A Comprehensive Monograph on Tegafur: Pharmacology, Clinical Application, and Therapeutic Context

Executive Summary

Tegafur is an orally bioavailable antineoplastic agent that functions as a prodrug of the widely used chemotherapeutic, 5-fluorouracil (5-FU). Developed to overcome the poor oral bioavailability and pharmacokinetic unpredictability of 5-FU, Tegafur’s clinical significance is realized almost exclusively through its incorporation into sophisticated combination drug products. These formulations, namely Tegafur/uracil (UFT) and Tegafur/gimeracil/oteracil (commercially known as S-1 or Teysuno), are rationally designed to modulate the pharmacology of 5-FU, enhancing its therapeutic index by increasing its systemic exposure while mitigating its characteristic toxicities.[1]

The primary mechanism of action involves the hepatic conversion of Tegafur to 5-FU, which then inhibits thymidylate synthase, a critical enzyme in the DNA synthesis pathway, leading to cell death.[1] The co-formulated agents in UFT and S-1 strategically inhibit dihydropyrimidine dehydrogenase (DPD), the enzyme responsible for 5-FU degradation, thereby prolonging its activity. S-1 further includes a gastrointestinal-protective agent that locally reduces 5-FU activation in the gut mucosa, decreasing common side effects like diarrhea and mucositis.[2]

Clinically, Tegafur-based therapies have become a cornerstone in the management of various solid tumors, particularly gastrointestinal malignancies such as advanced gastric and metastatic colorectal cancer.[1] Its application extends to breast, pancreatic, non-small cell lung, and head and neck cancers, among others, with a broad range of approved indications, especially in Japan.[6] The safety profile of Tegafur is critically influenced by patient pharmacogenetics, specifically the activity of the DPD enzyme. Genetic deficiencies in DPD can lead to severe or fatal toxicity, making pre-treatment screening a recommended standard of care in regions where the drug is approved.[5]

The global regulatory landscape for Tegafur is notably divergent. It holds widespread approval and is considered a standard of care for numerous indications in Japan (as TS-1) and has secured key approvals in the European Union (as Teysuno).[9] However, it remains unapproved by the U.S. Food and Drug Administration, reflecting differences in clinical development history and regulatory pathways.[11] Positioned as a critical oral alternative to intravenous 5-FU, Tegafur-based therapies offer comparable efficacy with distinct safety profiles, particularly when compared to the other major oral fluoropyrimidine, capecitabine, thus providing essential options in the oncologist's armamentarium.

Drug Identity and Physicochemical Properties

Nomenclature and Identifiers

To precisely define the molecule, a comprehensive list of its names and registry numbers is essential for research, clinical, and regulatory contexts.

• Generic Name: Tegafur [1]
• Alternate Names/Synonyms: Ftorafur, Fluorafur, FT-207, NSC 148958.[3] It is also a component of products known as TS-1 and Uftoral.[15]
• IUPAC Name: 5-fluoro-1-(oxolan-2-yl)pyrimidine-2,4-dione [14]
• Formal Name: 5-fluoro-1-(tetrahydro-2-furanyl)-2,4(1H,3H)-pyrimidinedione [3]
• Key Identifiers:
• CAS Number: 17902-23-7 [13]
• DrugBank ID: DB09256 [1]
• PubChem CID: 288216 [5]
• EC Number: 241-846-2 [18]
• MDL Number: MFCD00012351 [16]

Chemical Structure and Formula

Tegafur is a synthetic small molecule classified as a pyrimidine analogue and a congener of fluorouracil. Its structure is characterized by the attachment of a tetrahydro-2-furyl moiety to the N1 position of the 5-fluorouracil ring, a modification that is central to its function as an oral prodrug.[2]

• Molecular Formula: C8​H9​FN2​O3​ [13]
• SMILES String: FC1=CN(C2CCCO2)C(=O)NC1=O [17]
• InChIKey: WFWLQNSHRPWKFK-UHFFFAOYSA-N [18]

Physical and Chemical Properties

The physical state and solubility of Tegafur influence its formulation into oral dosage forms and its behavior in biological systems.

• Molecular Weight: 200.17 g/mol [13]
• Physical Form: A white to off-white solid powder [15]
• Melting Point: 171-173 °C [18]
• Solubility: Tegafur is highly soluble in dimethyl sulfoxide (DMSO) at concentrations exceeding 50 mg/mL. Its solubility is limited in other common solvents, measured at approximately 7 mg/ml in ethanol and 8 mg/ml in water.[15] Another study reported a solubility of 29.9 µg/mL at a physiological pH of 7.4, highlighting the importance of formulation strategies to ensure adequate absorption.[14]
• Polymorphism: The solid-state chemistry of Tegafur is complex, with the existence of multiple crystalline forms, or polymorphs, designated as α, β, δ, γ, and ε.[14] Of these, the α and β forms are the most relevant, as both are used in commercial therapeutic products. The α form is metastable and can undergo a solvent-mediated phase transformation (SMPT) into the more thermodynamically stable β form. This phenomenon is of great significance in the pharmaceutical industry. The choice of solvents and conditions during manufacturing and storage can dictate the final polymorphic composition of the active pharmaceutical ingredient (API). Since different polymorphs can possess distinct physicochemical properties, such as dissolution rate and stability, controlling the polymorphic form is critical to ensuring consistent drug bioavailability, and by extension, predictable clinical efficacy and safety.[14]

The fundamental properties of Tegafur are summarized in the table below.

Property	Value	Source(s)
Generic Name	Tegafur	1
IUPAC Name	5-fluoro-1-(oxolan-2-yl)pyrimidine-2,4-dione	14
CAS Number	17902-23-7	13
DrugBank ID	DB09256	1
Molecular Formula	C8​H9​FN2​O3​	13
Molecular Weight	200.17 g/mol	13
Physical Form	White to off-white powder	18
Melting Point	171-173 °C	18
Solubility (DMSO)	>50 mg/mL	18
Solubility (Water)	8 mg/ml	15
SMILES	FC1=CN(C2CCCO2)C(=O)NC1=O	18
InChIKey	WFWLQNSHRPWKFK-UHFFFAOYSA-N	18
Polymorphic Forms	α, β, δ, γ, ε (α and β are commercially used)	14

Clinical Pharmacology

Mechanism of Action and Pharmacodynamics

The antineoplastic activity of Tegafur is not intrinsic to the parent molecule but is entirely dependent on its multi-step metabolic conversion to 5-fluorouracil (5-FU) and its subsequent active metabolites.

The Prodrug Concept and Metabolic Activation

Tegafur is an orally administered, inactive prodrug designed to serve as a biological precursor to 5-FU.[1] This strategy was developed to provide a more convenient and pharmacokinetically favorable alternative to intravenous 5-FU.[14] Following oral absorption, Tegafur is transported to the liver, where it undergoes metabolic activation. This conversion is predominantly catalyzed by the cytochrome P450 enzyme CYP2A6, which mediates the 5-hydroxylation of Tegafur to form an unstable intermediate, 5'-hydroxytegafur, that subsequently breaks down to release 5-FU.[1] This controlled, enzyme-mediated release provides a more consistent and sustained supply of 5-FU to the systemic circulation, mimicking the pharmacokinetic profile of a continuous intravenous infusion and avoiding the sharp, potentially toxic peak concentrations associated with bolus IV injections.[14]

Intracellular Anabolism and Cytotoxic Mechanisms

Once 5-FU is formed, it is taken up by both normal and tumor cells and must be anabolized intracellularly to exert its cytotoxic effects. This process yields two primary active metabolites [1]:

1. 5-fluorodeoxyuridine monophosphate (FdUMP): This metabolite is the principal agent of DNA-directed cytotoxicity.
2. 5-fluorouridine triphosphate (FUTP): This metabolite is responsible for RNA-directed cytotoxicity.

The primary molecular target for Tegafur's therapeutic effect is the enzyme thymidylate synthase (TS).[1] FdUMP binds tightly to TS in the presence of the folate cofactor 5,10-methylenetetrahydrofolate, forming an inhibitory ternary complex.[3] This complex effectively blocks the catalytic function of TS, which is responsible for the conversion of 2'-deoxyuridylate (dUMP) to 2'-deoxythymidylate (dTMP). This reaction is the sole de novo source of thymidylate, a precursor of thymidine triphosphate (TTP), which is one of the four deoxyribonucleotides essential for DNA synthesis and repair.[1] The resulting depletion of the intracellular TTP pool leads to a state known as "thymineless death," characterized by DNA fragmentation, cell cycle arrest, and ultimately, apoptosis.[1]

A secondary mechanism of cytotoxicity is mediated by FUTP. This metabolite acts as a fraudulent nucleotide, being incorporated into various RNA species in place of the natural nucleotide, uridine triphosphate (UTP). This incorporation disrupts RNA synthesis, processing (e.g., splicing), and function, leading to errors in protein synthesis and contributing to the overall antitumor effect.[3]

Additionally, preclinical evidence suggests that certain tetrahydrofuran metabolites of Tegafur may possess antiangiogenic properties, potentially inhibiting the formation of new blood vessels that tumors require for growth and metastasis.[20]

Pharmacokinetics

The pharmacokinetic profile of Tegafur is defined by its efficient oral absorption, hepatic metabolism, and sustained release of its active metabolite, 5-FU.

Absorption

Tegafur is rapidly and effectively absorbed from the gastrointestinal tract following oral administration. Peak plasma concentrations of the parent drug are typically achieved within 1 to 2 hours.[1] Its absorption kinetics are dose-proportional, ensuring predictable exposure with increasing doses.[1] The development of Tegafur was a direct response to the poor and erratic oral bioavailability of 5-FU, a challenge that Tegafur successfully overcomes.[14]

Distribution

Tegafur distributes throughout the body with an apparent volume of distribution of 16 L/m².[1] It exhibits moderate binding to serum proteins, with approximately 52.3% of the drug bound. In contrast, its active metabolite, 5-FU, shows significantly lower protein binding at 18.4%, allowing for greater availability to target tissues.[1]

Metabolism

The biotransformation of Tegafur is the central event in its pharmacology and is governed by a critical balance between activation and degradation pathways. As previously described, the activation step is the hepatic conversion of Tegafur to 5-FU, primarily mediated by CYP2A6.[1] Once formed, 5-FU is subject to rapid catabolism by the enzyme dihydropyrimidine dehydrogenase (DPD), which is widely distributed in the liver and other tissues.[5]

This metabolic axis, involving activation by CYP2A6 and degradation by DPD, has profound clinical implications. Genetic polymorphisms in the CYP2A6 gene can lead to inter-individual and inter-ethnic variability in the rate of 5-FU formation. This has been identified as a reason for pharmacokinetic differences between Japanese and Western populations, with the latter often exhibiting higher 5-FU plasma concentrations, necessitating dose adjustments in clinical trials and practice.[22] Concurrently, genetic variations in the

DPYD gene, which encodes the DPD enzyme, can lead to impaired 5-FU clearance, dramatically increasing the risk of severe toxicity. Therefore, a patient's clinical outcome is intricately linked to their unique genetic makeup governing this metabolic balance, making Tegafur a prime candidate for pharmacogenomically-guided therapy.

Elimination and Excretion

The primary route of elimination for Tegafur is through metabolism. A relatively small portion of the administered dose, less than 20%, is excreted unchanged in the urine.[1] The elimination half-life of Tegafur is reported to be approximately 11 hours, with some studies indicating a range of 3.9 to 11 hours.[1] This extended half-life, relative to that of intravenously administered 5-FU, is a key feature of the prodrug design, contributing to the desired sustained systemic exposure to the active agent.

Parameter	Tegafur	5-FU (from Tegafur)	Source(s)
Tmax (Time to Peak Concentration)	1–2 hours	30–60 minutes	1
Volume of Distribution (Vd)	16 L/m²	Not specified	1
Serum Protein Binding (%)	52.3%	18.4%	1
Primary Metabolic Enzyme	CYP2A6 (activation)	DPD (degradation)	1
Elimination Half-life (t½)	~11 hours	Not specified (short)	1
Primary Route of Excretion	Metabolic; <20% unchanged in urine	Metabolic	1

Combination Formulations: Enhancing Efficacy and Safety

The clinical utility of Tegafur has been realized through its co-formulation with biochemical modulators designed to optimize the pharmacokinetics and pharmacodynamics of its active metabolite, 5-FU. This represents a clear and deliberate trajectory of pharmacological engineering, progressing from a simple prodrug to highly sophisticated multi-component systems.

Tegafur/Uracil (UFT)

UFT was the first major evolution of Tegafur therapy, designed to address the rapid degradation of 5-FU.

Composition and Rationale

UFT is an oral chemotherapeutic agent consisting of Tegafur and uracil combined in a fixed 1:4 molar ratio.[20] The fundamental problem with 5-FU therapy is its rapid catabolism by the enzyme DPD, which limits its therapeutic efficacy.[14] The rationale behind UFT is to counteract this degradation.

Mechanism of Uracil

Uracil, a natural pyrimidine base, acts as a competitive inhibitor of DPD.[2] Because uracil is a natural substrate for DPD, its co-administration in a four-fold molar excess effectively saturates the enzyme, competitively slowing the breakdown of the structurally similar 5-FU.[20] This inhibition results in significantly higher and more sustained plasma and tumor tissue concentrations of active 5-FU, thereby enhancing its antitumor activity from a given dose of Tegafur.[25] Some evidence also suggests that uracil may confer a protective effect on the gastrointestinal mucosa, reducing 5-FU-related toxicity.[20]

Clinical Applications and Efficacy

UFT, typically administered with leucovorin (calcium folinate) to further potentiate the cytotoxic effect of 5-FU by stabilizing the FdUMP-TS complex, has been approved in over 50 countries for a wide range of solid tumors.[20] Its indications include metastatic colorectal cancer, adjuvant therapy for lung and colorectal cancer, and treatment for breast, pancreatic, liver, and head and neck cancers.[5]

Key clinical findings for UFT include:

• Metastatic Colorectal Cancer (mCRC): Phase II trials of UFT plus leucovorin demonstrated substantial activity, with objective response rates ranging from approximately 20% to 42% and a median overall survival of around 11.6 months. These studies established UFT/leucovorin as a convenient and well-tolerated oral alternative to intravenous regimens.[27] A comprehensive meta-analysis later confirmed that oral UFT/leucovorin is equally efficacious to intravenous 5-FU in both metastatic and adjuvant settings for colorectal cancer, but with a superior safety profile, showing significantly lower rates of stomatitis, fever, infection, and leukopenia.[29]
• Adjuvant Lung Cancer: A landmark trial in patients with completely resected stage I T2 adenocarcinoma of the lung demonstrated that two years of postoperative adjuvant UFT therapy conferred a modest but statistically significant survival benefit compared to placebo, with 5-year overall survival rates of 88% versus 85%, respectively.[30]
• Adjuvant Colorectal Cancer: In patients with resected stage II/III colorectal cancer, a Phase III trial established that a twice-daily UFT/leucovorin regimen was non-inferior to a three-times-daily schedule, yielding excellent 5-year overall survival rates of 91.0% and 89.7%, respectively.[31]

Tegafur/Gimeracil/Oteracil (S-1 / Teysuno)

S-1 represents a further refinement of the oral fluoropyrimidine concept, incorporating a three-component system to maximize efficacy while actively minimizing toxicity.

Composition and Rationale

S-1, marketed as Teysuno in Europe, is an oral fixed-dose combination of Tegafur, gimeracil, and oteracil potassium, typically in a 1:0.4:1 molar ratio.[4] This formulation was engineered to solve a remaining challenge: the dose-limiting gastrointestinal toxicity that still occurred with higher systemic 5-FU levels. The goal was to decouple systemic antitumor activity from local gastrointestinal toxicity.

Mechanism of Gimeracil and Oteracil

1. Gimeracil (5-chloro-2,4-dihydroxypyridine): Like uracil, gimeracil is a DPD inhibitor, but it is significantly more potent and acts via a reversible mechanism.[2] Its inclusion allows for the achievement of higher and more prolonged plasma concentrations of 5-FU than is possible with UFT, thereby maximizing the potential for cytotoxic activity against tumor cells.[2]
2. Oteracil (Oteracil Potassium): Oteracil is the key gastrointestinal-protective component. It is an inhibitor of the enzyme orotate phosphoribosyltransferase (OPRT), which is involved in the intracellular activation (phosphorylation) of 5-FU.[4] Oteracil has low membrane permeability and is poorly absorbed systemically, meaning it remains concentrated within the gastrointestinal tract following oral administration. Here, it selectively inhibits the activation of 5-FU in the normal gut mucosa, reducing local exposure to active metabolites and thereby mitigating the severity of common toxicities like diarrhea and mucositis. This targeted action does not interfere with the systemic levels of 5-FU available to exert antitumor effects elsewhere in the body.[2]

Clinical Applications and Efficacy

S-1 is a standard-of-care treatment for several cancers in Japan and is approved in Europe for specific indications. Its primary uses are in advanced gastric and metastatic colorectal cancer, with demonstrated activity in pancreatic, breast, non-small-cell lung, and head and neck cancers.[1]

Analysis of pivotal S-1 clinical data reveals:

• Advanced Gastric Cancer: The global, randomized Phase III FLAGS trial was instrumental for its approval in the West. This study compared S-1 plus cisplatin to infusional 5-FU plus cisplatin. It successfully demonstrated that the S-1-based regimen was non-inferior in terms of overall survival. Notably, this was achieved using a lower S-1 dose in the Western population to account for pharmacokinetic differences. Furthermore, the S-1 arm exhibited a significantly better safety profile, with fewer treatment-related serious adverse events, establishing it as a valid and often preferable alternative to infused 5-FU.[22]
• Adjuvant Gastric Cancer: In Japan, the SAMIT trial directly compared S-1 monotherapy against UFT monotherapy for adjuvant treatment of high-risk (T4a/b) gastric cancer. The results demonstrated the superiority of S-1, with a 3-year disease-free survival rate of 58.2% versus 53.0% for UFT, cementing S-1 monotherapy as the standard of care in this setting.[33]
• Metastatic Colorectal Cancer (mCRC): The European Medicines Agency expanded the indication for Teysuno to include mCRC patients who are intolerant to other fluoropyrimidines (e.g., capecitabine) due to hand-foot syndrome or cardiovascular toxicity.[34] This decision was based on S-1's distinct and more favorable toxicity profile in this regard. A meta-analysis of ten randomized trials confirmed that S-1-based therapy is non-inferior to 5-FU or capecitabine-based therapy in mCRC for progression-free survival and at least as effective for overall survival and response rate, supporting its use as a key alternative.[36]

Feature	Tegafur/Uracil (UFT)	Tegafur/Gimeracil/Oteracil (S-1/Teysuno)
Molar Ratio	1:4 (Tegafur:Uracil)	1:0.4:1 (Tegafur:Gimeracil:Oteracil)
Role of Tegafur	Oral prodrug of 5-FU	Oral prodrug of 5-FU
DPD Inhibitor	Uracil	Gimeracil
Mechanism of DPD Inhibitor	Competitive inhibition of DPD, slowing 5-FU degradation.	Potent, reversible inhibition of DPD, leading to higher, more sustained 5-FU levels.
GI-Protective Agent	None (some minor protective effect from Uracil suggested)	Oteracil Potassium
Mechanism of GI-Protective Agent	N/A	Localized inhibition of OPRT in the GI tract, preventing 5-FU activation in gut mucosa.
Primary Clinical Advantage	Provides an oral alternative to IV 5-FU with enhanced 5-FU exposure.	Maximizes systemic 5-FU exposure while actively minimizing GI toxicity, improving the therapeutic index.

Clinical Indications and Therapeutic Use

Approved and Investigational Uses in Solid Tumors

Tegafur-based therapies have been evaluated and approved for a broad spectrum of solid malignancies, with notable variations in indications across different global regions.

• Advanced Gastric Cancer: This is a primary indication for S-1 (Teysuno), which is approved in the European Union for use in combination with cisplatin.[1] In Japan, S-1-based chemotherapy is a first-line standard of care for unresectable advanced gastric cancer.[22] Clinical trials continue to explore its role, with Phase 3 studies recruiting patients for adjuvant therapy in stage II gastric cancer.[37]
• Metastatic Colorectal Cancer (mCRC): Both UFT and S-1 are key treatments for mCRC. UFT, combined with leucovorin, is indicated for first-line treatment.[1] S-1 has a specific indication in Europe for patients who have developed intolerance (hand-foot syndrome or cardiovascular toxicity) to other fluoropyrimidines, providing a crucial sequential therapy option.[34]
• Non-Small Cell Lung Cancer (NSCLC): UFT has demonstrated a survival benefit as an adjuvant therapy for patients with resected stage I adenocarcinoma.[30] S-1 is an approved therapy for NSCLC in Japan.[7] Completed clinical trials have established Tegafur's activity in NSCLC [38], and a network meta-analysis suggests that Tegafur-uracil may offer a benefit comparable to that of immune checkpoint inhibitors plus chemotherapy in the specific subgroup of stage IB NSCLC.[6]
• Pancreatic Cancer: Both UFT and S-1 are approved for the treatment of pancreatic cancer in Japan, where they are integrated into standard therapeutic regimens.[6]
• Breast Cancer: UFT is utilized in the treatment of breast cancer.[5] S-1 holds approvals in Japan for both inoperable or recurrent breast cancer and, more recently, as a postoperative adjuvant therapy for patients with high-risk, hormone receptor-positive, HER2-negative disease.[7]
• Head and Neck Cancer: Both UFT and S-1 are approved and used for head and neck cancers in Japan.[6] UFT is also being explored as a potentially beneficial maintenance therapy in this setting.[39]
• Other Cancers: The range of approved indications in Japan is extensive, also including liver cancer, gallbladder and bile duct neoplasms, bladder cancer, prostatic cancer, and uterine cervical cancer.[6] Active clinical research is ongoing in other areas, with trials completed in hepatic carcinoma and underway in HER2-positive gastric cancer.[40]

Dosage and Administration Guidelines

The dosing of Tegafur-based therapies is complex, depending on the specific formulation, the indication, the patient's body surface area (BSA), and regional guidelines.

• S-1/Teysuno (European Guideline for Gastric Cancer): When used in combination with cisplatin, the recommended standard dose of Teysuno is 25 mg/m² (calculated as tegafur content) administered orally twice daily for 21 consecutive days, followed by a 7-day rest period. This 4-week cycle is repeated. The capsules should be taken with water at least one hour before or one hour after a meal.[35]
• S-1 (Japanese Guideline): Dosing is standardized based on BSA categories. The initial daily dose typically ranges from 80 to 120 mg (administered as 40 to 60 mg twice daily). A common schedule involves administration for 28 days followed by a 14-day rest, although other schedules (e.g., 14 days on, 7 days off) are also used depending on the cancer type and combination regimen.[7]
• UFT: Dosing is also based on BSA, typically ranging from 300-400 mg/m² per day, given in two or three divided doses.[44] For mCRC, a standard regimen is UFT 300 mg/m²/day plus oral leucovorin (e.g., 75 mg/day) administered for 28 days, followed by a 7-day rest period.[27]
• Dose Adjustments: Comprehensive guidelines exist for dose modifications in response to toxicity. For example, with Teysuno, the occurrence of Grade 3 or higher toxicity necessitates suspending treatment until recovery to Grade 1 or less, followed by a dose reduction at the start of the next cycle. Specific dose reduction steps are defined for both Tegafur and its combination partners (e.g., cisplatin).[35]

Special Populations

Careful consideration and dose adjustments are required when administering Tegafur-based therapies to certain patient populations.

• Renal Impairment: Renal function significantly impacts drug clearance and toxicity. For S-1/Teysuno, patients with moderate renal impairment (Creatinine Clearance [CrCl] 30-50 ml/min) require a reduced starting dose of 20 mg/m² twice daily. The drug is contraindicated in patients with end-stage renal disease requiring dialysis.[35]
• Hepatic Impairment: As Tegafur is metabolized in the liver, caution is warranted in patients with hepatic dysfunction. Regular monitoring of liver function tests is essential due to an increased risk of severe adverse effects.[45]
• Elderly Patients (≥70 years): While age alone may not necessitate an initial dose reduction, elderly patients may be more susceptible to toxicities, particularly myelosuppression. Dosing should be carefully managed based on individual tolerability and organ function.[46] A randomized trial in frail elderly patients with advanced colorectal cancer found that UFT/leucovorin had efficacy similar to capecitabine, highlighting its utility in this population.[47]
• Pediatric Population (<18 years): The safety and efficacy of Tegafur in children and adolescents have not been established, and its use is not recommended in this population.[35]

Safety, Tolerability, and Risk Management

Adverse Event Profile

The adverse events associated with Tegafur-based therapies are largely reflective of the known toxicities of 5-FU, although the specific profiles can be modulated by the co-formulated agents.[5]

• Gastrointestinal Toxicity: This is the most frequently encountered and often dose-limiting class of side effects. It commonly manifests as diarrhea, nausea, vomiting, mucositis (inflammation of mucosal linings), and stomatitis (mouth sores).[1] The inclusion of oteracil in the S-1 formulation was a specific design feature intended to reduce the incidence and severity of these gastrointestinal toxicities by limiting 5-FU activation in the gut.[2]
• Hematologic Toxicity (Myelosuppression): Tegafur and its active metabolites are potent myelosuppressive agents, frequently causing a decrease in blood cell counts. This can lead to neutropenia (low neutrophils), leukopenia (low white blood cells), thrombocytopenia (low platelets), and anemia (low red blood cells).[1] These conditions increase the patient's risk of serious infections, bleeding complications, and fatigue. Regular monitoring of complete blood counts is mandatory during treatment.[44]
• Neurotoxicity: Central neurotoxicity, which can include symptoms such as confusion, dizziness, and in more severe cases, leukoencephalopathy, has been reported to be more common with Tegafur than with intravenous 5-FU.[5] Peripheral neuropathy, characterized by numbness or tingling in the hands and feet, can also occur.[48]
• Dermatologic Toxicity: Skin-related side effects include skin discoloration, rashes, and alopecia (hair loss).[2] A notable advantage of S-1 is its significantly lower incidence of hand-foot syndrome (palmar-plantar erythrodysesthesia) compared to capecitabine, another oral fluoropyrimidine.[49] This difference has become a key factor in clinical decision-making, carving out a specific therapeutic niche for S-1 in patients who experience or are at high risk for this debilitating side effect.
• Other Adverse Events: Systemic side effects such as fatigue, anorexia (loss of appetite), and weight loss are common.[30] Less frequently, more serious toxicities like cardiotoxicity (irregular heartbeat, chest pain) and hepatotoxicity (elevated liver enzymes) can occur, requiring careful monitoring, especially in patients with pre-existing conditions.[48]

Pharmacogenetics: The Critical Role of DPD Deficiency

The safe administration of Tegafur is inextricably linked to the patient's genetic makeup, specifically the functionality of the DPD enzyme.

• DPD Function and Clinical Impact: The DPD enzyme, encoded by the DPYD gene, is the rate-limiting enzyme in the catabolism of 5-FU, responsible for detoxifying over 80% of the active drug.[5] Genetic variations within the DPYD gene can result in reduced or completely absent DPD enzyme activity. Patients with partial or complete DPD deficiency are unable to clear 5-FU effectively. This leads to prolonged and dramatically elevated exposure to the cytotoxic drug, placing them at a significantly increased risk of developing severe, life-threatening, or even fatal toxicities, including profound myelosuppression, severe mucositis, and neurotoxicity.[1]
• Clinical Recommendations for Testing: Recognizing this critical risk, regulatory bodies like the European Medicines Agency (EMA) strongly recommend pre-treatment screening for DPD deficiency before initiating therapy with Teysuno (S-1).[8] The drug is explicitly contraindicated in patients with known complete DPD deficiency. For patients identified with partial DPD deficiency, a reduced starting dose should be considered to mitigate the risk of severe toxicity.[8] Genotyping for specific high-risk DPYD variants, such as c.1905+1G>A (DPYD*2A), c.1679T>G (DPYD*13), c.2846A>T, and c.1236G>A/HapB3, is a key component of this screening strategy.[8]

Contraindications and Precautions

Several absolute contraindications and important precautions must be observed to ensure patient safety.

• Absolute Contraindications:
• Known complete dihydropyrimidine dehydrogenase (DPD) deficiency.[8]
• A history of severe and unexpected reactions to prior fluoropyrimidine therapy.[42]
• Pregnancy and breastfeeding, due to the potential for teratogenesis and harm to the infant.[1]
• Severe, pre-existing bone marrow suppression (leukopenia, neutropenia, or thrombocytopenia).[4]
• End-stage renal disease requiring dialysis.[35]
• Precautions:
• Treatment requires careful supervision by a physician experienced in cancer chemotherapy.[43]
• Use with caution in patients with moderate renal impairment (dose reduction required) and hepatic impairment (monitoring required).[42]
• Regular monitoring of complete blood counts, liver function tests, and renal function is essential throughout treatment.[45]

Significant Drug-Drug Interactions

Tegafur and its metabolites can interact with numerous other medications, potentially altering efficacy or increasing toxicity.

• DPD Inhibitors: The co-administration of Tegafur-based therapies with potent DPD inhibitors, such as the antiviral agents sorivudine and its analogue brivudine, is strictly contraindicated. This combination can lead to a dramatic and potentially fatal increase in 5-FU plasma concentrations. A washout period of at least four weeks must be observed between the use of these agents.[35]
• Coumarin-derivative Anticoagulants: Tegafur can potentiate the effects of anticoagulants like warfarin, leading to an increased risk of bleeding. Patients on concurrent therapy require close monitoring of their coagulation parameters (INR or PT) and may need adjustments to their anticoagulant dose.[1]
• Phenytoin: Concomitant use can lead to elevated plasma concentrations of phenytoin, increasing the risk of phenytoin-related toxicity.[1]
• Folic Acid/Leucovorin: While intentionally used to biochemically modulate and enhance the antitumor activity of 5-FU, this combination also increases the potential for 5-FU-related toxicities and must be managed carefully.[1]

Comparative Therapeutic Analysis

The clinical positioning of Tegafur-based therapies is best understood by comparing them to the historical standard, intravenous 5-FU, and their primary oral competitor, capecitabine.

Tegafur-based Regimens vs. Intravenous 5-FU

The development of oral Tegafur formulations was a direct attempt to replicate the efficacy of continuous infusion 5-FU while improving convenience and safety.

• Efficacy: Clinical evidence has largely validated this approach. The pivotal FLAGS trial established that S-1 plus cisplatin was non-inferior to a standard regimen of infusional 5-FU plus cisplatin for the treatment of advanced gastric cancer.[22] Similarly, meta-analyses have concluded that UFT plus leucovorin is equally efficacious to intravenous 5-FU regimens in the treatment of colorectal cancer.[29] These findings confirm that the oral prodrug strategy can achieve therapeutic outcomes comparable to the intravenous standard.
• Safety: The safety profiles differ significantly. Bolus intravenous 5-FU is primarily associated with myelosuppression, whereas continuous infusion is linked to a higher incidence of hand-foot syndrome and mucositis.[22] Tegafur-based regimens offer their own distinct profiles. For instance, the S-1 plus cisplatin arm in the FLAGS trial demonstrated significant safety advantages over the 5-FU plus cisplatin arm, partly due to a lower accompanying cisplatin dose.[22] UFT regimens are noted for being well-tolerated and avoiding the severe neutropenia often seen with bolus 5-FU schedules.[28]
• Convenience and Patient Preference: The most significant advantage of Tegafur-based therapies is the oral route of administration. This eliminates the need for central venous catheters, portable infusion pumps, and frequent hospital visits for drug administration. This improvement in convenience translates to a substantial enhancement in patient quality of life and a strong patient preference for oral over intravenous therapy.[20]

Tegafur-based Regimens vs. Capecitabine

Capecitabine is the other major oral 5-FU prodrug, making its comparison with Tegafur-based therapies, particularly S-1, highly relevant for clinical practice.

• Efficacy: A substantial body of evidence from head-to-head randomized trials and meta-analyses indicates that S-1-based and capecitabine-based chemotherapy regimens have comparable efficacy in the treatment of both gastric and colorectal cancer. Key endpoints such as overall survival, progression-free survival, and objective response rates are generally not significantly different between the two agents when used in similar settings.[36]
• Safety: The primary distinction between S-1 and capecitabine lies in their safety and tolerability profiles. This difference is a key driver of clinical decision-making.
• Hand-Foot Syndrome (HFS): There is consistent and robust evidence that S-1 is associated with a significantly lower incidence and severity of HFS compared to capecitabine.[47]
• Diarrhea and Neutropenia: Conversely, some meta-analyses suggest that S-1 may be associated with a higher incidence of diarrhea, while capecitabine may be linked to a higher rate of grade 3-4 neutropenia in certain combination regimens.[49]
• Clinical Choice: The decision between S-1 and capecitabine often hinges on the anticipated toxicity profile and patient-specific factors. S-1 is frequently considered a superior option for patients who have previously experienced HFS with capecitabine or for those deemed to be at high risk for developing this side effect. This has been formally recognized by the EMA's approval of Teysuno for mCRC patients intolerant to other fluoropyrimidines.[34]

Endpoint	S-1 Based Regimens	Capecitabine-Based Regimens	Odds Ratio (95% CI)	P-value	Source(s)
1-Year Survival Rate	Recurrence: 45.8%	Recurrence: 50.5%	0.80 (0.52–1.21)	0.29	54
Overall Response Rate (ORR)	37.6%	38.8%	0.94 (0.59–1.51)	0.93	54
Any Grade Hand-Foot Syndrome	Lower Incidence	Higher Incidence	0.16 (0.10–0.27)	<0.00001	54

Global Regulatory Status and Clinical Adoption

The clinical availability and adoption of Tegafur-based therapies vary dramatically across the globe, reflecting a complex history of drug development, regional clinical trials, and differing regulatory philosophies.

European Medicines Agency (EMA)

In the European Union, the combination of tegafur/gimeracil/oteracil is approved and marketed under the brand name Teysuno.[1]

• Approved Indications:

1. Advanced Gastric Cancer: Teysuno was first approved in March 2011 for the treatment of advanced gastric cancer when given in combination with cisplatin. This approval was based on the positive benefit-risk balance demonstrated in the pivotal FLAGS trial, which established non-inferiority to an infusional 5-FU regimen.[4]
2. Metastatic Colorectal Cancer: In late 2021, the Committee for Medicinal Products for Human Use (CHMP) recommended, and the indication was subsequently expanded, to include the treatment of patients with mCRC for whom it is not possible to continue therapy with another fluoropyrimidine due to the development of hand-foot syndrome or cardiovascular toxicity.[34]

• The EMA label for Teysuno carries strong recommendations for pre-treatment screening for DPD deficiency.[8]

Pharmaceuticals and Medical Devices Agency (PMDA) of Japan

Japan is the country of origin for Tegafur-based combination therapies, and as such, it has the most extensive history of clinical use and the broadest range of approvals.

• Brand Name: The tegafur/gimeracil/oteracil combination is known as TS-1.[7] It was first approved in Japan in 1999.[7]
• Approved Indications: TS-1 is a standard-of-care agent in Japan with a wide array of approved indications, including: gastric cancer, colorectal cancer, head and neck cancer, non-small cell lung cancer, inoperable or recurrent breast cancer, pancreatic cancer, and biliary tract cancer. A notable recent addition is its approval for postoperative adjuvant chemotherapy for hormone receptor-positive, HER2-negative breast cancer at high risk of recurrence.[6] The UFT formulation is also widely approved and utilized for many of these same cancers.[20]

U.S. Food and Drug Administration (FDA)

In stark contrast to its status in Asia and Europe, Tegafur and its combination formulations are not approved for medical use in the United States.[11]

• While the combination of tegafur/gimeracil/oteracil received an Orphan Drug Designation from the FDA for the treatment of gastric cancer in 2006, this designation did not culminate in a marketing approval.[12]
• This lack of approval signifies a major divergence in the global oncology landscape. This disparity is not arbitrary but rather a reflection of the drug's specific development pathway. Tegafur-based therapies were conceived and underwent their initial, extensive clinical evaluation primarily in Japan and with Asian patient populations.[20] The subsequent path to approval in Europe required a dedicated global trial (FLAGS) that utilized a modified, lower dose specifically for Western populations to account for known pharmacogenomic differences in CYP2A6 metabolism.[22] The absence of a similar large-scale, US-centric clinical development program designed to meet the specific evidentiary requirements of the FDA is the most likely reason for its non-approval in the United States. The regulatory status of Tegafur is therefore a clear illustration of how regional drug development, population-specific pharmacogenomics, and differing regulatory standards can shape the global availability of a cancer therapy.

Regulatory Agency	Region	Brand Name	Approval Status	Key Approved Indications
PMDA	Japan	TS-1	Approved	Gastric, Colorectal, Breast, Lung, Pancreatic, Head & Neck, Biliary Tract Cancers
EMA	European Union	Teysuno	Approved	Advanced Gastric Cancer; mCRC (post-intolerance to other fluoropyrimidines)
FDA	United States	N/A	Not Approved	N/A

Conclusion and Future Perspectives

Tegafur has firmly established its place in modern oncology not as a standalone agent, but as the central component of intelligently designed oral combination therapies, UFT and S-1. These formulations successfully translate the potent, time-tested cytotoxicity of 5-fluorouracil into a convenient, orally administered form. More importantly, they represent a triumph of rational drug design, employing biochemical modulators to manipulate the pharmacokinetics of 5-FU to enhance its therapeutic index—boosting efficacy by inhibiting its degradation while, in the case of S-1, actively protecting against localized gastrointestinal toxicity.

The clinical data are clear: Tegafur-based regimens offer efficacy comparable to that of intravenous 5-FU for major indications like gastric and colorectal cancer, but with the profound advantages of oral administration and often more manageable safety profiles. The comparison with capecitabine reveals two oral agents with similar efficacy but distinct toxicity profiles, a crucial distinction that allows for personalized treatment selection. The significantly lower incidence of hand-foot syndrome with S-1 has defined a vital clinical niche for patients intolerant to capecitabine, enabling the continuation of essential fluoropyrimidine therapy.

The safe and effective use of Tegafur is critically dependent on an understanding of patient pharmacogenetics. The high risk of severe toxicity in individuals with DPD deficiency underscores the necessity of pre-treatment screening, positioning Tegafur-based drugs at the forefront of personalized cancer medicine. The divergent global regulatory status further highlights the impact of regional drug development and population-specific pharmacogenomics on clinical practice worldwide.

Looking forward, the role of Tegafur is likely to continue evolving. Its established efficacy and favorable safety profile make it an attractive backbone for combination with novel agents, including targeted therapies and immunotherapies, in ongoing efforts to improve outcomes in gastrointestinal and other solid tumors. Further prospective trials, particularly in Western populations, are warranted to better define its optimal use and potentially expand its indications. Finally, the cost-effectiveness of established oral regimens like UFT may present a valuable option in resource-constrained healthcare settings, ensuring that the benefits of fluoropyrimidine therapy remain accessible to a broad range of patients globally.

Works cited

1. Tegafur: Uses, Interactions, Mechanism of Action | DrugBank Online, accessed August 29, 2025, https://go.drugbank.com/drugs/DB09256
2. Tegafur – Knowledge and References - Taylor & Francis, accessed August 29, 2025, https://taylorandfrancis.com/knowledge/Medicine_and_healthcare/Pharmaceutical_medicine/Tegafur/
3. Definition of tegafur - NCI Drug Dictionary, accessed August 29, 2025, https://www.cancer.gov/publications/dictionaries/cancer-drug/def/tegafur
4. Tegafur/gimeracil/oteracil - Wikipedia, accessed August 29, 2025, https://en.wikipedia.org/wiki/Tegafur/gimeracil/oteracil
5. Tegafur - Wikipedia, accessed August 29, 2025, https://en.wikipedia.org/wiki/Tegafur
6. Tegafur/Uracil - Drug Targets, Indications, Patents - Patsnap Synapse, accessed August 29, 2025, https://synapse.patsnap.com/drug/fedd118683564aa089a68b2bd8195dc3
7. Taiho Pharmaceutical Obtains Additional Indication of "Postoperative Adjuvant Chemotherapy for Hormone Receptor-Positive and HER2-Negative Breast Cancer at High Risk of Recurrence" for Oral Anticancer Agent TS-1, accessed August 29, 2025, https://www.taiho.co.jp/en/release/2022/20221124.html
8. Annotation of EMA Label for tegafur / gimeracil / oteracil and DPYD - PharmGKB, accessed August 29, 2025, https://www.pharmgkb.org/label/PA166271261
9. Teysuno | European Medicines Agency (EMA), accessed August 29, 2025, https://www.ema.europa.eu/en/medicines/human/EPAR/teysuno
10. Review Report October 18, 2022 Pharmaceuticals and Medical ..., accessed August 29, 2025, https://www.pmda.go.jp/files/000267330.pdf
11. Tegafur-uracil: Uses, Interactions, Mechanism of Action | DrugBank Online, accessed August 29, 2025, https://go.drugbank.com/drugs/DB09327
12. Search Orphan Drug Designations and Approvals - FDA, accessed August 29, 2025, https://www.accessdata.fda.gov/scripts/opdlisting/oopd/detailedIndex.cfm?cfgridkey=225006
13. Tegafur | CAS 17902-23-7 | SCBT - Santa Cruz Biotechnology, accessed August 29, 2025, https://www.scbt.com/p/tegafur-17902-23-7
14. CAS 17902-23-7 Tegafur - BOC Sciences, accessed August 29, 2025, https://www.bocsci.com/product/tegafur-cas-17902-23-7-61328.html
15. Tegafur - Cayman Chemical, accessed August 29, 2025, https://www.caymanchem.com/product/26076/tegafur
16. 17902-23-7|5-Fluoro-1-(tetrahydrofuran-2-yl)pyrimidine-2,4(1H,3H)-dione - BLDpharm, accessed August 29, 2025, https://www.bldpharm.com/products/17902-23-7.html
17. Tegafur | CAS 17902-23-7 - LGC Standards, accessed August 29, 2025, https://www.lgcstandards.com/FM/en/Tegafur/p/TRC-T013900?queryID=53021d31c6a7edcd190ad119e2715a18
18. Tegafur = 98 HPLC, powder 17902-23-7 - Sigma-Aldrich, accessed August 29, 2025, https://www.sigmaaldrich.com/US/en/product/sigma/t7205
19. tegafur | Ligand page - IUPHAR/BPS Guide to PHARMACOLOGY, accessed August 29, 2025, https://www.guidetopharmacology.org/GRAC/LigandDisplayForward?tab=clinical&ligandId=10513
20. Tegafur/uracil - Wikipedia, accessed August 29, 2025, https://en.wikipedia.org/wiki/Tegafur/uracil
21. UFT: mechanism of drug action - PubMed, accessed August 29, 2025, https://pubmed.ncbi.nlm.nih.gov/11098484/
22. Tegafur/gimeracil/oteracil (S-1) approved for the treatment of ..., accessed August 29, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC3233278/
23. Tegafur/gimeracil/oteracil (S-1) approved for the treatment of advance | OTT, accessed August 29, 2025, https://www.dovepress.com/tegafurgimeraciloteracil-s-1-approved-for-the-treatment-of-advanced-ga-peer-reviewed-fulltext-article-OTT
24. Definition of tegafur-uracil - NCI Drug Dictionary, accessed August 29, 2025, https://www.cancer.gov/publications/dictionaries/cancer-drug/def/tegafur-uracil
25. Uracil-tegafur in gastric carcinoma: a comprehensive review - PubMed, accessed August 29, 2025, https://pubmed.ncbi.nlm.nih.gov/9704742/
26. Variability in the anti-tumor effect of tegafur-uracil depending on histologic types of lung cancer - Journal of Thoracic Disease, accessed August 29, 2025, https://jtd.amegroups.org/article/view/4095/html
27. Tegafur and uracil plus leucovorin in advanced colorectal cancer: a phase II trial - PubMed, accessed August 29, 2025, https://pubmed.ncbi.nlm.nih.gov/12445378/
28. Phase II trial of uracil and tegafur plus oral leucovorin: an effective oral regimen in the treatment of metastatic colorectal carcinoma. - ASCO Publications, accessed August 29, 2025, https://ascopubs.org/doi/10.1200/JCO.1994.12.11.2296
29. Oral Tegafur-Uracil Combination plus Leucovorin versus Other Fluoropyrimidine Agents in Colorectal Cancer - Semantic Scholar, accessed August 29, 2025, https://pdfs.semanticscholar.org/8576/5227a7e6359ccf582d16abf6fc8d2148fd42.pdf
30. Uracil-Tegafur as Adjuvant Chemotherapy in Lung Cancer - AAFP, accessed August 29, 2025, https://www.aafp.org/pubs/afp/issues/2005/0101/p185.html
31. A twice-daily or a three-times-daily tegafur-uracil and leucovorin calcium regimen as adjuvant therapy in patients with resected colorectal cancer: A phase III study. - ASCO Publications, accessed August 29, 2025, https://ascopubs.org/doi/10.1200/JCO.2022.40.4_suppl.038
32. The European Medicines Agency Review of Tegafur/Gimeracil/Oteracil (Teysuno™) for the Treatment of Advanced Gastric Cancer When Given in Combination with Cisplatin - PubMed Central, accessed August 29, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC3228070/
33. Sequential paclitaxel followed by tegafur and uracil (UFT) or S-1 versus UFT or S-1 monotherapy as adjuvant chemotherapy for T4a/b gastric cancer (SAMIT): a phase 3 factorial randomised controlled trial - PubMed, accessed August 29, 2025, https://pubmed.ncbi.nlm.nih.gov/24954805/
34. Tegafur/gimeracil/oteracil (Teysuno®) for the treatment of metastatic colorectal cancer, accessed August 29, 2025, https://eprints.aihta.at/1357/1/Oncology%20Fact%20Sheet%20Nr.76_Update.pdf
35. Teysuno, INN-tegafur,gimeracil,oteracil - European Medicines Agency, accessed August 29, 2025, https://www.ema.europa.eu/en/documents/product-information/teysuno-epar-product-information_en.pdf
36. Systematic review and non-inferiority meta-analysis of randomised phase II/III trials on S-1-based therapy versus 5-fluorouracil- or capecitabine-based therapy in the treatment of patients with metastatic colorectal cancer - PubMed, accessed August 29, 2025, https://pubmed.ncbi.nlm.nih.gov/35279472/
37. Tegafur Recruiting Phase 3 Trials for Gastric Cancer Treatment | DrugBank Online, accessed August 29, 2025, https://go.drugbank.com/drugs/DB09256/clinical_trials?conditions=DBCOND0028483&phase=3&purpose=treatment&status=recruiting
38. Non-Small Cell Lung Cancer Completed Phase Trials for Tegafur (DB09256) - DrugBank, accessed August 29, 2025, https://go.drugbank.com/indications/DBCOND0132865/clinical_trials/DB09256?status=completed
39. Tegafur–Uracil Maintenance Therapy in Non-Metastatic Head and Neck Cancer: An Exploratory Systematic Review - MDPI, accessed August 29, 2025, https://www.mdpi.com/1718-7729/32/5/286
40. Hepatic Carcinoma Completed Phase 1 Trials for Tegafur (DB09256) | DrugBank Online, accessed August 29, 2025, https://go.drugbank.com/indications/DBCOND0043539/clinical_trials/DB09256?phase=1&status=completed
41. Her-2 Positive Gastric Cancer Unknown Status Phase 2 Trials for Tegafur (DB09256), accessed August 29, 2025, https://go.drugbank.com/indications/DBCOND0053277/clinical_trials/DB09256?phase=2&status=unknown_status
42. Teysuno, tegafur/gimeracil/oteracil, accessed August 29, 2025, https://ec.europa.eu/health/documents/community-register/2016/20161111136083/anx_136083_en.pdf
43. tegafur/gimeracil/oteracil 15mg/4.35mg/11.8mg and 20mg/5.8mg/15.8mg hard capsules (Teysuno®) SMC No. (802/12) Nordic Pharm - Scottish Medicines Consortium, accessed August 29, 2025, https://scottishmedicines.org.uk/media/2364/tegafur_gimeracil_oteracil_teysuno_final_august_2012_amended_110912_for_website.pdf
44. How is Tegafur (Ftorafur) administered? - Dr.Oracle AI, accessed August 29, 2025, https://www.droracle.ai/articles/129860/how-is-tegafur-given
45. Tegafur - Uses, Dosage, Side Effects, Price, Composition | Practo, accessed August 29, 2025, https://www.practo.com/medicine-info/tegafur-2841-api
46. Tegafur, Gimeracil, and Oteracil: View Uses, Side Effects and Medicines - MrMed, accessed August 29, 2025, https://www.mrmed.in/molecule/tegafur-gimeracil-oteracil
47. (PDF) Randomised study of tegafur–uracil plus leucovorin versus capecitabine as first-line therapy in elderly patients with advanced colorectal cancer — TLC study - ResearchGate, accessed August 29, 2025, https://www.researchgate.net/publication/278049803_Randomised_study_of_tegafur-uracil_plus_leucovorin_versus_capecitabine_as_first-line_therapy_in_elderly_patients_with_advanced_colorectal_cancer_-_TLC_study
48. What are the side effects of Tegafur? - Patsnap Synapse, accessed August 29, 2025, https://synapse.patsnap.com/article/what-are-the-side-effects-of-tegafur
49. Tegafur-uracil | CancerIndex, accessed August 29, 2025, http://www.cancerindex.org/Tegafur_uracil
50. The efficacy and safety of capecitabine-based versus S-1-based chemotherapy for metastatic or recurrent gastric cancer: a systematic review and meta-analysis of clinical randomized trials, accessed August 29, 2025, https://apm.amegroups.org/article/view/40988/html
51. UFT combination capsule T100 [Folinate combination therapy] | Kusuri-no-Shiori(Drug Information Sheet), accessed August 29, 2025, https://www.rad-ar.or.jp/siori/english/search/result?n=42195
52. Clinical studies of three oral prodrugs of 5-fluorouracil (capecitabine, UFT, S-1): a review - PubMed, accessed August 29, 2025, https://pubmed.ncbi.nlm.nih.gov/12185293/
53. Oral capecitabine vs intravenous 5-fluorouracil and leucovorin: integrated efficacy data and novel analyses from two large, randomised, phase III trials - PMC - PubMed Central, accessed August 29, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC2409640/
54. Efficacy of S-1 vs capecitabine for the treatment of gastric cancer: A ..., accessed August 29, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC4394098/
55. Positive EMA opinion for the use of Teysuno in metastatic colorectal cancer - Nordic Pharma, accessed August 29, 2025, https://www.nordicpharma.com/positive-ema-opinion-for-the-use-of-teysuno-in-metastatic-colorectal-cancer/
56. (PDF) The European Medicines Agency Review of Tegafur/Gimeracil/Oteracil (Teysuno (TM)) for the Treatment of Advanced Gastric Cancer When Given in Combination with Cisplatin - ResearchGate, accessed August 29, 2025, https://www.researchgate.net/publication/51686065_The_European_Medicines_Agency_Review_of_TegafurGimeracilOteracil_Teysuno_TM_for_the_Treatment_of_Advanced_Gastric_Cancer_When_Given_in_Combination_with_Cisplatin_Summary_of_the_Scientific_Assessment_o
57. Practical Consensus Guidelines for the Use of S-1 in GI Malignancies - PMC, accessed August 29, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC11076077/