Peripheral blood cell counts as predictors of response to neoadjuvant chemoimmunotherapy in esophageal squamous cell carcinoma: A retrospective study in a single center_Chinese Journal of Clinical Thoracic and Cardiovascular Surgery

Authors：

RAN Xingqiang , ZHANG Chengcheng , LUO Tao , XU Binwen , ZHANG Yue , ZHANG Liwen ,  FU Maoyong

Department of Thoracic Surgery, Affiliated Hospital of North Sichuan Medical College, Nanchong, 637000, Sichuan, P. R. China;

Corresponding?author：

FU Maoyong, Email: fumaoyongmd@163.com

Keywords：

Esophageal tumor; neoadjuvant therapy; immunotherapy; blood cells; efficacy; systemic immune-inflammation index; pathologic complete response

DOI：

10.7507/1007-4848.202404042

Video：

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Objective To explore the predictive value of peripheral blood cells in the efficacy of neoadjuvant immunotherapy combined with chemotherapy for esophageal squamous cell carcinoma. Methods A retrospective study was conducted on patients with esophageal squamous cell carcinoma (clinical stages Ⅱ-Ⅳa) who underwent neoadjuvant immunotherapy combined with chemotherapy at the Department of Thoracic Surgery, Affiliated Hospital of North Sichuan Medical College from April 2020 to November 2023. According to whether the pathology was completely relieved after treatment, patients were divided into a pathological complete remission group and a pathological incomplete remission group. The College of American Pathologists criteria were used to evaluate the tumor pathological regression grade (TRG) after neoadjuvant therapy (TRG=0, 1 defined as a good efficacy group, TRG=2, 3 defined as a poor efficacy group). Results A total of 92 patients with esophageal squamous cell carcinoma were collected, including 72 males and 20 females. The average age was (65.86±7.66) years. The complete remission of pathology was closely related to the number of lymphocytes in the blood before treatment (P=0.019). The area under the curve (AUC) for predicting complete remission of esophageal squamous cell carcinoma after neoadjuvant immunotherapy combined with chemotherapy was 0.678, the maximum Youden index was 0.328, and the optimal cutoff value was 1.845. The incidence of postoperative pulmonary infection in the pathological incomplete remission group was higher than that in the pathological complete remission group (25.0% vs. 5.6%, P=0.030). Using the optimal cutoff value, there were statistically significant differences in pathological N stage and pathological TNM stage between patients with lymphocyte counts <1.845×10⁹/L and ≥1.845×10⁹/L (P<0.05). Treatment response (by TRG) was significantly associated with the pretreatment red blood cell count (P=0.009). The AUC for predicting a good TRG response was 0.669, with a maximum Youden index of 0.385 and an optimal cutoff value of 4.235. Between the good and poor response groups, there were statistically significant differences in postoperative pathological T stage (P<0.001), N stage (P=0.041), and TNM stage (P＜0.001). When stratified by the optimal cutoff value, there were statistically significant differences in age (P＜0.001) and the prevalence of hypertension (P=0.022) between patients with red blood cell counts <4.235×10¹²/L and ≥4.235×10¹²/L. Conclusion A pretreatment absolute lymphocyte count ≥1.845×10⁹/L and a red blood cell count <4.235×10¹²/L are good predictors for pathological complete response and a good pathological response, respectively, following neoadjuvant immunotherapy combined with chemotherapy in patients with esophageal squamous cell carcinoma.

Citation： RAN Xingqiang, ZHANG Chengcheng, LUO Tao, XU Binwen, ZHANG Yue, ZHANG Liwen, FU Maoyong. Peripheral blood cell counts as predictors of response to neoadjuvant chemoimmunotherapy in esophageal squamous cell carcinoma: A retrospective study in a single center. Chinese Journal of Clinical Thoracic and Cardiovascular Surgery, 2026, 33(5): 743-750. doi: 10.7507/1007-4848.202404042 Copy

1.	Sung H, Ferlay J, Siegel RL, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin, 2021, 71(3): 209-249.
2.	Arnold M, Ferlay J, van Berge Henegouwen MI, et al. Global burden of oesophageal and gastric cancer by histology and subsite in 2018. Gut, 2020, 69(9): 1564-1571.
3.	Ando N, Kato H, Igaki H, et al. A randomized trial comparing postoperative adjuvant chemotherapy with cisplatin and 5-fluorouracil versus preoperative chemotherapy for localized advanced squamous cell carcinoma of the thoracic esophagus (JCOG9907). Ann Surg Oncol, 2012, 19(1): 68-74.
4.	van Hagen P, Hulshof MC, van Lanschot JJ, et al. Preoperative chemoradiotherapy for esophageal or junctional cancer. N Engl J Med, 2012, 366(22): 2074-2084.
5.	Yang H, Liu H, Chen Y, et al. Neoadjuvant chemoradiotherapy followed by surgery versus surgery alone for locally advanced squamous cell carcinoma of the esophagus (NEOCRTEC5010): a phaseⅢmulticenter, randomized, open-label clinical trial. J Clin Oncol, 2018, 36(27): 2796-2803.
6.	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.
7.	Yang H, Liu H, Chen Y, et al. Long-term efficacy of neoadjuvant chemoradiotherapy plus surgery for the treatment of locally advanced esophageal squamous cell carcinoma: the NEOCRTEC5010 randomized clinical trial. JAMA Surg, 2021, 156(8): 721-729.
8.	Shapiro J, van Lanschot JJB, Hulshof MCCM, et al. Neoadjuvant chemoradiotherapy plus surgery versus surgery alone for oesophageal or junctional cancer (CROSS): long-term results of a randomised controlled trial. Lancet Oncol, 2015, 16(9): 1090-1098.
9.	Duan H, Shao C, Pan M, et al. Neoadjuvant pembrolizumab and chemotherapy in resectable esophageal cancer: an open-label, single-arm study (PEN-ICE). Front Immunol, 2022, 13: 849984.
10.	Yamamoto S, Kato K, Daiko H, et al. FRONTiER: a feasibility trial of nivolumab with neoadjuvant CF or DCF therapy for locally advanced esophageal carcinoma (JCOG1804E): the short-term results of cohort A and B. Am Soc Clin Oncol, 2021.
11.	Matsuda S, Yamamoto S, Kato K, et al. FRONTiER: a feasibility trial of nivolumab with neoadjuvant CF or DCF, FLOT therapy for locally advanced esophageal carcinoma (JCOG1804E): short-term results for cohorts C and D. Am Soc Clin Oncol, 2022.
12.	Yang Y, Zhu L, Cheng Y, et al. Three-arm phaseⅡtrial comparing camrelizumab plus chemotherapy versus camrelizumab plus chemoradiation versus chemoradiation as preoperative treatment for locally advanced esophageal squamous cell carcinoma (NICE-2 study). BMC Cancer, 2022, 22(1): 506.
13.	Lv H, Tian Y, Li J, et al. Neoadjuvant sintilimab plus chemotherapy in resectable locally advanced esophageal squamous cell carcinoma. Front Oncol, 2022, 12: 864533.
14.	Gao L, Lu J, Zhang P, et al. Toripalimab combined with docetaxel and cisplatin neoadjuvant therapy for locally advanced esophageal squamous cell carcinoma: a single-center, single-arm clinical trial (ESONICT-2). J Gastrointest Oncol, 2022, 13(2): 478-487.
15.	Yan X, Duan H, Ni Y, et al. Tislelizumab combined with chemotherapy as neoadjuvant therapy for surgically resectable esophageal cancer: a prospective, single-arm, phaseⅡ study (TD-NICE). Int J Surg, 2022, 103: 106680.
16.	Wang Z, Shao C, Wang Y, et al. Efficacy and safety of neoadjuvant immunotherapy in surgically resectable esophageal cancer: a systematic review and meta-analysis. Int J Surg, 2022, 104: 106767.
17.	Tsai PL, Su WJ, Leung WH, et al. Neutrophil-lymphocyte ratio and CEA level as prognostic and predictive factors in colorectal cancer: a systematic review and meta-analysis. J Cancer Res Ther, 2016, 12(2): 582-589.
18.	Tan D, Fu Y, Su Q, et al. Prognostic role of platelet-lymphocyte ratio in colorectal cancer: a systematic review and meta-analysis. Medicine (Baltimore), 2016, 95(24): e3837.
19.	Platini H, Ferdinand E, Kohar K, et al. Neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio as prognostic markers for advanced non-small-cell lung cancer treated with immunotherapy: a systematic review and meta-analysis. Medicina (Kaunas), 2022, 58(8): 1069.
20.	Matsas S, Aguiar PN, Del Giglio A. Neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio as biomarkers to prognosticate survival in advanced gastric cancer patients in the era of immunotherapy: a systematic review and meta-analysis. J Gastrointest Oncol, 2024, 15(1): 33-51.
21.	Wang PF, Song SY, Guo H, et al. Prognostic role of pretreatment red blood cell distribution width in patients with cancer: a meta-analysis of 49 studies. J Cancer, 2019, 10(18): 4305-4317.
22.	Saito H, Shimizu S, Shishido Y, et al. Prognostic significance of the combination of preoperative red cell distribution width and platelet distribution width in patients with gastric cancer. BMC Cancer, 2021, 21(1): 1317.
23.	Xu WY, Yang XB, Wang WQ, et al. Prognostic impact of the red cell distribution width in esophageal cancer patients: a systematic review and meta-analysis. World J Gastroenterol, 2018, 24(19): 2120-2129.
24.	Yoshida N, Horinouchi T, Toihata T, et al. Clinical significance of pretreatment red blood cell distribution width as a predictive marker for postoperative morbidity after esophagectomy for esophageal cancer: a retrospective study. Ann Surg Oncol, 2022, 29(1): 606-613.
25.	Zhang P, Wang S, Wu JZ, et al. Clinical and prognostic significance of perioperative change in red cell distribution width in patients with esophageal squamous cell carcinoma. BMC Cancer, 2023, 23(1): 319.
26.	Coradduzza D, Medici S, Chessa C, et al. Assessing the predictive power of the hemoglobin/red cell distribution width ratio in cancer: a systematic review and future directions. Medicina (Kaunas), 2023, 59(12): 2124.
27.	Swisher SG, Maish M, Erasmus JJ, et al. Utility of PET, CT, and EUS to identify pathologic responders in esophageal cancer. Ann Thorac Surg, 2004, 78(4): 1152-1160.
28.	Park R, Da Silva LL, Saeed A. Immunotherapy predictive molecular markers in advanced gastroesophageal cancer: MSI and Beyond. Cancers (Basel), 2021, 13(7): 1715.
29.	Sato H, Tsubosa Y, Kawano T. Correlation between the pretherapeutic neutrophil to lymphocyte ratio and the pathologic response to neoadjuvant chemotherapy in patients with advanced esophageal cancer. World J Surg, 2012, 36(3): 617-622.
30.	Sun P, Zhang F, Chen C, et al. The ratio of hemoglobin to red cell distribution width as a novel prognostic parameter in esophageal squamous cell carcinoma: a retrospective study from southern China. Oncotarget, 2016, 7(27): 42650-42660.
31.	Yoshida N, Kosumi K, Tokunaga R, et al. Clinical importance of mean corpuscular volume as a prognostic marker after esophagectomy for esophageal cancer: a retrospective study. Ann Surg, 2020, 271(3): 494-501.
32.	Wang YY, Zhou N, Liu HS, et al. Circulating activated lymphocyte subsets as potential blood biomarkers of cancer progression. Cancer Med, 2020, 9(14): 5086-5094.
33.	Geng R, Tang H, You T, et al. Peripheral CD8+CD28+ T lymphocytes predict the efficacy and safety of PD-1/PD-L1 inhibitors in cancer patients. Front Immunol, 2023, 14: 1125876.
34.	Zhao L, He R, Long H, et al. Late-stage tumors induce anemia and immunosuppressive extramedullary erythroid progenitor cells. Nat Med, 2018, 24(10): 1536-1544.
35.	Long H, Jia Q, Wang L, et al. Tumor-induced erythroid precursor-differentiated myeloid cells mediate immunosuppression and curtail anti-PD-1/PD-L1 treatment efficacy. Cancer Cell, 2022, 40(6): 674-693.

1. Sung H, Ferlay J, Siegel RL, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin, 2021, 71(3): 209-249.
2. Arnold M, Ferlay J, van Berge Henegouwen MI, et al. Global burden of oesophageal and gastric cancer by histology and subsite in 2018. Gut, 2020, 69(9): 1564-1571.
3. Ando N, Kato H, Igaki H, et al. A randomized trial comparing postoperative adjuvant chemotherapy with cisplatin and 5-fluorouracil versus preoperative chemotherapy for localized advanced squamous cell carcinoma of the thoracic esophagus (JCOG9907). Ann Surg Oncol, 2012, 19(1): 68-74.
4. van Hagen P, Hulshof MC, van Lanschot JJ, et al. Preoperative chemoradiotherapy for esophageal or junctional cancer. N Engl J Med, 2012, 366(22): 2074-2084.
5. Yang H, Liu H, Chen Y, et al. Neoadjuvant chemoradiotherapy followed by surgery versus surgery alone for locally advanced squamous cell carcinoma of the esophagus (NEOCRTEC5010): a phaseⅢmulticenter, randomized, open-label clinical trial. J Clin Oncol, 2018, 36(27): 2796-2803.
6. 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.
7. Yang H, Liu H, Chen Y, et al. Long-term efficacy of neoadjuvant chemoradiotherapy plus surgery for the treatment of locally advanced esophageal squamous cell carcinoma: the NEOCRTEC5010 randomized clinical trial. JAMA Surg, 2021, 156(8): 721-729.
8. Shapiro J, van Lanschot JJB, Hulshof MCCM, et al. Neoadjuvant chemoradiotherapy plus surgery versus surgery alone for oesophageal or junctional cancer (CROSS): long-term results of a randomised controlled trial. Lancet Oncol, 2015, 16(9): 1090-1098.
9. Duan H, Shao C, Pan M, et al. Neoadjuvant pembrolizumab and chemotherapy in resectable esophageal cancer: an open-label, single-arm study (PEN-ICE). Front Immunol, 2022, 13: 849984.
10. Yamamoto S, Kato K, Daiko H, et al. FRONTiER: a feasibility trial of nivolumab with neoadjuvant CF or DCF therapy for locally advanced esophageal carcinoma (JCOG1804E): the short-term results of cohort A and B. Am Soc Clin Oncol, 2021.
11. Matsuda S, Yamamoto S, Kato K, et al. FRONTiER: a feasibility trial of nivolumab with neoadjuvant CF or DCF, FLOT therapy for locally advanced esophageal carcinoma (JCOG1804E): short-term results for cohorts C and D. Am Soc Clin Oncol, 2022.
12. Yang Y, Zhu L, Cheng Y, et al. Three-arm phaseⅡtrial comparing camrelizumab plus chemotherapy versus camrelizumab plus chemoradiation versus chemoradiation as preoperative treatment for locally advanced esophageal squamous cell carcinoma (NICE-2 study). BMC Cancer, 2022, 22(1): 506.
13. Lv H, Tian Y, Li J, et al. Neoadjuvant sintilimab plus chemotherapy in resectable locally advanced esophageal squamous cell carcinoma. Front Oncol, 2022, 12: 864533.
14. Gao L, Lu J, Zhang P, et al. Toripalimab combined with docetaxel and cisplatin neoadjuvant therapy for locally advanced esophageal squamous cell carcinoma: a single-center, single-arm clinical trial (ESONICT-2). J Gastrointest Oncol, 2022, 13(2): 478-487.
15. Yan X, Duan H, Ni Y, et al. Tislelizumab combined with chemotherapy as neoadjuvant therapy for surgically resectable esophageal cancer: a prospective, single-arm, phaseⅡ study (TD-NICE). Int J Surg, 2022, 103: 106680.
16. Wang Z, Shao C, Wang Y, et al. Efficacy and safety of neoadjuvant immunotherapy in surgically resectable esophageal cancer: a systematic review and meta-analysis. Int J Surg, 2022, 104: 106767.
17. Tsai PL, Su WJ, Leung WH, et al. Neutrophil-lymphocyte ratio and CEA level as prognostic and predictive factors in colorectal cancer: a systematic review and meta-analysis. J Cancer Res Ther, 2016, 12(2): 582-589.
18. Tan D, Fu Y, Su Q, et al. Prognostic role of platelet-lymphocyte ratio in colorectal cancer: a systematic review and meta-analysis. Medicine (Baltimore), 2016, 95(24): e3837.
19. Platini H, Ferdinand E, Kohar K, et al. Neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio as prognostic markers for advanced non-small-cell lung cancer treated with immunotherapy: a systematic review and meta-analysis. Medicina (Kaunas), 2022, 58(8): 1069.
20. Matsas S, Aguiar PN, Del Giglio A. Neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio as biomarkers to prognosticate survival in advanced gastric cancer patients in the era of immunotherapy: a systematic review and meta-analysis. J Gastrointest Oncol, 2024, 15(1): 33-51.
21. Wang PF, Song SY, Guo H, et al. Prognostic role of pretreatment red blood cell distribution width in patients with cancer: a meta-analysis of 49 studies. J Cancer, 2019, 10(18): 4305-4317.
22. Saito H, Shimizu S, Shishido Y, et al. Prognostic significance of the combination of preoperative red cell distribution width and platelet distribution width in patients with gastric cancer. BMC Cancer, 2021, 21(1): 1317.
23. Xu WY, Yang XB, Wang WQ, et al. Prognostic impact of the red cell distribution width in esophageal cancer patients: a systematic review and meta-analysis. World J Gastroenterol, 2018, 24(19): 2120-2129.
24. Yoshida N, Horinouchi T, Toihata T, et al. Clinical significance of pretreatment red blood cell distribution width as a predictive marker for postoperative morbidity after esophagectomy for esophageal cancer: a retrospective study. Ann Surg Oncol, 2022, 29(1): 606-613.
25. Zhang P, Wang S, Wu JZ, et al. Clinical and prognostic significance of perioperative change in red cell distribution width in patients with esophageal squamous cell carcinoma. BMC Cancer, 2023, 23(1): 319.
26. Coradduzza D, Medici S, Chessa C, et al. Assessing the predictive power of the hemoglobin/red cell distribution width ratio in cancer: a systematic review and future directions. Medicina (Kaunas), 2023, 59(12): 2124.
27. Swisher SG, Maish M, Erasmus JJ, et al. Utility of PET, CT, and EUS to identify pathologic responders in esophageal cancer. Ann Thorac Surg, 2004, 78(4): 1152-1160.
28. Park R, Da Silva LL, Saeed A. Immunotherapy predictive molecular markers in advanced gastroesophageal cancer: MSI and Beyond. Cancers (Basel), 2021, 13(7): 1715.
29. Sato H, Tsubosa Y, Kawano T. Correlation between the pretherapeutic neutrophil to lymphocyte ratio and the pathologic response to neoadjuvant chemotherapy in patients with advanced esophageal cancer. World J Surg, 2012, 36(3): 617-622.
30. Sun P, Zhang F, Chen C, et al. The ratio of hemoglobin to red cell distribution width as a novel prognostic parameter in esophageal squamous cell carcinoma: a retrospective study from southern China. Oncotarget, 2016, 7(27): 42650-42660.
31. Yoshida N, Kosumi K, Tokunaga R, et al. Clinical importance of mean corpuscular volume as a prognostic marker after esophagectomy for esophageal cancer: a retrospective study. Ann Surg, 2020, 271(3): 494-501.
32. Wang YY, Zhou N, Liu HS, et al. Circulating activated lymphocyte subsets as potential blood biomarkers of cancer progression. Cancer Med, 2020, 9(14): 5086-5094.
33. Geng R, Tang H, You T, et al. Peripheral CD8+CD28+ T lymphocytes predict the efficacy and safety of PD-1/PD-L1 inhibitors in cancer patients. Front Immunol, 2023, 14: 1125876.
34. Zhao L, He R, Long H, et al. Late-stage tumors induce anemia and immunosuppressive extramedullary erythroid progenitor cells. Nat Med, 2018, 24(10): 1536-1544.
35. Long H, Jia Q, Wang L, et al. Tumor-induced erythroid precursor-differentiated myeloid cells mediate immunosuppression and curtail anti-PD-1/PD-L1 treatment efficacy. Cancer Cell, 2022, 40(6): 674-693.

Chinese Journal of Clinical Thoracic and Cardiovascular Surgery

Peripheral blood cell counts as predictors of response to neoadjuvant chemoimmunotherapy in esophageal squamous cell carcinoma: A retrospective study in a single center

Abstract Full text Figures/Tables Video References Cited by

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