Variables related to locoregional and distant recurrence in esophageal cancer

FONSECA, Sarah; RAMOS, Igor Gabriel Silva; MAEGAWA, Felipe Antonio Boff; USON JUNIOR, Pedro Luiz Serrano; TUSTUMI, Francisco

doi:10.1590/0102-67202025000020e1889

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Original Article • ABCD, arq. bras. cir. dig. 38 • 2025 • https://doi.org/10.1590/0102-67202025000020e1889 linkcopy

Variables related to locoregional and distant recurrence in esophageal cancer

Variáveis relacionadas à recidiva locoregional e à distância no câncer de esôfago

Authorship SCIMAGO INSTITUTIONS RANKINGS

ABSTRACT

Background: Esophageal cancer remains one of the most aggressive malignancies of the gastrointestinal tract, with high rates of recurrence and mortality despite curative-intent surgery and adjuvant therapies. Identifying factors associated with recurrence is crucial for improving outcomes and guiding personalized treatment.

Aims: The aim of this study was to evaluate pretreatment and treatment-related variables associated with recurrence in patients with esophageal cancer undergoing surgical resection.

Methods: This retrospective study analyzed data from patients with stage I–III esophageal carcinoma who underwent esophagectomy between 2000 and 2025, using the Fundação Oncocentro de São Paulo (FOSP) database. Clinical, histological, and treatment-related variables were evaluated. Disease-free survival and recurrence patterns were assessed using Cox proportional hazards models and Fine–Gray subdistribution hazard models.

Results: A total of 2,057 patients were included, with a mean follow-up of 36.5 months (±44.8). In the multivariate analysis, advanced tumor stage (stage II: HR 1.68, 95%CI 1.21–2.33; stage III: HR 3.23, 95%CI 2.29–4.56; both p<0.01), location (middle esophagus: HR 1.31, 95%CI 1.11–1.54; p=0.001; upper esophagus: HR 1.54, 95%CI 1.21–1.96; p<0.001), and histological subtype (rare histologies: HR 2.17, 95%CI 1.35–3.49; p=0.001) were associated with worse disease-free survival. Multimodal therapy improved disease-free survival (HR 0.40, 95%CI 0.24–0.66) in stage III tumors. Squamous cell carcinoma was independently associated with locoregional recurrence (SHR 1.52, 95%CI 1.05–2.20; p=0.027). For distant recurrence, squamous cell carcinoma showed a protective effect (SHR 0.52, 95%CI 0.31–0.88; p=0.015), while high tumor grade (grade II: SHR 3.65, 95%CI 1.98–6.72; p<0.001) was associated with an increased risk. Multimodal treatments influenced recurrence patterns but did not independently predict outcomes after adjustment.

Conclusions: Tumor stage, location, and histology were strong predictors of disease-free survival after surgery for esophageal cancer. Histological subtypes significantly influenced recurrence patterns. Squamous cell carcinoma was associated with a higher risk of locoregional recurrence but a lower risk of distant metastasis compared to adenocarcinoma. Multimodal therapy demonstrated a protective effect in stage III disease.

Keywords:
Esophageal Neoplasms; Recurrence; Prognosis; Surgical Procedures; Neoplasm Staging

ARTICLE HIGHLIGHTS

Tumor stage, location, and histology were strong predictors of disease-free survival after surgery for esophageal cancer.
Histologic subtypes significantly influenced recurrence patterns.
Squamous cell carcinoma is associated with a higher risk of locoregional recurrence but a lower risk of distant metastasis compared with adenocarcinoma.
Multimodal therapy effectively reduces recurrence in stage III tumors, emphasizing the importance of stage-specific treatment strategies.

CENTRAL MESSAGE

In this population-based study of Brazilian patients undergoing surgery for esophageal cancer, tumor stage, tumor location, and histological subtype emerged as key predictors of disease-free survival. Squamous cell carcinoma was linked to an increased risk of locoregional recurrence but a reduced risk of distant metastasis compared to adenocarcinoma. Importantly, multimodal therapy significantly improved outcomes in patients with stage III disease.

PERSPECTIVES

This study helps doctors to better manage patients after surgery for esophageal cancer. Identifying who is most at risk for cancer returning, based on preoperative information, supports more personalized follow-up and treatment plans. The findings also suggest that doctors should carefully consider when to use treatments such as chemo or radiation, especially in patients with more aggressive cancers. This can lead to better care and outcomes for those facing this severe disease.

VISUAL ABSTRACT

	n	%
Total
-	2,057	100
Age (years)
≤65	1,529	74.33
>65	528	25.67
Sex
Male	1,683	81.82
Female	374	18.18
Location
Lower	491	41.36
Middle	568	47.85
Upper	128	10.78
Cancer type
Adenocarcinoma	417	21.26
SCC	1,499	76.44
Other histologies	45	2.29
Stage
I	334	16.24
II	807	39.23
III	916	44.53
T stage
T1	350	17.05
T2	379	18.46
T3	1,002	48.81
T4	322	15.68
N stage
N0	1,117	55.35
N1	790	39.15
N2	78	3.87
N3	33	1.64
Grade
1	255	37.17
2	421	61.37
3	10	1.46
Treatment
Surgery	652	35.53
Surgery + CRT	917	49.97
Surgery + CT	266	14.50

Disease-free survival
	HR	95%CI	p-value
Age (years)
>65	ref.		0.077
≤65	0.90	0.81–1.01	0.077
Sex
Female	ref.	25.67	0.010
Male	1.19	1.04–1.35	0.010
Location
Lower	ref.
Middle	1.30	1.13–1.49	<0.001
Upper	1.52	1.22–1.88	<0.001
Cancer type
Adenocarcinoma	ref.
SCC	1.29	1.14–1.47	<0.001
Other histologies	1.68	1.21–2.34	0.002
Stage
I	ref.
II	1.61	1.37–1.89	<0.001
III	2.36	2.01–2.75	<0.001
T stage
T1	ref.
T2	1.41	1.18–1.68	<0.001
T3	1.80	1.55–2.09	<0.001
T4	3.05	2.56–3.64	<0.001
N stage
N0
N1	1.32	1.19–1.46	<0.001
N2	1.31	1.00–1.71	0.054
N3	1.60	1.09–2.35	0.016
Grade
1	ref.
2	1.07	0.89–1.29	0.488
3	1.65	0.81–3.34	0.169
Treatment
Surgery	ref.
Surgery + CRT	1.36	1.21–1.52	<0.001
Surgery + CT	1.38	1.17–1.63	<0.001

Locoregional recurrence
	Univariate			Multivariate
	SHR	95%CI	p-value	SHR	95%CI	p-value
Age (years)
>65	ref.
≤65	1.08	0.81–1.45	0.597
Sex
Female	ref.
Male	1.45	1.00–2.08	0.048	1.27	0.87-1.86	0.210
Location
Lower
Middle	1.28	0.92–1.80	0.147
Upper	0.90	0.49–1.64	0.721
Cancer type
Adenocarcinoma	ref.
SCC	1.35	0.96–1.90	0.081	1.52	1.05-2.20	0.027
Other histologies	1.12	0.44–2.88	0.811	1.00	0.35-2.88	0.994
Stage
I	ref.
II	1.39	0.94–2.06	0.095	1.42	0.95-2.15	0.090
III	1.22	0.82–1.80	0.327	1.24	0.81–1.89	0.330
T stage*
T1	ref.
T2	1.44	0.95–2.19	0.088
T3	1.26	0.87–1.83	0.217
T4	0.97	0.60–1.57	0.913
N stage*
N0	ref.
N1	1.08	0.84–1.39	0.555
N2	0.70	0.31–1.59	0.396
N3	0.50	0.12–2.03	0.334
Grade†
I	ref.
II	0.78	0.48–1.27	0.321
III	~0	0.00–0.00	<0.001
Treatment
Surgery	ref.
Surgery + CRT	0.83	0.63–1.10	0.196	0.78	0.58-1.05	0.100
Surgery + CT	0.82	0.54–1.25	0.357	0.94	0.60–1.47	0.773
Distant recurrence
	Univariate			Multivariate
	SHR	95%CI	p-value	SHR	95%CI	p-value
Age (years)
>65
≤65	0.85	0.59–1.23	0.393
Sex
Female
Male	0.94	0.61–1.43	0.769
Location
Lower
Middle	0.94	0.63-1.39	0.748
Upper	0.47	0.20–1.10	0.082
Cancer type
Adenocarcinoma
SCC	0.65	0.45–0.95	0.025	0.52	0.31–0.88	0.015
Other histologies	1.18	0.46–3.03	0.726	0.55	0.13-2.31	0.414
Stage
I
II	2.05	1.11–3.79	0.023	1.14	0.50–2.59	0.756
III	1.98	1.07–3.66	0.029	1.27	0.56–2.87	0.572
T stage*
T1
T2	1.87	0.99–3.53	0.053
T3	1.91	1.08–3.38	0.026
T4	1.38	0.68–2.77	0.370
N stage*
N0
N1	0.92	0.64–1.33	0.666
N2	2.05	1.02–4.12	0.044
N3	3.65	1.69–7.89	0.001
Grade
I
II	4.13	2.20–7.77	<0.001	3.65	1.98–6.72	<0.001
III	5.21	1.11–24.43	0.036	4.75	0.97–23.29	0.055
Treatment
Surgery
Surgery + CRT	2.64	1.70–4.10	<0.001	1.65	0.83-3.27	0.154
Surgery + CT	1.58	0.84–2.99	0.159	0.49	0.17–1.37	0.173

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[T1FN1] SCC: Squamous cell carcinoma; CRT: Chemoradiotherapy; CT: Chemotherapy.