Exploring the Contribution of Curcumin to Cancer Therapy: A Systematic Review of Randomized Controlled Trials

Although the anticancer role of curcumin has been extensively addressed in preclinical research, only a few studies were carried out in humans, with conflicting results. The aim of this systematic review is to collate together the results of the therapeutic effect of curcumin in cancer patients. A literature search was carried out in Pubmed, Scopus, and the Cochrane Central Register of Controlled Trials up to 29 January 2023. Only randomized controlled trials (RCTs) designed to evaluate the effects of curcumin on cancer progression, patient survival, or surgical/histological response were included. Seven out of 114 articles, published between 2016 and 2022, were analyzed. They evaluated patients with locally advanced and/or metastatic prostate, colorectal, and breast cancers, as well as multiple myeloma and oral leucoplakia. Curcumin was given as an add-on therapy in five studies. Cancer response was the most investigated primary endpoint and curcumin issued some positive results. On the contrary, curcumin was ineffective in improving overall or progression-free survival. The curcumin safety profile was favorable. In conclusion, available clinical evidence is not strong enough to support the therapeutic use of curcumin in cancer. New RCTs exploring the effects of different curcumin formulations in early-stage cancers would be welcome.


Introduction
Curcumin (1,7-bis[4-hydroxy 3-methoxy phenyl]-1,6-heptadiene-3,5-dione) is a polyphenol extracted from the rhizome of Curcuma longa Linn (family Zingiberaceae). It is commonly known as turmeric and is extensively used in the Asian continent to make food colored and flavored [1,2]. In addition to culinary use, traditional Indian medicine considers turmeric an effective remedy in the treatment of several diseases [2][3][4]. Together with curcumin, which is the most abundant polyphenol (~77%), the rhizome of Curcuma longa also contains other phenol-based compounds called curcuminoids, the most important being desmethoxycurcumin (~15%) and bisdemethoxycurcumin (~3%) [3,4]. Considering that curcumin prevails over the other congeners, most of the preclinical literature in this field has explored the effects of the pure compound in several experimental systems, whereas only a few papers have studied the biological properties of curcuminoids [5][6][7][8][9]. Unlike preclinical research, which suggested a beneficial role for curcumin in neurodegenerative, cardiovascular, hematological, and infectious diseases, only a few studies have been carried out to confirm these therapeutic effects in humans [10][11][12]. A plausible reason for this underestimation is that curcumin has unfavorable pharmacokinetics, characterized by poor bioavailability after oral administration and negligible plasma and tissue levels [2]. Therefore, with the purpose to improve absorption, distribution, and tissue accumulation, novel oral formulations of curcumin have been prepared, including either an extract enriched with curcuminoids and sesquiterpenoid components of turmeric (BCM-95 CG) or complexes with liposoluble vehicles, such as phospholipids or nanoparticles (Table 1). A careful analysis of Table 1 shows that either the presence of sesquiterpenoids (45% Ar-turmerone) or the complexation with phospholipids (~40% soy lecithin and~40% microcrystalline cellulose) and nanoparticles (containing 46% glycerin, 4% gum ghatti, and 38% water) markedly increases the curcumin peak plasma concentration (C max ), suggesting a more effective absorption of the active ingredient. Simultaneously, the increase in the area under the curve (AUC 0-24h ) demonstrates how the presence of either sesquiterpenoids or nanoparticles is capable of improving the bioavailability of curcumin. Lastly, the increase in half-life (T 1/2 ) implies an extension of the time of persistence of curcumin in the body and, therefore, a more prolonged pharmacological action. The composition of these formulations is provided in Table 1.  [17] a 73-80% curcumin, 20-27% demethoxycurcumin, and bisdemethoxycurcumin. b 95% curcuminoid complex (~95% curcumin; the remainder is demethoxycurcumin and bisdemethoxycurcumin) combined with turmeric essential oil enriched to sesquiterpenoids (see text). c 18-22% curcuminoids (curcumin, demethoxycurcumin, and bisdemethoxycurcumin in their natural ratios), phospholipids, and other compounds (see text). d 10% curcumin, 2% demethoxycurcumin and bisdemethoxycurcumin, and 88% other compounds (see text). e Dose: 4 g/day for 7 days. f Dose: 2 g/day, single dose. g Dose: 2 g/day for 7 days. h Dose: 150 mg, single dose. i Dose: 210 mg, single dose. AUC, area under the curve; C max : peak plasma concentration; NP, nanoparticles; PC, phosphatidylcholine; T 1/2 , half-life; T max , time to reach the peak plasma concentration.
With regard to pharmacodynamics, preclinical studies have shown that curcumin reduces free radical-or copper-induced lipid peroxidation in several experimental systems [18,19]. Furthermore, structure activity studies demonstrated the importance of the β-diketone moiety and phenolic hydroxyl group for cytoprotective activity [18,19]. Together with this direct antioxidant effect, curcumin has been shown to regulate several intracellular systems, such as the transcription factors nuclear factor kB (NFkB) and vascular endothelial growth factor (VEGF), the kinases phosphoinositide-3 kinase/Akt (PI3K/Akt) and cyclindependent kinase (cdk), the proinflammatory interleukins (IL) IL-1β, IL-6, and IL-23, and many other proteins involved in apoptosis (Bax and Bcl-2) and cell stress response (heme oxygenase-1 and heat shock-protein-70) [3,11,20,21]. This wide array of interactions, in particular those with genes/proteins involved in cell proliferation/survival and angiogenesis, prompted investigators to explore the therapeutic role of curcumin in cancer. In this context, thousands of articles demonstrated that curcumin, alone or in combination with chemotherapeutic agents, is able to counteract cell proliferation, invasion, and metastatic potential through the regulation of specific targets or epigenetic mechanisms [20,21]. Unfortunately, the vast majority of these studies were carried out on laboratory animals or cell lines, using curcumin at concentrations several orders of magnitude greater than those achieved in human plasma and tissues, thus limiting the translational interest of these studies. Conversely, only a handful of clinical trials investigated the anticancer effects of curcumin, and only a fraction of these studies were focused on its impact on cancer progression and/or patient survival, with conflicting results. Nevertheless, the interest of the scientific community in the efficacy of this nutraceutical in cancer is still alive thanks to clinical evidence that corroborates the beneficial role of curcumin in improving the quality of life of cancer patients and preventing radiotherapy-induced adverse effects. In this regard, several systematic reviews and meta-analyses, supporting the beneficial role of curcumin in counteracting radiation-induced mucositis or skin lesions, are available in the literature [22][23][24][25].
In this context, the aim of this paper is to provide a systematic review of the articles that assessed the therapeutic effects of curcumin in cancer patients. With the purpose of providing an original contribution to the field, this analysis has been narrowed to randomized controlled trials (RCTs) in which hard endpoints were evaluated. In particular, the attention was focused on RCTs designed to evaluate the effects of curcumin, alone or as an add-on therapy, on cancer progression, patient survival, or surgical/histological response.

Materials and Methods
This systematic review was conducted and reported according to the preferred reporting items for systematic reviews and meta-analyses (PRISMA) [26].

Study Selection
A two-step approach was used to select eligible articles after the removal of duplicate publications. First, articles were screened based on titles and abstracts, and then full texts of potential eligible papers were obtained and checked for final inclusion. For each potentially included study, two investigators independently conducted the selection and data abstraction. Disagreements were resolved by discussion or consultation with a third author. Articles were considered eligible if they reported the results of RCTs with parallel arm design and aimed to explore the use of curcumin-alone or as an add-on to other anticancer therapies-in any dosage and formulation in patients with any cancer in improving the clinical response, in terms of the following hard endpoints, studied as either primary or secondary outcomes: overall survival (OS), progression-free survival (PFS), objective response, time to tumor progression (TTP), and duration of off treatment. The following studies were excluded: single-arm or open-label RCTs, including those designed to address the pharmacokinetics of curcumin; RCTs whose outcomes were assessed through soft endpoints or related to local effects of curcumin on mucositis, radiodermatitis and other skin lesions; RCTs analyzing the effects of curcumin in combination with other nutraceuticals (e.g., piperine to improve bioavailability or resveratrol to increase the cytoprotective effect); study protocols, conference abstracts, and reviews; and publications describing the therapeutic effects of curcumin on diseases different than cancer.

Quality Assessment
The quality of included RCTs was assessed by the Cochrane Risk of Bias Tool (RoB-Tool 2) [27] by two researchers independently, and any disagreement was solved with the involvement of a third researcher. The RoB-Tool 2 allows issuing a judgment on the risk of bias (low, some concerns, high) with respect to the following domains: randomization process, deviations from intended interventions, missing outcome data, measurement of the outcome, and selection of the reported results. The overall risk of bias is then considered low, if all domains are judged to be at a low risk, or high, if at least one domain is judged to be at a high risk of bias or multiple domains are judged to have some concerns in a way that substantially lowers the confidence of the results. The results of the quality assessment were reported in a descriptive way.

Data Extraction and Synthesis
A data extraction form was used to gather information on the following aspects: first author's last name, year of publication, country, trial design and duration, study population characteristics (type and stage of cancer, previous treatment, gender, age), number of participants in the experimental and control arms, type of intervention (dosage and formulation of curcumin), type of control, and study endpoints and their results. This information was collected by one researcher and checked by a second one. A narrative synthesis of the results was planned in the light of expected heterogeneity in terms of cancer patients, curcumin dosage and formulation, and time of the assessment of the study endpoints.

Study Search and Selection
As shown in Figure 1, the literature search yielded 160 records. After removing duplicates (n = 46), 114 articles underwent screening based on title and abstract. Among these, 58 articles were excluded based on the criteria reported in the Section 2, leaving 56 articles whose full text was searched. Unfortunately, the full text of 11 articles was not found and only 45 articles underwent further analysis. Finally, based on the exclusion criteria, seven studies were selected and analyzed [28][29][30][31][32][33][34]. of bias (low, some concerns, high) with respect to the following domains: randomization process, deviations from intended interventions, missing outcome data, measurement of the outcome, and selection of the reported results. The overall risk of bias is then considered low, if all domains are judged to be at a low risk, or high, if at least one domain is judged to be at a high risk of bias or multiple domains are judged to have some concerns in a way that substantially lowers the confidence of the results. The results of the quality assessment were reported in a descriptive way.

Data Extraction and Synthesis
A data extraction form was used to gather information on the following aspects: first author's last name, year of publication, country, trial design and duration, study population characteristics (type and stage of cancer, previous treatment, gender, age), number of participants in the experimental and control arms, type of intervention (dosage and formulation of curcumin), type of control, and study endpoints and their results. This information was collected by one researcher and checked by a second one. A narrative synthesis of the results was planned in the light of expected heterogeneity in terms of cancer patients, curcumin dosage and formulation, and time of the assessment of the study endpoints.

Study Search and Selection
As shown in Figure 1, the literature search yielded 160 records. After removing duplicates (n = 46), 114 articles underwent screening based on title and abstract. Among these, 58 articles were excluded based on the criteria reported in the Section 2, leaving 56 articles whose full text was searched. Unfortunately, the full text of 11 articles was not found and only 45 articles underwent further analysis. Finally, based on the exclusion criteria, seven studies were selected and analyzed [28][29][30][31][32][33][34].

Discussion
The results summarized in this systematic review, unfortunately, are n enough to support the therapeutic use of curcumin, either as monotherapy on to other standard antineoplastic drugs in patients with solid tumors (loca or metastatic colorectal cancer, advanced metastatic breast cancer, metast cancer, and oral leukoplakia) or hematologic malignancies (multiple myelom tors may explain these inconclusive results, including the low number of cli the small number of subjects enrolled, the formulation and route of administ cumin, and the stage of the tumors studied (Table 2).
Among the seven RCTs analyzed, two studies were stopped early by the because of the lack of any effect due to the small sample size, and one stu pleted, although the researchers were aware that the number of patients lower than that calculated in the protocol description [28,30,32,35]. Therefo RCTs recruited the number of patients expected to achieve adequate stat [29,31,33,34]. Three out of these four RCTs were judged to have a low risk of [31,33,34]. Furthermore, some RCTs had several dropouts that further reduce of patients analyzed and the results obtained [29,[31][32][33]. For these reasons, t results discussed below could be originally flawed by an inappropriate exp sign and under-sizing.
The heterogeneity of the curcumin formulations was another relevant out of the seven RCTs analyzed, curcumin was given as the C3 complex [2 others, curcumin was administered as the high bioavailable formulation [29,34], and three studies did not provide any detail on the curcumin form [30,31,33]. The large dose range (the highest was 8 g/day for 6 weeks and th 1.44 g/day for 6 months) and erratic pharmacokinetic profile (Table 1) Table 3. Quality assessment and risk of bias in the analyzed RCTs.

Discussion
The results summarized in this systematic review, unfortun enough to support the therapeutic use of curcumin, either as mon on to other standard antineoplastic drugs in patients with solid tu or metastatic colorectal cancer, advanced metastatic breast canc cancer, and oral leukoplakia) or hematologic malignancies (multip tors may explain these inconclusive results, including the low nu the small number of subjects enrolled, the formulation and route o cumin, and the stage of the tumors studied (Table 2).
Among the seven RCTs analyzed, two studies were stopped e because of the lack of any effect due to the small sample size, a pleted, although the researchers were aware that the number o lower than that calculated in the protocol description [28,30,32,3 RCTs recruited the number of patients expected to achieve ade [29,31,33,34]. Three out of these four RCTs were judged to have a l [31,33,34]. Furthermore, some RCTs had several dropouts that furt of patients analyzed and the results obtained [29,[31][32][33]. For these results discussed below could be originally flawed by an inappro sign and under-sizing.
The heterogeneity of the curcumin formulations was anothe out of the seven RCTs analyzed, curcumin was given as the C3 others, curcumin was administered as the high bioavailable fo [29,34], and three studies did not provide any detail on the curc [30,31,33]. The large dose range (the highest was 8 g/day for 6 we 1.44 g/day for 6 months) and erratic pharmacokinetic profile (Tab cult to compare the efficacy of these formulations. It is probably only studies showing the beneficial effect of curcumin on cance  Gunther et al. [28] Santosa et al. [29] Passildas-Jahanmohan et al. [30] Saghatelyan et al. [31] Howells et al. [32] Choi et al. [33] Kuriakose et al. [34] Domain (D) D1, randomization process; D2, deviations from outcome data; D4, measurement of the outcome; D5, selecti evaluation (for further information, see the Section 2). Red cir yellow circles: some concerns.

Discussion
The results summarized in this systematic review enough to support the therapeutic use of curcumin, eit on to other standard antineoplastic drugs in patients w or metastatic colorectal cancer, advanced metastatic b cancer, and oral leukoplakia) or hematologic malignanc tors may explain these inconclusive results, including t the small number of subjects enrolled, the formulation a cumin, and the stage of the tumors studied (Table 2).
Among the seven RCTs analyzed, two studies were because of the lack of any effect due to the small sam pleted, although the researchers were aware that the lower than that calculated in the protocol description RCTs recruited the number of patients expected to a [29,31,33,34]. Three out of these four RCTs were judged [31,33,34]. Furthermore, some RCTs had several dropou of patients analyzed and the results obtained [29,[31][32][33] results discussed below could be originally flawed by a sign and under-sizing.
The heterogeneity of the curcumin formulations w out of the seven RCTs analyzed, curcumin was given others, curcumin was administered as the high bioa [29,34], and three studies did not provide any detail o [30,31,33]. The large dose range (the highest was 8 g/da 1.44 g/day for 6 months) and erratic pharmacokinetic p cult to compare the efficacy of these formulations. It is only studies showing the beneficial effect of curcumin  Gunther et al. [28] Santosa et al. [29] Passildas-Jahanmohan et al. [30] Saghatelyan et al. [31] Howells et al. [32] Choi et al. [33] Kuriakose et al. [34] Domain (D) D1, randomization process; D2, dev outcome data; D4, measurement of the outcome; evaluation (for further information, see the Sectio yellow circles: some concerns.

Discussion
The results summarized in this systema enough to support the therapeutic use of cur on to other standard antineoplastic drugs in or metastatic colorectal cancer, advanced m cancer, and oral leukoplakia) or hematologic tors may explain these inconclusive results, i the small number of subjects enrolled, the for cumin, and the stage of the tumors studied (T Among the seven RCTs analyzed, two stu because of the lack of any effect due to the pleted, although the researchers were awar lower than that calculated in the protocol de RCTs recruited the number of patients exp [29,31,33,34]. Three out of these four RCTs we [31,33,34]. Furthermore, some RCTs had sever of patients analyzed and the results obtained results discussed below could be originally fl sign and under-sizing.
The heterogeneity of the curcumin form out of the seven RCTs analyzed, curcumin w others, curcumin was administered as the [29,34], and three studies did not provide an [30,31,33]. The large dose range (the highest 1.44 g/day for 6 months) and erratic pharma cult to compare the efficacy of these formula only studies showing the beneficial effect of  Gunther et al. [28] Santosa et al. [29] Passildas-Jahanmohan et al. [30] Saghatelyan et al. [31] Howells et al. [32] Choi et al. [33] Kuriakose et al. [34] Domain (D) D1, randomization proce outcome data; D4, measurement of th evaluation (for further information, se yellow circles: some concerns.

Discussion
The results summarized in th enough to support the therapeutic on to other standard antineoplastic or metastatic colorectal cancer, ad cancer, and oral leukoplakia) or hem tors may explain these inconclusiv the small number of subjects enroll cumin, and the stage of the tumors Among the seven RCTs analyz because of the lack of any effect d pleted, although the researchers w lower than that calculated in the p RCTs recruited the number of pa [29,31,33,34]. Three out of these fou [31,33,34]. Furthermore, some RCT of patients analyzed and the result results discussed below could be o sign and under-sizing.
The heterogeneity of the curc out of the seven RCTs analyzed, c others, curcumin was administer [29,34], and three studies did not [30,31,33]. The large dose range (th 1.44 g/day for 6 months) and errat cult to compare the efficacy of the only studies showing the benefici

Discussion
The results summa enough to support the th on to other standard ant or metastatic colorectal cancer, and oral leukopla tors may explain these in the small number of sub cumin, and the stage of t Among the seven R because of the lack of a pleted, although the res lower than that calculat RCTs recruited the num [29,31,33,34]. Three out o [31,33,34]. Furthermore, of patients analyzed and results discussed below sign and under-sizing.
The heterogeneity o out of the seven RCTs a others, curcumin was a [29,34], and three studie [30,31,33]. The large dos 1.44 g/day for 6 months) cult to compare the effic only studies showing th Santosa et al. [29] Pharmaceutics 2023, 15, x FOR PEER REVIEW Table 3. Quality assessment and risk of bias in the analyzed RCTs.

Discussion
The results summarized in this systematic review, unfortunately, are n enough to support the therapeutic use of curcumin, either as monotherapy on to other standard antineoplastic drugs in patients with solid tumors (loca or metastatic colorectal cancer, advanced metastatic breast cancer, metast cancer, and oral leukoplakia) or hematologic malignancies (multiple myelom tors may explain these inconclusive results, including the low number of cli the small number of subjects enrolled, the formulation and route of administ cumin, and the stage of the tumors studied (Table 2).
Among the seven RCTs analyzed, two studies were stopped early by the because of the lack of any effect due to the small sample size, and one stu pleted, although the researchers were aware that the number of patients lower than that calculated in the protocol description [28,30,32,35]. Therefo RCTs recruited the number of patients expected to achieve adequate stat [29,31,33,34]. Three out of these four RCTs were judged to have a low risk of [31,33,34]. Furthermore, some RCTs had several dropouts that further reduce of patients analyzed and the results obtained [29,[31][32][33]. For these reasons, t results discussed below could be originally flawed by an inappropriate exp sign and under-sizing.
The heterogeneity of the curcumin formulations was another relevant out of the seven RCTs analyzed, curcumin was given as the C3 complex [2 others, curcumin was administered as the high bioavailable formulation [29,34], and three studies did not provide any detail on the curcumin form [30,31,33]. The large dose range (the highest was 8 g/day for 6 weeks and th 1.44 g/day for 6 months) and erratic pharmacokinetic profile (Table 1)   Gunther et al. [28] Santosa et al. [29] Passildas-Jahanmohan et al. [30] Saghatelyan et al. [31] Howells et al. [32] Choi et al. [33] Kuriakose et al. [34] Domain (D) D1, randomization process; D2, deviations from intended interventions; D outcome data; D4, measurement of the outcome; D5, selection of the reported results evaluation (for further information, see the Section 2). Red circles: high risk; green circle yellow circles: some concerns.

Discussion
The results summarized in this systematic review, unfortunately, are not enough to support the therapeutic use of curcumin, either as monotherapy or a on to other standard antineoplastic drugs in patients with solid tumors (locally or metastatic colorectal cancer, advanced metastatic breast cancer, metastatic cancer, and oral leukoplakia) or hematologic malignancies (multiple myeloma). tors may explain these inconclusive results, including the low number of clinic the small number of subjects enrolled, the formulation and route of administrat cumin, and the stage of the tumors studied (Table 2).
Among the seven RCTs analyzed, two studies were stopped early by the inv because of the lack of any effect due to the small sample size, and one study pleted, although the researchers were aware that the number of patients enr lower than that calculated in the protocol description [28,30,32,35]. Therefore, RCTs recruited the number of patients expected to achieve adequate statisti [29,31,33,34]. Three out of these four RCTs were judged to have a low risk of bia [31,33,34]. Furthermore, some RCTs had several dropouts that further reduced th of patients analyzed and the results obtained [29,[31][32][33]. For these reasons, the c results discussed below could be originally flawed by an inappropriate experim sign and under-sizing.
The heterogeneity of the curcumin formulations was another relevant fact out of the seven RCTs analyzed, curcumin was given as the C3 complex [28,3 others, curcumin was administered as the high bioavailable formulation BC [29,34], and three studies did not provide any detail on the curcumin formula [30,31,33]. The large dose range (the highest was 8 g/day for 6 weeks and the lo 1.44 g/day for 6 months) and erratic pharmacokinetic profile (  Gunther et al. [28] Santosa et al. [29] Passildas-Jahanmohan et al. [30] Saghatelyan et al. [31] Howells et al. [32] Choi et al. [33] Kuriakose et al. [34] Domain (D) D1, randomization process; D2, deviations from outcome data; D4, measurement of the outcome; D5, selecti evaluation (for further information, see the Section 2). Red cir yellow circles: some concerns.

Discussion
The results summarized in this systematic review enough to support the therapeutic use of curcumin, eit on to other standard antineoplastic drugs in patients w or metastatic colorectal cancer, advanced metastatic b cancer, and oral leukoplakia) or hematologic malignanc tors may explain these inconclusive results, including t the small number of subjects enrolled, the formulation a cumin, and the stage of the tumors studied (Table 2).
Among the seven RCTs analyzed, two studies were because of the lack of any effect due to the small sam pleted, although the researchers were aware that the lower than that calculated in the protocol description RCTs recruited the number of patients expected to a [29,31,33,34]. Three out of these four RCTs were judged [31,33,34]. Furthermore, some RCTs had several dropou of patients analyzed and the results obtained [29,[31][32][33] results discussed below could be originally flawed by a sign and under-sizing.
The heterogeneity of the curcumin formulations w out of the seven RCTs analyzed, curcumin was given others, curcumin was administered as the high bioa [29,34], and three studies did not provide any detail o [30,31,33]. The large dose range (the highest was 8 g/da 1.44 g/day for 6 months) and erratic pharmacokinetic p cult to compare the efficacy of these formulations. It is only studies showing the beneficial effect of curcumin  Gunther et al. [28] Santosa et al. [29] Passildas-Jahanmohan et al. [30] Saghatelyan et al. [31] Howells et al. [32] Choi et al. [33] Kuriakose et al. [34] Domain (D) D1, randomization process; D2, dev outcome data; D4, measurement of the outcome; evaluation (for further information, see the Sectio yellow circles: some concerns.

Discussion
The results summarized in this systema enough to support the therapeutic use of cur on to other standard antineoplastic drugs in or metastatic colorectal cancer, advanced m cancer, and oral leukoplakia) or hematologic tors may explain these inconclusive results, i the small number of subjects enrolled, the for cumin, and the stage of the tumors studied (T Among the seven RCTs analyzed, two stu because of the lack of any effect due to the pleted, although the researchers were awar lower than that calculated in the protocol de RCTs recruited the number of patients exp [29,31,33,34]. Three out of these four RCTs we [31,33,34]. Furthermore, some RCTs had sever of patients analyzed and the results obtained results discussed below could be originally fl sign and under-sizing.
The heterogeneity of the curcumin form out of the seven RCTs analyzed, curcumin w others, curcumin was administered as the [29,34], and three studies did not provide an [30,31,33]. The large dose range (the highest 1.44 g/day for 6 months) and erratic pharma cult to compare the efficacy of these formula only studies showing the beneficial effect of  Gunther et al. [28] Santosa et al. [29] Passildas-Jahanmohan et al. [30] Saghatelyan et al. [31] Howells et al. [32] Choi et al. [33] Kuriakose et al. [34] Domain (D) D1, randomization proce outcome data; D4, measurement of th evaluation (for further information, se yellow circles: some concerns.

Discussion
The results summarized in th enough to support the therapeutic on to other standard antineoplastic or metastatic colorectal cancer, ad cancer, and oral leukoplakia) or hem tors may explain these inconclusiv the small number of subjects enroll cumin, and the stage of the tumors Among the seven RCTs analyz because of the lack of any effect d pleted, although the researchers w lower than that calculated in the p RCTs recruited the number of pa [29,31,33,34]. Three out of these fou [31,33,34]. Furthermore, some RCT of patients analyzed and the result results discussed below could be o sign and under-sizing.

Discussion
The results summarized in this s enough to support the therapeutic use on to other standard antineoplastic dr or metastatic colorectal cancer, advan cancer, and oral leukoplakia) or hemat tors may explain these inconclusive re the small number of subjects enrolled, cumin, and the stage of the tumors stu Among the seven RCTs analyzed, because of the lack of any effect due pleted, although the researchers wer lower than that calculated in the prot RCTs recruited the number of patien [29,31,33,34]. Three out of these four R [31,33,34]. Furthermore, some RCTs ha of patients analyzed and the results ob results discussed below could be orig sign and under-sizing.
The heterogeneity of the curcum out of the seven RCTs analyzed, curc others, curcumin was administered [29,34], and three studies did not pro [30,31,33]. The large dose range (the h 1.44 g/day for 6 months) and erratic p cult to compare the efficacy of these f only studies showing the beneficial e Passildas-Jahanmohan et al. [30] Pharmaceutics 2023, 15, x FOR PEER REVIEW Table 3. Quality assessment and risk of bias in the analyzed RCTs.

Discussion
The results summarized in this systematic review, unfortunately, are n enough to support the therapeutic use of curcumin, either as monotherapy on to other standard antineoplastic drugs in patients with solid tumors (loca or metastatic colorectal cancer, advanced metastatic breast cancer, metast cancer, and oral leukoplakia) or hematologic malignancies (multiple myelom tors may explain these inconclusive results, including the low number of cli the small number of subjects enrolled, the formulation and route of administ cumin, and the stage of the tumors studied (Table 2).
Among the seven RCTs analyzed, two studies were stopped early by the because of the lack of any effect due to the small sample size, and one stu pleted, although the researchers were aware that the number of patients lower than that calculated in the protocol description [28,30,32,35]. Therefo RCTs recruited the number of patients expected to achieve adequate stat [29,31,33,34]. Three out of these four RCTs were judged to have a low risk of [31,33,34]. Furthermore, some RCTs had several dropouts that further reduce of patients analyzed and the results obtained [29,[31][32][33]. For these reasons, t results discussed below could be originally flawed by an inappropriate exp sign and under-sizing.
The heterogeneity of the curcumin formulations was another relevant out of the seven RCTs analyzed, curcumin was given as the C3 complex [2 others, curcumin was administered as the high bioavailable formulation [29,34], and three studies did not provide any detail on the curcumin form [30,31,33]. The large dose range (the highest was 8 g/day for 6 weeks and th 1.44 g/day for 6 months) and erratic pharmacokinetic profile (  Gunther et al. [28] Santosa et al. [29] Passildas-Jahanmohan et al. [30] Saghatelyan et al. [31] Howells et al. [32] Choi et al. [33] Kuriakose et al. [34] Domain (D) D1, randomization process; D2, deviations from intended interventions; D outcome data; D4, measurement of the outcome; D5, selection of the reported results evaluation (for further information, see the Section 2). Red circles: high risk; green circle yellow circles: some concerns.

Discussion
The results summarized in this systematic review, unfortunately, are not enough to support the therapeutic use of curcumin, either as monotherapy or a on to other standard antineoplastic drugs in patients with solid tumors (locally or metastatic colorectal cancer, advanced metastatic breast cancer, metastatic cancer, and oral leukoplakia) or hematologic malignancies (multiple myeloma). tors may explain these inconclusive results, including the low number of clinic the small number of subjects enrolled, the formulation and route of administrat cumin, and the stage of the tumors studied (Table 2).
Among the seven RCTs analyzed, two studies were stopped early by the inv because of the lack of any effect due to the small sample size, and one study pleted, although the researchers were aware that the number of patients enr lower than that calculated in the protocol description [28,30,32,35]. Therefore, RCTs recruited the number of patients expected to achieve adequate statisti [29,31,33,34]. Three out of these four RCTs were judged to have a low risk of bia [31,33,34]. Furthermore, some RCTs had several dropouts that further reduced th of patients analyzed and the results obtained [29,[31][32][33]. For these reasons, the c results discussed below could be originally flawed by an inappropriate experim sign and under-sizing.
The heterogeneity of the curcumin formulations was another relevant fact out of the seven RCTs analyzed, curcumin was given as the C3 complex [28,3 others, curcumin was administered as the high bioavailable formulation BC [29,34], and three studies did not provide any detail on the curcumin formula [30,31,33]. The large dose range (the highest was 8 g/day for 6 weeks and the lo 1.44 g/day for 6 months) and erratic pharmacokinetic profile (  Gunther et al. [28] Santosa et al. [29] Passildas-Jahanmohan et al. [30] Saghatelyan et al. [31] Howells et al. [32] Choi et al. [33] Kuriakose et al. [34] Domain (D) D1, randomization process; D2, deviations from outcome data; D4, measurement of the outcome; D5, selecti evaluation (for further information, see the Section 2). Red cir yellow circles: some concerns.

Discussion
The results summarized in this systematic review enough to support the therapeutic use of curcumin, eit on to other standard antineoplastic drugs in patients w or metastatic colorectal cancer, advanced metastatic b cancer, and oral leukoplakia) or hematologic malignanc tors may explain these inconclusive results, including t the small number of subjects enrolled, the formulation a cumin, and the stage of the tumors studied (Table 2).
Among the seven RCTs analyzed, two studies were because of the lack of any effect due to the small sam pleted, although the researchers were aware that the lower than that calculated in the protocol description RCTs recruited the number of patients expected to a [29,31,33,34]. Three out of these four RCTs were judged [31,33,34]. Furthermore, some RCTs had several dropou of patients analyzed and the results obtained [29,[31][32][33] results discussed below could be originally flawed by a sign and under-sizing.
The heterogeneity of the curcumin formulations w out of the seven RCTs analyzed, curcumin was given others, curcumin was administered as the high bioa [29,34], and three studies did not provide any detail o [30,31,33]. The large dose range (the highest was 8 g/da 1.44 g/day for 6 months) and erratic pharmacokinetic p cult to compare the efficacy of these formulations. It is only studies showing the beneficial effect of curcumin  Gunther et al. [28] Santosa et al. [29] Passildas-Jahanmohan et al. [30] Saghatelyan et al. [31] Howells et al. [32] Choi et al. [33] Kuriakose et al. [34] Domain (D) D1, randomization process; D2, dev outcome data; D4, measurement of the outcome; evaluation (for further information, see the Sectio yellow circles: some concerns.

Discussion
The results summarized in this systema enough to support the therapeutic use of cur on to other standard antineoplastic drugs in or metastatic colorectal cancer, advanced m cancer, and oral leukoplakia) or hematologic tors may explain these inconclusive results, i the small number of subjects enrolled, the for cumin, and the stage of the tumors studied (T Among the seven RCTs analyzed, two stu because of the lack of any effect due to the pleted, although the researchers were awar lower than that calculated in the protocol de RCTs recruited the number of patients exp [29,31,33,34]. Three out of these four RCTs we [31,33,34]. Furthermore, some RCTs had sever of patients analyzed and the results obtained results discussed below could be originally fl sign and under-sizing.
The heterogeneity of the curcumin form out of the seven RCTs analyzed, curcumin w others, curcumin was administered as the [29,34], and three studies did not provide an [30,31,33]. The large dose range (the highest 1.44 g/day for 6 months) and erratic pharma cult to compare the efficacy of these formula only studies showing the beneficial effect of  Gunther et al. [28] Santosa et al. [29] Passildas-Jahanmohan et al. [30] Saghatelyan et al. [31] Howells et al. [32] Choi et al. [33] Kuriakose et al. [34] Domain (D) D1, randomization proce outcome data; D4, measurement of th evaluation (for further information, se yellow circles: some concerns.

Discussion
The results summarized in th enough to support the therapeutic on to other standard antineoplastic or metastatic colorectal cancer, ad cancer, and oral leukoplakia) or hem tors may explain these inconclusiv the small number of subjects enroll cumin, and the stage of the tumors Among the seven RCTs analyz because of the lack of any effect d pleted, although the researchers w lower than that calculated in the p RCTs recruited the number of pa [29,31,33,34]. Three out of these fou [31,33,34]. Furthermore, some RCT of patients analyzed and the result results discussed below could be o sign and under-sizing.

Discussion
The results summarized in this s enough to support the therapeutic use on to other standard antineoplastic dr or metastatic colorectal cancer, advan cancer, and oral leukoplakia) or hemat tors may explain these inconclusive re the small number of subjects enrolled, cumin, and the stage of the tumors stu Among the seven RCTs analyzed, because of the lack of any effect due pleted, although the researchers wer lower than that calculated in the prot RCTs recruited the number of patien [29,31,33,34]. Three out of these four R [31,33,34]. Furthermore, some RCTs ha of patients analyzed and the results ob results discussed below could be orig sign and under-sizing.
The heterogeneity of the curcum out of the seven RCTs analyzed, curc others, curcumin was administered [29,34], and three studies did not pro [30,31,33]. The large dose range (the h 1.44 g/day for 6 months) and erratic p cult to compare the efficacy of these f only studies showing the beneficial e Saghatelyan et al. [31] Pharmaceutics 2023, 15, x FOR PEER REVIEW Table 3. Quality assessment and risk of bias in the analyzed RCTs.

Discussion
The results summarized in this systematic review, unfortunately, are n enough to support the therapeutic use of curcumin, either as monotherapy on to other standard antineoplastic drugs in patients with solid tumors (loca or metastatic colorectal cancer, advanced metastatic breast cancer, metast cancer, and oral leukoplakia) or hematologic malignancies (multiple myelom tors may explain these inconclusive results, including the low number of cli the small number of subjects enrolled, the formulation and route of administ cumin, and the stage of the tumors studied (Table 2).
Among the seven RCTs analyzed, two studies were stopped early by the because of the lack of any effect due to the small sample size, and one stu pleted, although the researchers were aware that the number of patients lower than that calculated in the protocol description [28,30,32,35]. Therefo RCTs recruited the number of patients expected to achieve adequate stat [29,31,33,34]. Three out of these four RCTs were judged to have a low risk of [31,33,34]. Furthermore, some RCTs had several dropouts that further reduce of patients analyzed and the results obtained [29,[31][32][33]. For these reasons, t results discussed below could be originally flawed by an inappropriate exp sign and under-sizing.
The heterogeneity of the curcumin formulations was another relevant out of the seven RCTs analyzed, curcumin was given as the C3 complex [2 others, curcumin was administered as the high bioavailable formulation [29,34], and three studies did not provide any detail on the curcumin form [30,31,33]. The large dose range (the highest was 8 g/day for 6 weeks and th 1.44 g/day for 6 months) and erratic pharmacokinetic profile (Table 1) have cult to compare the efficacy of these formulations. It is probably no coincid  Table 3. Quality assessment and risk of bias in the analyzed RCTs.

Discussion
The results summarized in this systematic review, unfortun enough to support the therapeutic use of curcumin, either as mon on to other standard antineoplastic drugs in patients with solid tu or metastatic colorectal cancer, advanced metastatic breast canc cancer, and oral leukoplakia) or hematologic malignancies (multip tors may explain these inconclusive results, including the low nu the small number of subjects enrolled, the formulation and route o cumin, and the stage of the tumors studied (Table 2).
Among the seven RCTs analyzed, two studies were stopped e because of the lack of any effect due to the small sample size, a pleted, although the researchers were aware that the number o lower than that calculated in the protocol description [28,30,32,3 RCTs recruited the number of patients expected to achieve ade [29,31,33,34]. Three out of these four RCTs were judged to have a l [31,33,34]. Furthermore, some RCTs had several dropouts that furt of patients analyzed and the results obtained [29,[31][32][33]. For these results discussed below could be originally flawed by an inappro sign and under-sizing.
The heterogeneity of the curcumin formulations was anothe out of the seven RCTs analyzed, curcumin was given as the C3 others, curcumin was administered as the high bioavailable fo [29,34], and three studies did not provide any detail on the curc [30,31,33]. The large dose range (the highest was 8 g/day for 6 we 1.44 g/day for 6 months) and erratic pharmacokinetic profile (Tab cult to compare the efficacy of these formulations. It is probably  Gunther et al. [28] Santosa et al. [29] Passildas-Jahanmohan et al. [30] Saghatelyan et al. [31] Howells et al. [32] Choi et al. [33] Kuriakose et al. [34] Domain (D) D1, randomization process; D2, deviations from outcome data; D4, measurement of the outcome; D5, selecti evaluation (for further information, see the Section 2). Red cir yellow circles: some concerns.

Discussion
The results summarized in this systematic review enough to support the therapeutic use of curcumin, eit on to other standard antineoplastic drugs in patients w or metastatic colorectal cancer, advanced metastatic b cancer, and oral leukoplakia) or hematologic malignanc tors may explain these inconclusive results, including t the small number of subjects enrolled, the formulation a cumin, and the stage of the tumors studied (Table 2).
Among the seven RCTs analyzed, two studies were because of the lack of any effect due to the small sam pleted, although the researchers were aware that the lower than that calculated in the protocol description RCTs recruited the number of patients expected to a [29,31,33,34]. Three out of these four RCTs were judged [31,33,34]. Furthermore, some RCTs had several dropou of patients analyzed and the results obtained [29,[31][32][33] results discussed below could be originally flawed by a sign and under-sizing.
The heterogeneity of the curcumin formulations w out of the seven RCTs analyzed, curcumin was given others, curcumin was administered as the high bioa [29,34], and three studies did not provide any detail o [30,31,33]. The large dose range (the highest was 8 g/da 1.44 g/day for 6 months) and erratic pharmacokinetic p cult to compare the efficacy of these formulations. It is Pharmaceutics 2023, 15, x FOR PEER REVIEW Table 3. Quality assessment and risk of bias in the

Discussion
The results summarized in this systema enough to support the therapeutic use of cur on to other standard antineoplastic drugs in or metastatic colorectal cancer, advanced m cancer, and oral leukoplakia) or hematologic tors may explain these inconclusive results, i the small number of subjects enrolled, the for cumin, and the stage of the tumors studied (T Among the seven RCTs analyzed, two stu because of the lack of any effect due to the pleted, although the researchers were awar lower than that calculated in the protocol de RCTs recruited the number of patients exp [29,31,33,34]. Three out of these four RCTs we [31,33,34]. Furthermore, some RCTs had sever of patients analyzed and the results obtained results discussed below could be originally fl sign and under-sizing.

Discussion
The results summarized in th enough to support the therapeutic on to other standard antineoplastic or metastatic colorectal cancer, ad cancer, and oral leukoplakia) or hem tors may explain these inconclusiv the small number of subjects enroll cumin, and the stage of the tumors Among the seven RCTs analyz because of the lack of any effect d pleted, although the researchers w lower than that calculated in the p RCTs recruited the number of pa [29,31,33,34]. Three out of these fou [31,33,34]. Furthermore, some RCT of patients analyzed and the result results discussed below could be o sign and under-sizing.
The heterogeneity of the curc out of the seven RCTs analyzed, c others, curcumin was administer [29,34], and three studies did not [30,31,33]. The large dose range (th 1.44 g/day for 6 months) and errat cult to compare the efficacy of the  Table 3. Quality assessmen

Discussion
The results summa enough to support the th on to other standard ant or metastatic colorectal cancer, and oral leukopla tors may explain these in the small number of sub cumin, and the stage of t Among the seven R because of the lack of a pleted, although the res lower than that calculat RCTs recruited the num [29,31,33,34]. Three out o [31,33,34]. Furthermore, of patients analyzed and results discussed below sign and under-sizing.
The heterogeneity o out of the seven RCTs a others, curcumin was a [29,34], and three studie [30,31,33]. The large dos 1.44 g/day for 6 months) cult to compare the effic Howells et al. [32] Pharmaceutics 2023, 15, x FOR PEER REVIEW Table 3. Quality assessment and risk of bias in the analyzed RCTs.

Discussion
The results summarized in this systematic review, unfortunately, are n enough to support the therapeutic use of curcumin, either as monotherapy on to other standard antineoplastic drugs in patients with solid tumors (loca or metastatic colorectal cancer, advanced metastatic breast cancer, metast cancer, and oral leukoplakia) or hematologic malignancies (multiple myelom tors may explain these inconclusive results, including the low number of cl the small number of subjects enrolled, the formulation and route of adminis cumin, and the stage of the tumors studied (Table 2).
Among the seven RCTs analyzed, two studies were stopped early by the because of the lack of any effect due to the small sample size, and one stu pleted, although the researchers were aware that the number of patients lower than that calculated in the protocol description [28,30,32,35]. Therefo RCTs recruited the number of patients expected to achieve adequate stat [29,31,33,34]. Three out of these four RCTs were judged to have a low risk of [31,33,34]. Furthermore, some RCTs had several dropouts that further reduce of patients analyzed and the results obtained [29,[31][32][33]. For these reasons, t results discussed below could be originally flawed by an inappropriate exp sign and under-sizing.
The heterogeneity of the curcumin formulations was another relevant out of the seven RCTs analyzed, curcumin was given as the C3 complex [2 others, curcumin was administered as the high bioavailable formulation [29,34], and three studies did not provide any detail on the curcumin form [30,31,33]. The large dose range (the highest was 8 g/day for 6 weeks and th 1.44 g/day for 6 months) and erratic pharmacokinetic profile (Table 1) Table 3. Quality assessment and risk of bias in the analyzed RCTs.

Discussion
The results summarized in this systematic review, unfortun enough to support the therapeutic use of curcumin, either as mon on to other standard antineoplastic drugs in patients with solid tu or metastatic colorectal cancer, advanced metastatic breast canc cancer, and oral leukoplakia) or hematologic malignancies (multip tors may explain these inconclusive results, including the low nu the small number of subjects enrolled, the formulation and route o cumin, and the stage of the tumors studied (Table 2).
Among the seven RCTs analyzed, two studies were stopped e because of the lack of any effect due to the small sample size, a pleted, although the researchers were aware that the number o lower than that calculated in the protocol description [28,30,32,3 RCTs recruited the number of patients expected to achieve ade [29,31,33,34]. Three out of these four RCTs were judged to have a l [31,33,34]. Furthermore, some RCTs had several dropouts that furt of patients analyzed and the results obtained [29,[31][32][33]. For these results discussed below could be originally flawed by an inappro sign and under-sizing.
The heterogeneity of the curcumin formulations was anothe out of the seven RCTs analyzed, curcumin was given as the C3 others, curcumin was administered as the high bioavailable fo [29,34], and three studies did not provide any detail on the curc [30,31,33]. The large dose range (the highest was 8 g/day for 6 we 1.44 g/day for 6 months) and erratic pharmacokinetic profile (Tab cult to compare the efficacy of these formulations. It is probably only studies showing the beneficial effect of curcumin on cance  Gunther et al. [28] Santosa et al. [29] Passildas-Jahanmohan et al. [30] Saghatelyan et al. [31] Howells et al. [32] Choi et al. [33] Kuriakose et al. [34] Domain (D) D1, randomization process; D2, deviations from outcome data; D4, measurement of the outcome; D5, selecti evaluation (for further information, see the Section 2). Red cir yellow circles: some concerns.

Discussion
The results summarized in this systematic review enough to support the therapeutic use of curcumin, eit on to other standard antineoplastic drugs in patients w or metastatic colorectal cancer, advanced metastatic b cancer, and oral leukoplakia) or hematologic malignanc tors may explain these inconclusive results, including t the small number of subjects enrolled, the formulation a cumin, and the stage of the tumors studied (Table 2).
Among the seven RCTs analyzed, two studies were because of the lack of any effect due to the small sam pleted, although the researchers were aware that the lower than that calculated in the protocol description RCTs recruited the number of patients expected to a [29,31,33,34]. Three out of these four RCTs were judged [31,33,34]. Furthermore, some RCTs had several dropou of patients analyzed and the results obtained [29,[31][32][33] results discussed below could be originally flawed by a sign and under-sizing.
The heterogeneity of the curcumin formulations w out of the seven RCTs analyzed, curcumin was given others, curcumin was administered as the high bioa [29,34], and three studies did not provide any detail o Pharmaceutics 2023, 15, x FOR PEER REVIEW Table 3. Quality assessment and risk of bias in the analyzed RCT Gunther et al. [28] Santosa et al. [29] Passildas-Jahanmohan et al. [30] Saghatelyan et al. [31] Howells et al. [32] Choi et al. [33] Kuriakose et al. [34] Domain (D) D1, randomization process; D2, deviations from int outcome data; D4, measurement of the outcome; D5, selection o evaluation (for further information, see the Section 2). Red circles yellow circles: some concerns.

Discussion
The results summarized in this systematic review, un enough to support the therapeutic use of curcumin, either on to other standard antineoplastic drugs in patients with or metastatic colorectal cancer, advanced metastatic brea cancer, and oral leukoplakia) or hematologic malignancies tors may explain these inconclusive results, including the l the small number of subjects enrolled, the formulation and cumin, and the stage of the tumors studied (Table 2).
Among the seven RCTs analyzed, two studies were sto because of the lack of any effect due to the small sample pleted, although the researchers were aware that the num lower than that calculated in the protocol description [28, RCTs recruited the number of patients expected to achie [29,31,33,34]. Three out of these four RCTs were judged to h [31,33,34]. Furthermore, some RCTs had several dropouts th of patients analyzed and the results obtained [29,[31][32][33]. Fo results discussed below could be originally flawed by an i sign and under-sizing.
The heterogeneity of the curcumin formulations was out of the seven RCTs analyzed, curcumin was given as t others, curcumin was administered as the high bioavail [29,34], and three studies did not provide any detail on th [30,31,33]. The large dose range (the highest was 8 g/day f 1.44 g/day for 6 months) and erratic pharmacokinetic profi cult to compare the efficacy of these formulations. It is pro  Gunther et al. [28] Santosa et al. [29] Passildas-Jahanmohan et al. [30] Saghatelyan et al. [31] Howells et al. [32] Choi et al. [33] Kuriakose et al. [34] Domain (D) D1, randomization proce outcome data; D4, measurement of th evaluation (for further information, se yellow circles: some concerns.

Discussion
The results summarized in th enough to support the therapeutic on to other standard antineoplastic or metastatic colorectal cancer, ad cancer, and oral leukoplakia) or hem tors may explain these inconclusiv the small number of subjects enroll cumin, and the stage of the tumors Among the seven RCTs analyz because of the lack of any effect d pleted, although the researchers w lower than that calculated in the p RCTs recruited the number of pa [29,31,33,34]. Three out of these fou [31,33,34]. Furthermore, some RCT of patients analyzed and the result results discussed below could be o sign and under-sizing.
The heterogeneity of the curc out of the seven RCTs analyzed, c others, curcumin was administer [29,34], and three studies did not

Discussion
The results summa enough to support the th on to other standard ant or metastatic colorectal cancer, and oral leukopla tors may explain these in the small number of sub cumin, and the stage of t Among the seven R because of the lack of a pleted, although the res lower than that calculat RCTs recruited the num [29,31,33,34]. Three out o [31,33,34]. Furthermore, of patients analyzed and results discussed below sign and under-sizing.
The heterogeneity o out of the seven RCTs a others, curcumin was a [29,34], and three studie [30,31,33]. The large dos 1.44 g/day for 6 months) cult to compare the effic only studies showing th Choi et al. [33] Pharmaceutics 2023, 15, x FOR PEER REVIEW Table 3. Quality assessment and risk of bias in the analyzed RCTs.

Discussion
The results summarized in this systematic review, unfortunately, are n enough to support the therapeutic use of curcumin, either as monotherapy on to other standard antineoplastic drugs in patients with solid tumors (loca or metastatic colorectal cancer, advanced metastatic breast cancer, metast cancer, and oral leukoplakia) or hematologic malignancies (multiple myelom tors may explain these inconclusive results, including the low number of cli the small number of subjects enrolled, the formulation and route of administ cumin, and the stage of the tumors studied (Table 2).
Among the seven RCTs analyzed, two studies were stopped early by the because of the lack of any effect due to the small sample size, and one stu pleted, although the researchers were aware that the number of patients lower than that calculated in the protocol description [28,30,32,35]. Therefo RCTs recruited the number of patients expected to achieve adequate stat [29,31,33,34]. Three out of these four RCTs were judged to have a low risk of [31,33,34]. Furthermore, some RCTs had several dropouts that further reduce of patients analyzed and the results obtained [29,[31][32][33]. For these reasons, t results discussed below could be originally flawed by an inappropriate exp sign and under-sizing.
The heterogeneity of the curcumin formulations was another relevant out of the seven RCTs analyzed, curcumin was given as the C3 complex [2 Pharmaceutics 2023, 15, x FOR PEER REVIEW Table 3. Quality assessment and risk of bias in the analyzed RCTs.

Discussion
The results summarized in this systematic review, unfortun enough to support the therapeutic use of curcumin, either as mon on to other standard antineoplastic drugs in patients with solid tu or metastatic colorectal cancer, advanced metastatic breast canc cancer, and oral leukoplakia) or hematologic malignancies (multip tors may explain these inconclusive results, including the low nu the small number of subjects enrolled, the formulation and route o cumin, and the stage of the tumors studied (Table 2).
Among the seven RCTs analyzed, two studies were stopped e because of the lack of any effect due to the small sample size, a pleted, although the researchers were aware that the number o lower than that calculated in the protocol description [28,30,32,3 RCTs recruited the number of patients expected to achieve ade [29,31,33,34]. Three out of these four RCTs were judged to have a l [31,33,34]. Furthermore, some RCTs had several dropouts that furt of patients analyzed and the results obtained [29,[31][32][33]. For these results discussed below could be originally flawed by an inappro sign and under-sizing.

Discussion
The results summarized in this systematic review enough to support the therapeutic use of curcumin, eit on to other standard antineoplastic drugs in patients w or metastatic colorectal cancer, advanced metastatic b cancer, and oral leukoplakia) or hematologic malignanc tors may explain these inconclusive results, including t the small number of subjects enrolled, the formulation a cumin, and the stage of the tumors studied (Table 2).
Among the seven RCTs analyzed, two studies were because of the lack of any effect due to the small sam pleted, although the researchers were aware that the lower than that calculated in the protocol description RCTs recruited the number of patients expected to a [29,31,33,34]. Three out of these four RCTs were judged [31,33,34]. Furthermore, some RCTs had several dropou of patients analyzed and the results obtained [29,[31][32][33] results discussed below could be originally flawed by a sign and under-sizing.

Discussion
The results summarized in this systema enough to support the therapeutic use of cur on to other standard antineoplastic drugs in or metastatic colorectal cancer, advanced m cancer, and oral leukoplakia) or hematologic tors may explain these inconclusive results, i the small number of subjects enrolled, the for cumin, and the stage of the tumors studied (T Among the seven RCTs analyzed, two stu because of the lack of any effect due to the pleted, although the researchers were awar lower than that calculated in the protocol de RCTs recruited the number of patients exp [29,31,33,34]. Three out of these four RCTs we [31,33,34]. Furthermore, some RCTs had sever of patients analyzed and the results obtained results discussed below could be originally fl sign and under-sizing.

Discussion
The results summarized in th enough to support the therapeutic on to other standard antineoplastic or metastatic colorectal cancer, ad cancer, and oral leukoplakia) or hem tors may explain these inconclusiv the small number of subjects enroll cumin, and the stage of the tumors Among the seven RCTs analyz because of the lack of any effect d pleted, although the researchers w lower than that calculated in the p RCTs recruited the number of pa [29,31,33,34]. Three out of these fou [31,33,34]. Furthermore, some RCT of patients analyzed and the result results discussed below could be o sign and under-sizing.

Discussion
The results summa enough to support the th on to other standard ant or metastatic colorectal cancer, and oral leukopla tors may explain these in the small number of sub cumin, and the stage of t Among the seven R because of the lack of a pleted, although the res lower than that calculat RCTs recruited the num [29,31,33,34]. Three out o [31,33,34]. Furthermore, of patients analyzed and results discussed below sign and under-sizing.
The heterogeneity o out of the seven RCTs a Kuriakose et al. [34] Pharmaceutics 2023, 15, x FOR PEER REVIEW Table 3. Quality assessment and risk of bias in the analyzed RCTs.

Discussion
The results summarized in this systematic review, unfortunately, are n enough to support the therapeutic use of curcumin, either as monotherapy on to other standard antineoplastic drugs in patients with solid tumors (loca or metastatic colorectal cancer, advanced metastatic breast cancer, metast cancer, and oral leukoplakia) or hematologic malignancies (multiple myelom tors may explain these inconclusive results, including the low number of cli the small number of subjects enrolled, the formulation and route of administ cumin, and the stage of the tumors studied (Table 2).
Among the seven RCTs analyzed, two studies were stopped early by the because of the lack of any effect due to the small sample size, and one stu pleted, although the researchers were aware that the number of patients lower than that calculated in the protocol description [28,30,32,35]. Therefo RCTs recruited the number of patients expected to achieve adequate stat [29,31,33,34]. Three out of these four RCTs were judged to have a low risk of [31,33,34]. Furthermore, some RCTs had several dropouts that further reduce of patients analyzed and the results obtained [29,[31][32][33]. For these reasons, t results discussed below could be originally flawed by an inappropriate exp sign and under-sizing.  Table 3. Quality assessment and risk of bias in the analyzed RCTs.

Discussion
The results summarized in this systematic review, unfortun enough to support the therapeutic use of curcumin, either as mon on to other standard antineoplastic drugs in patients with solid tu or metastatic colorectal cancer, advanced metastatic breast canc cancer, and oral leukoplakia) or hematologic malignancies (multip tors may explain these inconclusive results, including the low nu the small number of subjects enrolled, the formulation and route o cumin, and the stage of the tumors studied (Table 2).
Among the seven RCTs analyzed, two studies were stopped e because of the lack of any effect due to the small sample size, a pleted, although the researchers were aware that the number o lower than that calculated in the protocol description [28,30,32,3 RCTs recruited the number of patients expected to achieve ade [29,31,33,34]. Three out of these four RCTs were judged to have a l [31,33,34]. Furthermore, some RCTs had several dropouts that furt of patients analyzed and the results obtained [29,[31][32][33]. For these results discussed below could be originally flawed by an inappro sign and under-sizing.  Gunther et al. [28] Santosa et al. [29] Passildas-Jahanmohan et al. [30] Saghatelyan et al. [31] Howells et al. [32] Choi et al. [33] Kuriakose et al. [34] Domain (D) D1, randomization process; D2, deviations from outcome data; D4, measurement of the outcome; D5, selecti evaluation (for further information, see the Section 2). Red cir yellow circles: some concerns.

Discussion
The results summarized in this systematic review enough to support the therapeutic use of curcumin, eit on to other standard antineoplastic drugs in patients w or metastatic colorectal cancer, advanced metastatic b cancer, and oral leukoplakia) or hematologic malignanc tors may explain these inconclusive results, including t the small number of subjects enrolled, the formulation a cumin, and the stage of the tumors studied (Table 2).
Among the seven RCTs analyzed, two studies were because of the lack of any effect due to the small sam pleted, although the researchers were aware that the lower than that calculated in the protocol description RCTs recruited the number of patients expected to a [29,31,33,34]. Three out of these four RCTs were judged [31,33,34]. Furthermore, some RCTs had several dropou of patients analyzed and the results obtained [29,[31][32][33] results discussed below could be originally flawed by a sign and under-sizing.  Gunther et al. [28] Santosa et al. [29] Passildas-Jahanmohan et al. [30] Saghatelyan et al. [31] Howells et al. [32] Choi et al. [33] Kuriakose et al. [34] Domain (D) D1, randomization process; D2, dev outcome data; D4, measurement of the outcome; evaluation (for further information, see the Sectio yellow circles: some concerns.

Discussion
The results summarized in this systema enough to support the therapeutic use of cur on to other standard antineoplastic drugs in or metastatic colorectal cancer, advanced m cancer, and oral leukoplakia) or hematologic tors may explain these inconclusive results, i the small number of subjects enrolled, the for cumin, and the stage of the tumors studied (T Among the seven RCTs analyzed, two stu because of the lack of any effect due to the pleted, although the researchers were awar lower than that calculated in the protocol de RCTs recruited the number of patients exp [29,31,33,34]. Three out of these four RCTs we [31,33,34]. Furthermore, some RCTs had sever of patients analyzed and the results obtained results discussed below could be originally fl sign and under-sizing.  Gunther et al. [28] Santosa et al. [29] Passildas-Jahanmohan et al. [30] Saghatelyan et al. [31] Howells et al. [32] Choi et al. [33] Kuriakose et al. [34] Domain (D) D1, randomization proce outcome data; D4, measurement of th evaluation (for further information, se yellow circles: some concerns.

Discussion
The results summarized in th enough to support the therapeutic on to other standard antineoplastic or metastatic colorectal cancer, ad cancer, and oral leukoplakia) or hem tors may explain these inconclusiv the small number of subjects enroll cumin, and the stage of the tumors Among the seven RCTs analyz because of the lack of any effect d pleted, although the researchers w lower than that calculated in the p RCTs recruited the number of pa [29,31,33,34]. Three out of these fou [31,33,34]. Furthermore, some RCT of patients analyzed and the result results discussed below could be o sign and under-sizing.  Santosa et al. [29] Passildas-Jahanmohan et al. [30] Saghatelyan et al. [31] Howells et al. [32] Choi et al. [33] Kuriakose et al. [34] Domain (D) D1, randomiz outcome data; D4, measur evaluation (for further info yellow circles: some concer

Discussion
The results summa enough to support the th on to other standard ant or metastatic colorectal cancer, and oral leukopla tors may explain these in the small number of sub cumin, and the stage of t Among the seven R because of the lack of a pleted, although the res lower than that calculat RCTs recruited the num [29,31,33,34]. Three out o [31,33,34]. Furthermore, of patients analyzed and results discussed below sign and under-sizing. Domain (D) D1, randomization process; D2, deviations from intended interventions; D3, missing outcome data; D4, measurement of the outcome; D5, selection of the reported results; O, overall evaluation (for further information, see the Section 2). Red circles: high risk; green circles: low risk; yellow circles: some concerns.
Most of the study populations considered in the included studies showed locally advanced or metastatic cancer and underwent other treatments (chemotherapy, radiotherapy) beyond the administration of curcumin, except for the studies by Kuriakose et al. [34] on patients with oral leukoplakia and Choi et al. [33] on patients with prostate cancers during the first androgen deprivation therapy withdrawal (Table 2).
In all studies, curcumin was administered orally, except in one study where the administration was intravenously [31]. The duration of the studies ranged between 16 weeks and 13 years ( Table 2).
All the studies evaluated hard endpoints as primary outcomes, except for the study by Howells et al. [32], which only addressed the clinical benefit of curcumin in terms of OS and PFS as secondary outcomes (Table 2).
Cancer response, either clinical or objective/pathologic, was investigated as the primary endpoint in 57.1% of the studies [28,29,31,34]. Choi et al. [33] considered off-treatment duration, namely the time from the start of therapy withdrawal until progression, as the primary endpoint, while Passildas-Jahanmohan et al. [30] examined the time from inclusion to the first objective progression of the disease ( Table 2).
The OS was considered in three studies (42.9%) [28,30,32]. On the whole, the OS did not show significant differences between arms except in the study by Howells et al. [32], which showed a better OS in the curcumin arm compared to the placebo (median time to death of 502 days and 200 days, respectively, in the per-protocol analysis). The PFS was assessed in five studies (71.4%) and did not show significant differences between patients receiving curcumin [28,[30][31][32]. Lastly, regarding the cancer response, better results were detected in the curcumin arm compared to the placebo in three out of four studies (75%) [29,31,34], albeit the study by Gunther et al. [28] on colorectal cancer issued discordant results ( Table 2).
The toxicity of curcumin was also taken into consideration in five studies (71.4%) [30][31][32][33][34]. Overall, few adverse events were reported in the curcumin arm even though the difference reached the significance in one study only [33] (Table 2).

Discussion
The results summarized in this systematic review, unfortunately, are not consistent enough to support the therapeutic use of curcumin, either as monotherapy or as an add-on to other standard antineoplastic drugs in patients with solid tumors (locally advanced or metastatic colorectal cancer, advanced metastatic breast cancer, metastatic prostatic cancer, and oral leukoplakia) or hematologic malignancies (multiple myeloma). Many factors may explain these inconclusive results, including the low number of clinical studies, the small number of subjects enrolled, the formulation and route of administration of curcumin, and the stage of the tumors studied (Table 2).
Among the seven RCTs analyzed, two studies were stopped early by the investigators because of the lack of any effect due to the small sample size, and one study was completed, although the researchers were aware that the number of patients enrolled was lower than that calculated in the protocol description [28,30,32,35]. Therefore, only four RCTs recruited the number of patients expected to achieve adequate statistical power [29,31,33,34]. Three out of these four RCTs were judged to have a low risk of bias (Table 3) [31,33,34]. Furthermore, some RCTs had several dropouts that further reduced the number of patients analyzed and the results obtained [29,[31][32][33]. For these reasons, the conflicting results discussed below could be originally flawed by an inappropriate experimental design and under-sizing.
The heterogeneity of the curcumin formulations was another relevant factor. In two out of the seven RCTs analyzed, curcumin was given as the C3 complex [28,32]; in two others, curcumin was administered as the high bioavailable formulation BCM-95 CG [29,34], and three studies did not provide any detail on the curcumin formulation used [30,31,33]. The large dose range (the highest was 8 g/day for 6 weeks and the lowest was 1.44 g/day for 6 months) and erratic pharmacokinetic profile (Table 1) have made it difficult to compare the efficacy of these formulations. It is probably no coincidence that the only studies showing the beneficial effect of curcumin on cancer size or OS were those using high-dose BCM-95 CG (3.6 g/day for 6 months or 8 g/day for 28 days) [29,34]. Another approach to enhance absorption was to administer curcumin via the intravenous route because intravenous administration allows for bypassing the first-pass effect. Indeed, 300 mg of curcumin was intravenously administered once per week for 12 weeks as an add-on to paclitaxel, which induced a partial response in 50.7% of breast cancer patients treated with the taxane with respect to the placebo group [31]. Closely related to irregular absorption is the concern about the low levels of curcumin in tissues, in particular when considering that malignant cells uptake curcumin at a greater extent than normal ones [36]. In this regard, Gunther et al. [28] and Garcea et al. [37], who treated patients with colorectal tumors with the oral curcumin C3 complex (8 g/day for 6 weeks and 3.6 g/day for 1 week, respectively), found median curcumin concentration in the tumor tissues of 33.7 ng/mg and 12.7 ± 5.7 nmol/g tissue, respectively. Furthermore, in the rectal mucosa of healthy volunteers treated with the curcumin-phosphatidylcholine formulation, the mean level of curcumin was even lower, with a value of 2.8 ng/mL [13]. These concentrations, in the low nanomolar range, are several orders of magnitude lower than those used in cellbased studies to exert biological effects and may explain the diverse effects of curcumin in humans with respect to in vitro systems [28,38]. Unfortunately, no data are available about the concentration of curcumin in malignant tissues following the administration of BCM-95 CG or nanoparticle formulations, and this kind of study would be more than welcome. Taken together, these observations imply that the formulation and route of administration are key determinants of the therapeutic efficacy of curcumin.
Another issue worthy of discussion is the type of tumor and the stage of the disease. Five out of seven RCTs reviewed in this article were carried out in patients with metastatic colorectal, breast, or prostate cancer [28,[30][31][32][33]. The lack of effect of curcumin in improving the OS, PFS, and TTP may be due to the advanced and disseminated stage of the tumors, which has rendered any proapoptotic, anti-inflammatory, and anti-angiogenic modification useless. This hypothesis is confirmed by the evidence that curcumin decreased proinflam-matory cytokines and transcription factors (tumor necrosis factor, IL-6, NFkB, and VEGF) in multiple myeloma patients, as well as the tumor markers carcinoembryonic antigen and prostate-specific antigen in breast and prostate cancer patients, respectively [29,31,33]. As a whole, these findings suggest that the compound has been able to reach the targets, but these modifications were not strong enough to counteract tumor progression [31,33]. Studying the effects of curcumin in patients with early-stage tumors would give us a correct evaluation of its full therapeutic potential.
A working hypothesis that could justify the use of curcumin as an add-on to antiblastic agents is the ability of the former to inhibit drug-metabolizing enzymes. Curcumin has been reported to inhibit liver cytochrome P450 (CYP) isoform 3A4 (CYP3A4), glutathione-S-transferase (GST), and UDP-glucuronosyltransferase (UGT) and, by doing so, it could increase both the plasma and tissue levels of antineoplastic drugs, enhancing their therapeutic effect [2,39]. The clinical studies described above do not seem to support this theory. Indeed, docetaxel and paclitaxel both undergo liver metabolism through CYP3A4; therefore, if curcumin had inhibited this isozyme, one would have expected a potentiation of taxane anticancer effects in metastatic prostate and breast cancer patients but unfortunately, this has not occurred [30,31,40]. Actually, neither Passildas et al. [30] nor Saghatelyan et al. [31] measured the taxane plasma levels in curcumin-treated patients, and this possible drugdrug interaction was not adequately addressed. The use of oral curcumin for boosting anticancer drugs is an attractive approach and could open new avenues for alternative therapeutic use of curcumin in cancer.
A common outcome of these studies is the appreciable safety profile of curcumin. Cancer patients, treated with either oral curcumin (at doses up to 8 g/day for a maximum of 6 months) or intravenous curcumin (300 mg once a week for 12 weeks), experienced mild and transient adverse effects, including gastrointestinal discomfort (diarrhea, nausea, vomiting, and dyspepsia), hypertension, tachycardia, and anemia [30][31][32][33][34]. Interestingly, a reduced rate of lymphopenia and hypocalcemia were reported in breast or prostate cancer patients treated with curcumin [30,31].
The theme of drug-drug interactions, introduced above, can be a double-edged sword. Indeed, CYP3A4, GST, and UGT metabolize several drugs used by cancer patients for concomitant diseases, such as opioid analgesics (methadone, morphine), macrolide antibacterials (erythromycin, clarithromycin), azole antifungals (itraconazole, miconazole), corticosteroids (prednisone, prednisolone), etc. [40]. Therefore, curcumin, by inhibiting phase I and phase II enzymes, could increase the plasma levels of concomitant drugs giving rise to harmful side effects.
The results summarized in this systematic review, however, should be read bearing in mind the limitations of the work. As with all systematic reviews, a selection bias could not be completely ruled out, albeit a standardized approach was undertaken to perform the search and selection of eligible studies. Furthermore, as already addressed, included studies were deeply heterogeneous and showed several concerns that prevented making a quantitative synthesis and reaching a conclusive picture of the effect of curcumin on hard endpoints.

Conclusions and Future Directions
After a careful evaluation of the clinical evidence currently available, the conclusion that can be drawn is that curcumin is not an effective compound in either blocking or slowing down the progression of cancer. These conclusions, however, were drawn after a thorough analysis of only seven RCTs that evaluated hard endpoints, many of which were affected by some level of bias or undersized and/or had many dropouts that affected the final evaluation. Furthermore, the heterogeneity of the curcumin formulations, with their pharmacokinetic variability, and their use in patients with locally advanced or metastatic cancers, undoubtedly contributed to a possible underestimation of its potential clinical benefit.
Nevertheless, the acceptable safety profile and the evidence that curcumin may improve local symptoms of cancer-related radiodermatitis or mucositis bolster the interest of the scientific community to continue studying this compound [22][23][24][25]. In addition, the increased uptake of curcumin by tumor cells, along with the in vitro evidence that curcumin's pro-apoptotic effect increases with the intracellular concentration, deserve more attention and should be taken into greater consideration for further development of novel formulations targeting cancer cells [36]. Finally, closer collaboration between basic researchers and oncologists would be desirable, not only to foster the exchange of expertise but also to enhance knowledge and accelerate the transition from preclinical to clinical research. The study of the efficacy of curcumin in early-stage tumors could also reserve pleasant surprises in a therapeutic sense.