Current status and future perspectives for the treatment of resectable locally advanced esophagogastric junction cancer: A narrative review

Table 1 Patients with Siewert type I esophagogastric junction adenocarcinoma who underwent surgery at our institute

n	35
Male	34 (97.1%)
Age (yr)	67 (42-79)
Field of LN dissection 2/3	2/33
Open/MIE/Robot assisted	6/24/5
Preoperative chemotherapy	4 (11.4%)
Tumor size (mm)	35.3 (9-110)
Esophageal invasion length (mm)	30 (18-110)
pT 1a/1b/2/3/4a/4b1	4/10/3/18/0/0
pN 0/1/2/31	15/4/4/12
pM 0/11	30/5
pStage IA/IB/IIA/IIB/IIIA/IIIB/IVA/IVB1	3/7/2/6/0/4/8/5
Upper mediastinal LN metastasis	11/35 (31.4%)
Middle mediastinal LN metastasis	10/34 (29.4%)
Lower mediastinal LN metastasis	11/32 (34.4%)
Recurrence	14 (40.0%)
Site of recurrence2
Liver	5
Adrenal gland	5
Distant LN	3
Peritoneum	2
Bone	2
Pleura	1
Pancreas	1

¹Classified by the 8^th edition of the Union for International Cancer Control (UICC)-Tumor Node Metastasis (TNM) classification.

²Including overlapped cases.

EGJAC: Esophagogastric adenocarcinoma; LN: Lymph node; MIE: Minimally invasive esophagectomy.

Table 2 Details of the mediastinal lymph node metastasis for the patients in Table 1

LN location		Metastasis rate (%)
Upper mediastinum	Upper thoracic paraesophageal LN	8.5	(3/35)
	Left recurrent nerve LN	15.2	(5/33)
	Right recurrent nerve LN	20.6	(7/34)
	Left trachebronchial LN	17.4	(4/23)
Meddle mediastinum	Subcranial LN	18.2	(6/33)
	Middle thoracic paraesophageal LN	20.0	(7/35)
	Left main bronchus LN	12.9	(4/31)
	Right main bronchus LN	16.2	(5/31)
Lower mediastinum	Lower thoracic paraesophageal LN	17.1	(6/35)
	Supradiaphragmatic LN	13.3	(4/30)
	Posterior mediastinal LN	17.2	(5/29)

Number of patients with metastasis/number of patients who underwent lymph node dissection is indicated in each parenthesis. LN: Lymph node.

Table 3 Clinical trials of neoadjuvant therapy for esophagogastric junction cancer included in this review

Study name	FLOT4[3,32]	CROSS[4,33]	PRODIGY[34]
Ref.	Al-Batran et al[3,32]	Shapiro et al[33], van Hagen et al[4]	Kang et al[34]
Year	2016/2019	2012/2015	2021
Study design	Phase II/III	Phase III	Phase III
Eligible patients	cT2-4 and/or cN+, cM0	cT1N+ or cT2-3, cM0	cT2-3N+ or cT4, cM0
	Gastric or EGJ cancer	Esophageal or EGJ cancer	Gastric or EGJ cancer
Experimental arm	FLOT	CBDCA + PTX + RT	DOS + adjuvant S1
Control arm	ECF/ECX	Surgery alone	Adjuvant S1
Total number of patients	716	366	484
EGJ cancer patients	56%	24%	6%
Primary outcome	OS	OS	Progression free survival
OS	50 vs 35 mo	48.6 vs 24.0 mo	NA
pCR rate	16% vs 6%	29%	10.40%
R0 resection rate	85% vs 78%	92% vs 69%	89% vs 84%
Special notes	Effective for EGJ cancer		Progression free survival, 66.3 months vs 60.2 months. Equivalent OS. Small population of EGJ cancer patients (27 patients)

EGJ: Esophagogastric junction; pCR: Pathological complete response; FLOT: 5-fluorouracil + leucovorin + oxaliplatin + docetaxel; ECF: Epirubicin + cisplatin + 5-fluorouracil; ECX: Epirubicin + cisplatin + capecitabine; CBDCA: Carboplatin; PTX: Paclitaxel; RT: Radiation therapy; DOS: Docetaxel + oxaliplatin + S-1; NA: Not available; OS: Overall survival.

Table 4 Clinical trials comparing neoadjuvant chemotherapy versus chemoradiotherapy for esophagogastric junction cancer included in this review

Study name	NeoRes[35,36]	POET[37]	Neo-AEGIS[38]
Ref.	Klevebro et al[35,36]	Stahl et al[37]	John et al[38]
Year	2015/2016	2009	2021
Study design	Randomized phase II	Phase III	Phase III
Eligible patients	cT1N+ or cT2-3, M0	cT3-4, M0	cT2-3N0-3M0
	Esophageal or EGJ cancer	EGJ cancer	Esophageal or EGJ cancer
Experimental arm	CF + RT	PLF + RT	CROSS
Control arm	CF	PLF	MAGIC/FLOT
Total number of patients	181	119	377
EGJ cancer patients	17%	100%	NA
Primary outcome	pCR	OS	OS
OS	NA	33 vs 21 mo	NA
pCR rate	24% vs 8%	15.6% vs 2.0%	NA
R0 resection rate	76% vs 64%	69.5% vs 71.5%	NA
Special notes	Equivalent 3-year OS	Study closed early due to low accrual, high in-hospital mortality after chemoradiotherapy	Equivalent 3-year estimated survival probability

EGJ: Esophagogastric junction; pCR: Pathological complete response; CF: Cisplatin + 5-fluorouracil; RT: Radiation therapy; PLF: Paclitaxel + leucovorin + 5-fluorouracil; CROSS: Carboplatin + paclitaxel + radiation therapy; MAGIC: Epirubicin + cisplatin (oxaliplatin) + 5-fluorouracil; FLOT: 5-fluorouracil + leucovorin + oxaliplatin + docetaxel; NA: Not available; OS: Overall survival.

Table 5 Clinical trials of neoadjuvant immunotherapy/targeted therapy for esophagogastric junction cancer included in this review

Study name	Neo-PLANET[13]	NEONIPIGA[14]	NRG Oncology/RTOG 1010[44]
Ref.	Tang et al[13]	Andre et al[14]	Safran et al[44]
Yr	2022	2023	2022
Study design	Phase II	Phase II	Phase III
Eligible patients	cT3-4N+, M0	cT2-4, M0, dMMR/MSI-H	cT1N1-2 or cT2-3N0-2 HER2 positive
	Gastric or EGJ cancer	Gastric or EGJ cancer	Esophageal adenocarcinoma
Experimental arm	Camrelizumab plus chemoradiotherapy	Nivolumab plus ipilimumab	Trastuzumab plus chemoradiotherapy
Control arm	NA	NA	Chemoradiotherapy
Total number of patients	36	29	203
EGJ cancer patients	53.80%	50.00%	NA
Primary endpoint	pCR	pCR	Disease-free survival
OS	NA	NA	38.5 vs 38.9 mo
pCR rate	33.30%	58.60%	27% vs 29%
R0 resection rate	91.70%	100%	98% vs 100%
Special notes	Two-year OS, 76.2%		Disease-free survival, 19.6 vs 14.2 mo

EGJ: Esophagogastric junction; pCR: Pathological complete response; NA: Not available; OS: Overall survival.