World J Oncol

World Journal of Oncology, ISSN 1920-4531 print, 1920-454X online, Open Access

Article copyright, the authors; Journal compilation copyright, World J Oncol and Elmer Press Inc

Journal website https://wjon.elmerpub.com

Original Article

Volume 16, Number 6, December 2025, pages 609-620

Efficacy of Tegafur-Uracil Maintenance Therapy in Non-Metastatic Head and Neck Squamous Cell Carcinoma: A Meta-Analysis With Trial Sequential Analysis

Figure 1. PRISMA flow diagram for study selection. PRISMA: Preferred Reporting Items for Systematic Reviews and Meta-Analyses.

Figure 2. Forest plot for progression-free survival (PFS) in head and neck squamous cell carcinoma (HNSCC). HR: hazard ratio; CI: confidence interval.

Figure 3. Trial sequential analysis for progression-free survival (PFS-TSA). The blue line represents the cumulative Z-curve, which crosses both the conventional boundary for benefit (inner green line, Z = 1.96) and the trial sequential monitoring boundary for benefit (outer dashed red line). The cumulative sample size (1,280 patients) has reached 90.6% of the required information size (APIS = 1,413 patients, vertical red line), suggesting that the evidence for a benefit in PFS is sufficient and conclusive.

Figure 4. Forest plot for overall survival (OS) in head and neck squamous cell carcinoma (HNSCC). HR: hazard ratio; CI: confidence interval.

Figure 5. Trial sequential analysis for overall survival (OS-TSA). The blue line represents the cumulative Z-curve. Although the Z-curve has crossed the conventional boundary for benefit (inner green line, Z = 1.96), it has not yet crossed the more stringent trial sequential monitoring boundary (outer dashed red line). The cumulative sample size (1,373 patients) has only reached 75.6% of the required information size (APIS = 1,816 patients, vertical red line). This indicates that while there is a trend towards benefit, the evidence is not yet conclusive, and further studies are needed.

**Table 1.** Characteristics of Studies Evaluating UFT Maintenance Therapy in Advanced Head and Neck Cancers
Study (HNSCC)	Cancer type	Stage	Prior treatment	Treatment groups	Sample size
UFT: tegafur-uracil; HNSCC: head and neck squamous cell carcinoma; CCRT: concurrent chemoradiotherapy; OC: oral cavity; OPx: oropharynx; HPx: hypopharynx; Lx: larynx.
Huang et al, 2021 [19]	OC	IVa and IVb	Surgical resection and CCRT with cisplatin-based regimen	UFT vs. non-UFT	93 (51 UFT, 42 non-UFT)
Huang et al, 2022 [20]	OC	IVa and IVb	Curative surgical resection followed by adjuvant cisplatin-based CCRT	UFT vs. non-UFT	103 (64 UFT, 39 non-UFT)
Lien et al, 2023 [21]	HPx	25% III, 75% IVa-IVb	Total laryngopharyngectomy followed by adjuvant CRT	UFT vs. non-UFT in cortactin-positive and cortactin-negative patients	157 total (53 cortactin+, 104 cortactin-)
Yeh et al, 2021 [22]	OC, OPx, HPx	21% III, 79% IVa-IVb	Surgical resection, CCRT or chemotherapy	UFT vs. non-UFT	240 (96 UFT, 144 non-UFT)
Hsieh et al, 2018 [9]	OC	13% III, 87% IV	Curative surgery and postoperative chemoradiotherapy	UFT vs. non-UFT	356 (114 UFT, 242 non-UFT)
Hsieh et al, 2025 [23]	OC, OPx, HPx, Lx	9% stage I-II, 91% stage III-IVB	Definitive chemoradiotherapy without surgical intervention	UFT vs. non-UFT	424 (212 UFT, 212 non-UFT)

Table 1. Characteristics of Studies Evaluating UFT Maintenance Therapy in Advanced Head and Neck Cancers

Study (HNSCC)

Cancer type

Stage

Prior treatment

Treatment groups

Sample size

UFT: tegafur-uracil; HNSCC: head and neck squamous cell carcinoma; CCRT: concurrent chemoradiotherapy; OC: oral cavity; OPx: oropharynx; HPx: hypopharynx; Lx: larynx.

Huang et al, 2021 [19]

IVa and IVb

Surgical resection and CCRT with cisplatin-based regimen

UFT vs. non-UFT

93 (51 UFT, 42 non-UFT)

Huang et al, 2022 [20]

IVa and IVb

Curative surgical resection followed by adjuvant cisplatin-based CCRT

UFT vs. non-UFT

103 (64 UFT, 39 non-UFT)

Lien et al, 2023 [21]

HPx

25% III, 75% IVa-IVb

Total laryngopharyngectomy followed by adjuvant CRT

UFT vs. non-UFT in cortactin-positive and cortactin-negative patients

157 total (53 cortactin+, 104 cortactin-)

Yeh et al, 2021 [22]

OC, OPx, HPx

21% III, 79% IVa-IVb

Surgical resection, CCRT or chemotherapy

UFT vs. non-UFT

240 (96 UFT, 144 non-UFT)

Hsieh et al, 2018 [9]

13% III, 87% IV

Curative surgery and postoperative chemoradiotherapy

UFT vs. non-UFT

356 (114 UFT, 242 non-UFT)

Hsieh et al, 2025 [23]

OC, OPx, HPx, Lx

9% stage I-II, 91% stage III-IVB

Definitive chemoradiotherapy without surgical intervention

UFT vs. non-UFT

424 (212 UFT, 212 non-UFT)

**Table 2.** Patient Demographics and Disease Characteristics in UFT Maintenance Therapy Studies
Study (HNSCC)	Mean age (years)	Gender (male %)	ECOG PS (0 - 1) %	T classification	N classification
UFT: tegafur-uracil; HNSCC: head and neck squamous cell carcinoma; ECOG PS: Eastern Cooperative Oncology Group performance status.
Huang et al, 2021 [19]	UFT: 51.61	UFT: 90.2%	UFT: 92.0%	T3-T4: UFT 72.55%	N2-N3: UFT 60.78%, non-UFT 57.14%
	Non-UFT: 57.10	Non-UFT: 88.1%	Non-UFT: 66.66%	Non-UFT 73.81%
Huang et al, 2022 [20]	UFT: 49.8 ± 8.8	UFT: 90.6%	100% (all ECOG PS 1)	T4: UFT 46.9%	N3B: UFT 82.8%, non-UFT 92.3%
	Non-UFT: 49.9 ± 11.5	Non-UFT: 92.3%		Non-UFT 61.5%
Lien et al, 2023 [21]	Median: 54	98% (both groups)	Not reported	pT3-4: cortactin+ 70%, cortactin- 65%	pN3: cortactin+ 68%, cortactin- 51%
Yeh et al, 2021 [22]	UFT: 56 ± 10	UFT: 97.9%	Not reported	Not reported	Not reported
	Non-UFT: 54 ± 10	Non-UFT: 97.2%
Hsieh et al, 2018 [9]	UFT: 52 ± 10	UFT: 98%	Not reported	Not reported	Not reported
	Non-UFT: 54 ± 11	Non-UFT: 93%
Hsieh et al, 2025 [23]	UFT: 42% > 60 years	UFT: 95%	Not reported	T1-T2: UFT 39%, non-UFT 41%;	N0-N1: UFT 37%, non-UFT 30%
	Non-UFT: 36% > 60 years	Non-UFT: 92%		T3-T4: UFT 61%, non-UFT 59%	N2-N3: UFT 63%, non-UFT 70%

Table 2. Patient Demographics and Disease Characteristics in UFT Maintenance Therapy Studies

Study (HNSCC)

Mean age (years)

Gender (male %)

ECOG PS (0 - 1) %

T classification

N classification

UFT: tegafur-uracil; HNSCC: head and neck squamous cell carcinoma; ECOG PS: Eastern Cooperative Oncology Group performance status.

Huang et al, 2021 [19]

UFT: 51.61

UFT: 90.2%

UFT: 92.0%

T3-T4: UFT 72.55%

N2-N3: UFT 60.78%, non-UFT 57.14%

Non-UFT: 57.10

Non-UFT: 88.1%

Non-UFT: 66.66%

Non-UFT 73.81%

Huang et al, 2022 [20]

UFT: 49.8 ± 8.8

UFT: 90.6%

100% (all ECOG PS 1)

T4: UFT 46.9%

N3B: UFT 82.8%, non-UFT 92.3%

Non-UFT: 49.9 ± 11.5

Non-UFT: 92.3%

Non-UFT 61.5%

Lien et al, 2023 [21]

Median: 54

98% (both groups)

Not reported

pT3-4: cortactin+ 70%, cortactin- 65%

pN3: cortactin+ 68%, cortactin- 51%

Yeh et al, 2021 [22]

UFT: 56 ± 10

UFT: 97.9%

Not reported

Non-UFT: 54 ± 10

Non-UFT: 97.2%

Hsieh et al, 2018 [9]

UFT: 52 ± 10

UFT: 98%

Not reported

Non-UFT: 54 ± 11

Non-UFT: 93%

Hsieh et al, 2025 [23]

UFT: 42% > 60 years

UFT: 95%

Not reported

T1-T2: UFT 39%, non-UFT 41%;

N0-N1: UFT 37%, non-UFT 30%

Non-UFT: 36% > 60 years

Non-UFT: 92%

T3-T4: UFT 61%, non-UFT 59%

N2-N3: UFT 63%, non-UFT 70%