Interpretation of the updates of NCCN esophageal and esophagogastric junction cancers clinical practice guidelines in oncology (version 1.2025)_Chinese Journal of Clinical Thoracic and Cardiovascular Surgery

Authors：

WANG Yi , CHEN Siyu , YIN Weitong ,  WANG Jun

Department of Radiotherapy, The Fourth Hospital of Hebei Medical University, Shijiazhuang, 050011, P. R. China;

Corresponding author：

WANG Jun, Email: wangjun0818@hebmu.edu

Keywords：

Esophageal cancer; esophagogastric junction cancer; National Comprehensive Cancer Network guideline; interpretation

DOI：

10.7507/1007-4848.202504066

Video：

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According to the latest GLOBOCAN data released in 2024, esophageal cancer ranks the 11th in global cancer incidence and represents the 7th leading cause of cancer-related mortality worldwide. In 2022, there were approximately 511000 newly diagnosed cases of esophageal cancer and 445000 deaths globally. On February 28, 2025, the National Comprehensive Cancer Network (NCCN) published updated clinical practice guidelines for esophageal and esophagogastric junction cancers (version 1.2025). This article provides a comprehensive analysis of the major diagnostic and therapeutic updates in the guidelines compared to the version 5.2024, encompassing key domains including screening stratification protocols, perioperative treatment optimization strategies, dynamic efficacy evaluation systems, molecular subtyping-guided therapeutic approaches, and immunotherapy expansion algorithms. The findings aim to provide references for esophageal cancer treatment in China.

1.	Bray F, Laversanne M, Sung H, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin, 2024, 74(3): 229-263.
2.	Chen R, Zheng R, Zhang S, et al. Patterns and trends in esophageal cancer incidence and mortality in China: an analysis based on cancer registry data. J Natl Cancer Cent, 2023, 3(1): 21-27.
3.	National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: esophageal and esophagogastric junction cancers (version 1.2025). 2025.
4.	ASGE Standards of Practice Committee, Qumseya B, Sultan S, et al. ASGE guideline on screening and surveillance of Barrett's esophagus. Gastrointest Endosc, 2019, 90(3): 335-359.
5.	Muthusamy VR, Wani S, Gyawali CP, et al. AGA clinical practice update on new technology and innovation for surveillance and screening in Barrett's esophagus: expert review. Clin Gastroenterol Hepatol, 2022, 20(12): 2696-2706.
6.	Shaheen NJ, Falk GW, Iyer PG, et al. Diagnosis and management of Barrett's esophagus: an updated ACG guideline. Am J Gastroenterol, 2022, 117(4): 559-587.
7.	Roshandel G, Nourouzi A, Pourshams A, et al. Endoscopic screening for esophageal squamous cell carcinoma. Arch Iran Med, 2013, 16(6): 351-357.
8.	Pech O, May A, Manner H, et al. Long-term efficacy and safety of endoscopic resection for patients with mucosal adenocarcinoma of the esophagus. Gastroenterology, 2014, 146(3): 652-660.
9.	van Vilsteren FG, Pouw RE, Seewald S, et al. Stepwise radical endoscopic resection versus radiofrequency ablation for Barrett’s oesophagus with high-grade dysplasia or early cancer: a multicentre randomised trial. Gut, 2011, 60(6): 765-773.
10.	Wu TT, Chirieac LR, Abraham SC, et al. Excellent interobserver agreement on grading the extent of residual carcinoma after preoperative chemoradiation in esophageal and esophagogastric junction carcinoma: a reliable predictor for patient outcome. Am J Surg Pathol, 2007, 31(1): 58-64.
11.	Brucher BL, Becker K, Lordick F, et al. The clinical impact of histopathologic response assessment by residual tumor cell quantification in esophageal squamous cell carcinomas. Cancer, 2006, 106(9): 2119-2127.
12.	Ryan R, Gibbons D, Hyland JM, et al. Pathological response following long-course neoadjuvant chemoradiotherapy for locally advanced rectal cancer. Histopathology, 2005, 47(2): 141-146.
13.	Shi C, Berlin J, Branton PA, et al. Protocol for the examination of specimens from patients with carcinoma of the esophagus. College of American Pathologists, 2017.
14.	Gu Y, Swisher SG, Ajani JA, et al. The number of lymph nodes with metastasis predicts survival in patients with esophageal or esophagogastric junction adenocarcinoma who receive preoperative chemoradiation. Cancer, 2006, 106(5): 1017-1025.
15.	Amin MB, Edge SB, Greene FL, et al. AJCC cancer staging manual. 8th ed. New York: Springer, 2017.
16.	Bartley AN, Washington MK, Colasacco C, et al. HER2 testing and clinical decision making in gastroesophageal adenocarcinoma: guideline from the College of American Pathologists, American Society of Clinical Pathology, and American Society of Clinical Oncology. J Clin Oncol, 2017, 35(4): 446-464.
17.	Shah MA, Shitara K, Ajani JA, et al. Zolbetuximab plus CAPOX in CLDN18.2-positive gastric or gastroesophageal junction adenocarcinoma: the randomized, phase 3 GLOW trial. Nat Med, 2023, 29(9): 2133-2141.
18.	Shitara K, Lordick F, Bang YJ, et al. Zolbetuximab plus mFOLFOX6 in patients with CLDN18.2-positive, HER2-negative, untreated, locally advanced unresectable or metastatic gastric or gastro-oesophageal junction adenocarcinoma (SPOTLIGHT): a multicentre, randomised, double-blind, phase 3 trial. Lancet, 2023, 401(10387): 1655-1668.
19.	Shitara K, Xu RH, Ajani JA, et al. Global prevalence of claudin 18 isoform 2 in tumors of patients with locally advanced unresectable or metastatic gastric or gastroesophageal junction adenocarcinoma. Gastric Cancer, 2024, 27(6): 1058-1068.
20.	Le DT, Uram JN, Wang H, et al. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med, 2015, 372(26): 2509-2520.
21.	Bartley AN, Fitzgibbons PL, Broaddus RR, et al. Template for reporting results of DNA mismatch repair testing in patients being considered for checkpoint inhibitor immunotherapy. College of American Pathologists, 2018.
22.	Kato S, Okamura R, Baumgartner JM, et al. Analysis of circulating tumor DNA and clinical correlates in patients with esophageal, gastroesophageal junction, and gastric adenocarcinoma. Clin Cancer Res, 2018, 24(24): 6248-6256.
23.	Willis J, Lefterova MI, Artyomenko A, et al. Validation of microsatellite instability detection using a comprehensive plasma-based genotyping panel. Clin Cancer Res, 2019, 25(23): 7035-7045.
24.	Hoeppner J, Brunner T, Schmoor C, et al. Perioperative chemotherapy or preoperative chemoradiotherapy in esophageal cancer. N Engl J Med, 2025, 392(4): 323-335.
25.	André T, Tougeron D, Piessen G, et al. Neoadjuvant nivolumab plus ipilimumab and adjuvant nivolumab in localized deficient mismatch repair/microsatellite instability-high gastric or esophagogastric junction adenocarcinoma: the GERCOR NEONIPIGA phaseⅡstudy. J Clin Oncol, 2023, 41(2): 255-265.
26.	Gao YH, Wang YX, Li J, et al. Impact factor of postoperative prognosis of esophageal cancer patients with stage pT2N0~1M0. Zhonghua Zhong Liu Za Zhi, 2017, 39(9): 683-688.
27.	Smalley SR, Benedetti JK, Haller DG, et al. Updated analysis of SWOG-directed intergroup study 0116: a phaseⅢ trial of adjuvant radiochemotherapy versus observation after curative gastric cancer resection. J Clin Oncol, 2012, 30(19): 2327-2333.
28.	Kang J, Chang JY, Sun X, et al. Role of postoperative concurrent chemoradiotherapy for esophageal carcinoma: a meta-analysis of 2165 patients. J Cancer, 2018, 9(3): 584-593.
29.	Ribeiro A, Franceschi D, Parra J, et al. Endoscopic ultrasound restaging after neoadjuvant chemotherapy in esophageal cancer. Am J Gastroenterol, 2006, 101(6): 1216-1221.
30.	Sarkaria IS, Rizk NP, Bains MS, et al. Post-treatment endoscopic biopsy is a poor-predictor of pathologic response in patients undergoing chemoradiation therapy for esophageal cancer. Ann Surg, 2009, 249(5): 764-767.
31.	Ychou M, Boige V, Pignon JP, et al. Perioperative chemotherapy compared with surgery alone for resectable gastroesophageal adenocarcinoma: an FNCLCC and FFCD multicenter phaseⅢ trial. J Clin Oncol, 2011, 29(13): 1715-1721.
32.	Eyck BM, van Lanschot JJB, Hulshof MCCM, et al. Ten-year outcome of neoadjuvant chemoradiotherapy plus surgery for esophageal cancer: the randomized controlled CROSS trial. J Clin Oncol, 2021, 39(18): 1995-2004.
33.	Albiges L, Bourlon MT, Chacón M, et al. Subcutaneous versus intravenous nivolumab for renal cell carcinoma. Ann Oncol, 2025, 36(1): 99-107.
34.	Bang YJ, Van Cutsem E, Feyereislova A, et al. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet, 2010, 376(9742): 687-697.
35.	Janjigian YY, Kawazoe A, Yanez P, et al. The KEYNOTE-811 trial of dual PD-1 and HER2 blockade in HER2-positive gastric cancer. Nature, 2021, 600(7890): 727-730.
36.	Janjigian YY, Kawazoe A, Bai Y, et al. Pembrolizumab plus trastuzumab and chemotherapy for HER2-positive gastric or gastro-oesophageal junction adenocarcinoma: interim analyses from the phase 3 KEYNOTE-811 randomised placebo-controlled trial. Lancet, 2023, 402(10412): 2197-2208.
37.	Janjigian YY, Shitara K, Moehler M, et al. First-line nivolumab plus chemotherapy versus chemotherapy alone for advanced gastric, gastro-oesophageal junction, and oesophageal adenocarcinoma (CheckMate 649): a randomised, open-label, phase 3 trial. Lancet, 2021, 398(10294): 27-39.
38.	Sun JM, Shen L, Shah MA, et al. Pembrolizumab plus chemotherapy versus chemotherapy alone for first-line treatment of advanced oesophageal cancer (KEYNOTE-590): a randomised, placebo-controlled, phase 3 study. Lancet, 2021, 398(10302): 759-771.
39.	Rha SY, Oh DY, Yanez P, et al. Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for HER2-negative advanced gastric cancer (KEYNOTE-859): a multicentre, randomised, double-blind, phase 3 trial. Lancet Oncol, 2023, 24(10): 1181-1195.
40.	Qiu MZ, Oh DY, Kato K, et al. Tislelizumab plus chemotherapy versus placebo plus chemotherapy as first line treatment for advanced gastric or gastroesophageal junction adenocarcinoma: RATIONALE-305 randomised, double blind, phase 3 trial. BMJ, 2024, 385: e078876.
41.	Doebele RC, Drilon A, Paz-Ares L, et al. Entrectinib in patients with advanced or metastatic NTRK fusion-positive solid tumours: integrated analysis of three phase 1-2 trials. Lancet Oncol, 2020, 21(2): 271-282.
42.	Drilon A, Laetsch TW, Kummar S, et al. Efficacy of larotrectinib in TRK fusion-positive cancers in adults and children. N Engl J Med, 2018, 378(8): 731-739.
43.	Solomon BJ, Drilon A, Lin JJ, et al. Repotrectinib in patients with NTRK fusion-positive advanced solid tumors, including NSCLC: update from the phaseⅠ/ⅡTRIDENT-1 trial. Ann Oncol, 2023, 34(Suppl 2): S787-S788.
44.	Shitara K, Lordick F, Bang YJ, et al. Zolbetuximab plus mFOLFOX6 in patients with CLDN18.2-positive, HER2-negative, untreated, locally advanced unresectable or metastatic gastric or gastro-oesophageal junction adenocarcinoma (SPOTLIGHT): a multicentre, randomised, double-blind, phase 3 trial. Lancet, 2023, 401(10389): 1655-1668.

1. Bray F, Laversanne M, Sung H, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin, 2024, 74(3): 229-263.
2. Chen R, Zheng R, Zhang S, et al. Patterns and trends in esophageal cancer incidence and mortality in China: an analysis based on cancer registry data. J Natl Cancer Cent, 2023, 3(1): 21-27.
3. National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: esophageal and esophagogastric junction cancers (version 1.2025). 2025.
4. ASGE Standards of Practice Committee, Qumseya B, Sultan S, et al. ASGE guideline on screening and surveillance of Barrett's esophagus. Gastrointest Endosc, 2019, 90(3): 335-359.
5. Muthusamy VR, Wani S, Gyawali CP, et al. AGA clinical practice update on new technology and innovation for surveillance and screening in Barrett's esophagus: expert review. Clin Gastroenterol Hepatol, 2022, 20(12): 2696-2706.
6. Shaheen NJ, Falk GW, Iyer PG, et al. Diagnosis and management of Barrett's esophagus: an updated ACG guideline. Am J Gastroenterol, 2022, 117(4): 559-587.
7. Roshandel G, Nourouzi A, Pourshams A, et al. Endoscopic screening for esophageal squamous cell carcinoma. Arch Iran Med, 2013, 16(6): 351-357.
8. Pech O, May A, Manner H, et al. Long-term efficacy and safety of endoscopic resection for patients with mucosal adenocarcinoma of the esophagus. Gastroenterology, 2014, 146(3): 652-660.
9. van Vilsteren FG, Pouw RE, Seewald S, et al. Stepwise radical endoscopic resection versus radiofrequency ablation for Barrett’s oesophagus with high-grade dysplasia or early cancer: a multicentre randomised trial. Gut, 2011, 60(6): 765-773.
10. Wu TT, Chirieac LR, Abraham SC, et al. Excellent interobserver agreement on grading the extent of residual carcinoma after preoperative chemoradiation in esophageal and esophagogastric junction carcinoma: a reliable predictor for patient outcome. Am J Surg Pathol, 2007, 31(1): 58-64.
11. Brucher BL, Becker K, Lordick F, et al. The clinical impact of histopathologic response assessment by residual tumor cell quantification in esophageal squamous cell carcinomas. Cancer, 2006, 106(9): 2119-2127.
12. Ryan R, Gibbons D, Hyland JM, et al. Pathological response following long-course neoadjuvant chemoradiotherapy for locally advanced rectal cancer. Histopathology, 2005, 47(2): 141-146.
13. Shi C, Berlin J, Branton PA, et al. Protocol for the examination of specimens from patients with carcinoma of the esophagus. College of American Pathologists, 2017.
14. Gu Y, Swisher SG, Ajani JA, et al. The number of lymph nodes with metastasis predicts survival in patients with esophageal or esophagogastric junction adenocarcinoma who receive preoperative chemoradiation. Cancer, 2006, 106(5): 1017-1025.
15. Amin MB, Edge SB, Greene FL, et al. AJCC cancer staging manual. 8th ed. New York: Springer, 2017.
16. Bartley AN, Washington MK, Colasacco C, et al. HER2 testing and clinical decision making in gastroesophageal adenocarcinoma: guideline from the College of American Pathologists, American Society of Clinical Pathology, and American Society of Clinical Oncology. J Clin Oncol, 2017, 35(4): 446-464.
17. Shah MA, Shitara K, Ajani JA, et al. Zolbetuximab plus CAPOX in CLDN18.2-positive gastric or gastroesophageal junction adenocarcinoma: the randomized, phase 3 GLOW trial. Nat Med, 2023, 29(9): 2133-2141.
18. Shitara K, Lordick F, Bang YJ, et al. Zolbetuximab plus mFOLFOX6 in patients with CLDN18.2-positive, HER2-negative, untreated, locally advanced unresectable or metastatic gastric or gastro-oesophageal junction adenocarcinoma (SPOTLIGHT): a multicentre, randomised, double-blind, phase 3 trial. Lancet, 2023, 401(10387): 1655-1668.
19. Shitara K, Xu RH, Ajani JA, et al. Global prevalence of claudin 18 isoform 2 in tumors of patients with locally advanced unresectable or metastatic gastric or gastroesophageal junction adenocarcinoma. Gastric Cancer, 2024, 27(6): 1058-1068.
20. Le DT, Uram JN, Wang H, et al. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med, 2015, 372(26): 2509-2520.
21. Bartley AN, Fitzgibbons PL, Broaddus RR, et al. Template for reporting results of DNA mismatch repair testing in patients being considered for checkpoint inhibitor immunotherapy. College of American Pathologists, 2018.
22. Kato S, Okamura R, Baumgartner JM, et al. Analysis of circulating tumor DNA and clinical correlates in patients with esophageal, gastroesophageal junction, and gastric adenocarcinoma. Clin Cancer Res, 2018, 24(24): 6248-6256.
23. Willis J, Lefterova MI, Artyomenko A, et al. Validation of microsatellite instability detection using a comprehensive plasma-based genotyping panel. Clin Cancer Res, 2019, 25(23): 7035-7045.
24. Hoeppner J, Brunner T, Schmoor C, et al. Perioperative chemotherapy or preoperative chemoradiotherapy in esophageal cancer. N Engl J Med, 2025, 392(4): 323-335.
25. André T, Tougeron D, Piessen G, et al. Neoadjuvant nivolumab plus ipilimumab and adjuvant nivolumab in localized deficient mismatch repair/microsatellite instability-high gastric or esophagogastric junction adenocarcinoma: the GERCOR NEONIPIGA phaseⅡstudy. J Clin Oncol, 2023, 41(2): 255-265.
26. Gao YH, Wang YX, Li J, et al. Impact factor of postoperative prognosis of esophageal cancer patients with stage pT2N0~1M0. Zhonghua Zhong Liu Za Zhi, 2017, 39(9): 683-688.
27. Smalley SR, Benedetti JK, Haller DG, et al. Updated analysis of SWOG-directed intergroup study 0116: a phaseⅢ trial of adjuvant radiochemotherapy versus observation after curative gastric cancer resection. J Clin Oncol, 2012, 30(19): 2327-2333.
28. Kang J, Chang JY, Sun X, et al. Role of postoperative concurrent chemoradiotherapy for esophageal carcinoma: a meta-analysis of 2165 patients. J Cancer, 2018, 9(3): 584-593.
29. Ribeiro A, Franceschi D, Parra J, et al. Endoscopic ultrasound restaging after neoadjuvant chemotherapy in esophageal cancer. Am J Gastroenterol, 2006, 101(6): 1216-1221.
30. Sarkaria IS, Rizk NP, Bains MS, et al. Post-treatment endoscopic biopsy is a poor-predictor of pathologic response in patients undergoing chemoradiation therapy for esophageal cancer. Ann Surg, 2009, 249(5): 764-767.
31. Ychou M, Boige V, Pignon JP, et al. Perioperative chemotherapy compared with surgery alone for resectable gastroesophageal adenocarcinoma: an FNCLCC and FFCD multicenter phaseⅢ trial. J Clin Oncol, 2011, 29(13): 1715-1721.
32. Eyck BM, van Lanschot JJB, Hulshof MCCM, et al. Ten-year outcome of neoadjuvant chemoradiotherapy plus surgery for esophageal cancer: the randomized controlled CROSS trial. J Clin Oncol, 2021, 39(18): 1995-2004.
33. Albiges L, Bourlon MT, Chacón M, et al. Subcutaneous versus intravenous nivolumab for renal cell carcinoma. Ann Oncol, 2025, 36(1): 99-107.
34. Bang YJ, Van Cutsem E, Feyereislova A, et al. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet, 2010, 376(9742): 687-697.
35. Janjigian YY, Kawazoe A, Yanez P, et al. The KEYNOTE-811 trial of dual PD-1 and HER2 blockade in HER2-positive gastric cancer. Nature, 2021, 600(7890): 727-730.
36. Janjigian YY, Kawazoe A, Bai Y, et al. Pembrolizumab plus trastuzumab and chemotherapy for HER2-positive gastric or gastro-oesophageal junction adenocarcinoma: interim analyses from the phase 3 KEYNOTE-811 randomised placebo-controlled trial. Lancet, 2023, 402(10412): 2197-2208.
37. Janjigian YY, Shitara K, Moehler M, et al. First-line nivolumab plus chemotherapy versus chemotherapy alone for advanced gastric, gastro-oesophageal junction, and oesophageal adenocarcinoma (CheckMate 649): a randomised, open-label, phase 3 trial. Lancet, 2021, 398(10294): 27-39.
38. Sun JM, Shen L, Shah MA, et al. Pembrolizumab plus chemotherapy versus chemotherapy alone for first-line treatment of advanced oesophageal cancer (KEYNOTE-590): a randomised, placebo-controlled, phase 3 study. Lancet, 2021, 398(10302): 759-771.
39. Rha SY, Oh DY, Yanez P, et al. Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for HER2-negative advanced gastric cancer (KEYNOTE-859): a multicentre, randomised, double-blind, phase 3 trial. Lancet Oncol, 2023, 24(10): 1181-1195.
40. Qiu MZ, Oh DY, Kato K, et al. Tislelizumab plus chemotherapy versus placebo plus chemotherapy as first line treatment for advanced gastric or gastroesophageal junction adenocarcinoma: RATIONALE-305 randomised, double blind, phase 3 trial. BMJ, 2024, 385: e078876.
41. Doebele RC, Drilon A, Paz-Ares L, et al. Entrectinib in patients with advanced or metastatic NTRK fusion-positive solid tumours: integrated analysis of three phase 1-2 trials. Lancet Oncol, 2020, 21(2): 271-282.
42. Drilon A, Laetsch TW, Kummar S, et al. Efficacy of larotrectinib in TRK fusion-positive cancers in adults and children. N Engl J Med, 2018, 378(8): 731-739.
43. Solomon BJ, Drilon A, Lin JJ, et al. Repotrectinib in patients with NTRK fusion-positive advanced solid tumors, including NSCLC: update from the phaseⅠ/ⅡTRIDENT-1 trial. Ann Oncol, 2023, 34(Suppl 2): S787-S788.
44. Shitara K, Lordick F, Bang YJ, et al. Zolbetuximab plus mFOLFOX6 in patients with CLDN18.2-positive, HER2-negative, untreated, locally advanced unresectable or metastatic gastric or gastro-oesophageal junction adenocarcinoma (SPOTLIGHT): a multicentre, randomised, double-blind, phase 3 trial. Lancet, 2023, 401(10389): 1655-1668.

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Latest ArticlesInterpretation of the updates of NCCN esophageal and esophagogastric junction cancers clinical practice guidelines in oncology (version 1.2025)

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