed with early-stage breast cancer revealed a greater likelihood of breast cancer-free survival regardless of the study group assignment correlation with higher biological exposure to carotenoids in the 6-year assessment time ^[81][178].

Patterns of smoking tend to be closely associated with less healthful diets, including lower consumption of fruits and vegetables ^[82][83][180,181]. A meta-analysis of 18 prospective studies found that higher blood concentrations of lycopene, α-carotene, and β-carotene were associated with a significant decrease in lung cancer risk ^[84][182]. Similarly, a study of 35 studies found that high consumption of lycopene, α-carotene, β-cryptoxanthin, and lutein/zeaxanthin were all associated with a significant decrease in lung cancer risk ^[85][183]. Notably, these associations were only observed in the current smokers. These associations were lost in individuals that were former smokers or individuals that never smoked ^[85][183]. However, high doses of β-carotene supplementation have been found to increase the lung cancer risk in current smokers and individuals with asbestos exposure ^[86][87][184,185]. These studies used much higher doses of β-carotene compared to consumption in a normal diet, which may have produced the pro-oxidant effects in the highly oxidative lung environment caused by the cigarette smoke. In the Beta-Carotene and Retinol Efficacy Trial (CARET) ^[86][88][184,186], a combination of 30 mg beta-carotene and 25,000 IU retinyl palmitate (vitamin A) taken daily was tested against a placebo in 18,314 men and women at a high risk of developing lung cancer. However, the intervention was stopped 21 months early due to the evidence of no benefit and possible harm. The active intervention group had 28% more lung cancers and 17% more deaths compared to the placebo group. The participants who received the combination of the beta-carotene and vitamin A did not experience any benefits and instead had a higher incidence and mortality rates from lung cancer. These results align with those of the Alpha-Tocopherol Beta-Carotene Cancer Prevention Study conducted with 29,133 male smokers in Finland, which also found no benefit from beta-carotene ^[89][187].

The consumption of the β-carotene was linked to a lowered chance of esophageal adenocarcinoma ^[90][188]. A meta-analysis on pancreatic cancer conducted before 2014 synthesized the available data, indicating that of the 18 studies examined on the correlation between dietary carotenoids and pancreatic cancer, lycopene, β-carotene, and β-cryptoxanthin exhibited a significant association with a decreased risk of pancreatic cancer, as reported in a reference ^[91][189]. In a 2013 study, comparing the highest and lowest quartiles of lycopene exposure, both dietary and blood lycopene were not found to be associated with gastric cancer, but an interesting finding was that increased tomato consumption was linked to a reduced risk of gastric cancer ^[92][190].

A study was conducted starting in July 2010, which recruited 538 individuals with colorectal cancer and 564 controls who were matched for age (in 5-year intervals) and sex ^[93][191]. The study measured the levels of certain nutrients (α-carotene, β-carotene, β-cryptoxanthin, lycopene, and lutein/zeaxanthin) in the participants’ serum using HPLC. After adjusting for the various factors that could affect the results, the study found that there was an inverse relationship between the serum levels of α-carotene, β-cryptoxanthin, and lycopene and the risk of colorectal cancer. The adjusted odds ratios of the highest quartile of serum levels compared to the lowest quartile were 0.49 for α-carotene, 0.44 for β-cryptoxanthin, and 0.36 for lycopene. However, there was no significant statistical association between the serum levels of β-carotene and lutein/zeaxanthin and colorectal cancer risk. These findings suggest that lower levels of the α-carotene, β-cryptoxanthin, and lycopene in the serum are associated with a higher incidence of colorectal cancer in the Chinese population residing in Guangdong. Between July 2010 and October 2013, a study was conducted involving 845 individuals with colorectal cancer and 845 controls who were matched for the age and sex. Participants completed the in-person interviews, and their dietary intake was estimated using a validated food frequency questionnaire. The study found a strong inverse association between the intake of β-cryptoxanthin and the risk of colorectal cancer. Participants in the highest quartile of intake had a 77% reduced risk compared to those in the lowest quartile. Similarly, inverse associations were found for α-carotene, β-carotene, and lycopene. However, there was no statistically significant association between lutein/zeaxanthin intake and colorectal cancer risk. These findings were consistent across cancer sites, sources of controls, and smoking statuses. The study found that both males and females had inverse associations between the dietary intake of α-carotene, β-cryptoxanthin, and lycopene and colorectal cancer risk, while inverse associations between β-carotene intake and colorectal cancer risk were only observed in males.

Meyer and Bairati conducted extensive research on the influence of nutritional compounds on head and neck cancer patients. Over the course of the clinical trial, investigators evaluated the relationship between α-tocopherol and β-carotene administration and the occurrence of secondary primary cancers, adverse effects of radiotherapy, and mortality. Supplementation consisted of a daily dose of vitamin E (1 capsule of 400 IU DL-α-tocopherol) and β-carotene (1 capsule of 30 mg) or placebos during the radiation therapy and for 3 years after the radiation therapy ended ^{[94][95][96][97]}[192,193,194,195]. Among a clinical group of 273 patients with stage I or II squamous cell carcinoma of the head and neck treated with radiotherapy, a statistically significant increased all-cause mortality rate, with HR = 1.38 (95% CI = 1.03–1.85), was reported in comparison to that in the placebo group. The median duration of the radiation therapy was 43 days, and the median duration of the supplementation was 3.1 years. Overall survival was consistently lower among the participants randomized to the supplement arm (p = 0.033) ^[97][195]. During the supplementation period, the rate of a second primary cancers was statistically significantly higher among patients in the supplement arm (60 per 1000 person-years) than among patients in the placebo arm (25 per 1000 person-years), which became inverse after supplement discontinuation with 39 per 1000 person-years in the previous supplement users and 69 per 1000 person-years in the former placebo users ^[95][193]. A higher dietary intake of beta carotene was associated with approximately 40% lower frequencies of severe acute adverse effects of radiation therapy to the specific sites and overall. A similar pattern of inverse relationships was observed between the plasma beta carotene and severe acute adverse effects of radiation therapy ^[94][96][192,194].

Furthermore, lycopene, α-carotene, and β-cryptoxanthin were also found to be associated with a significant reduction in the incidence of oral and pharyngeal cancer ^[98][196].

Lutein, by lowering the very-low-density lipoprotein (VLDL) and the intermediate density lipoprotein (IDL) levels, has been associated with a lower incidence of skin cancer ^[99][197]. In several long-term, large-cohort studies on the effect of the beta-carotene supplementation on the chemoprevention of skin cancer (basal cell carcinoma or squamous cell carcinoma), no significant evidence has been found ^{[100][101][102]}[198,199,200].

In 1999, Green et al.’s study of 621 residents of Nambour, a township in southeast Queensland, analyzed skin cancer chemoprevention with daily sunscreen application and beta-carotene supplementation. An evaluation of the effect of beta-carotene supplementation was based on skin cancer occurring on any part of the body. After 4.5 years of follow-up, there was no difference in the incidence of basal-cell carcinoma in the beta-carotene and placebo groups. The incidence of SCC was slightly but not significantly higher in the beta-carotene group than in the placebo group ^[103][201].

A study by Heinen et al. was a further follow-up from 1996 until the end of 2004 of randomly selected Nambour Skin Cancer Study participants. The 8-year prospective study was evaluating all occurrences of BCC and SCC among the 1027 participants according to their dietary beta-carotene intake measured via a self-administered, semi-quantitative food frequency questionnaire consisting of 129 food or food group items. The BCC tumor risk was found to be double in persons with intake levels in the second tertile for β-carotene (multivariable adjusted RR = 2.2, 95% CI: 1.2–4.1). In the 191 participants with a history of BCC, the cancer risk was found to be equally as high (multivariable adjusted second tertile estimates for β-carotene: RR = 1.9, 95% CI: 0.97–3.6, P for trend = 0.75, and vitamin E: RR = 2.4, 95% CI: 1.3–4.7, P for trend = 0.20) ^[99][197].

In the clinical trial ‘Correlation Between Skin Carotenoid Levels and Previous History of Skin Cancer’, Alexandra Kimball from Massachusetts General Hospital investigated the skin beta-carotenoid levels in relation to the skin cancer status in groups with a history of BCC or SCC and a control group without a skin cancer history. No difference in the mean carotenoid levels between subjects in the investigation groups and control subjects was found ^[104][202].