Tolga DOĞAN, Arzu YAREN, Atike Gökçen DEMİRAY, Burcu YAPAR TAŞKÖYLÜ, Burçin ÇAKAN DEMİREL, Melek ÖZDEMİR, Taliha GÜÇLÜ KANTAR, Serkan DEĞİRMENCİOĞLU, Gamze GOKOZ DOGU

Lokal ileri rezeke edilemeyen ve metastatik mide kanserinde tedavi öncesi inflamasyon yanıtı belirteçlerinin sağkalım üzerine etkisi

Amaç: Lokal ileri rezeke edilemeyen ve metastatik mide kanserli hastalarda tedavi öncesi inflamasyon yanıtı belirteçlerinin tüm sağkalım (TSK) ve progresyonsuz sağkalım (PSK) üzerine etkisini değerlendirildi. Gereç ve yöntem: Ocak 2016-Aralık 2021 tarihleri arasında lokal ileri rezeke edilemeyen ve metastatik mide kanserli hastalar alındı. Bu hastalardan en az bir sıra kemoterapi almış ECOG (Eastern Cooperative Oncology Group) Performans durumu 0-2 olan, komorbiditesi ve beyin metastazı olmayan 114 hasta çalışmaya dahil edildi. Tedavi öncesi platelet, lenfosit, lökosit, nötrofil, monosit, albümin, C-reaktif protein (CRP), laktatdehidrogenaz (LDH) düzeyleri, histoloji tipleri, yaşı, cerrahi öyküsü, tedavi öyküsü ve ECOG Performans durumu dosyalarından retrospektif olarak incelendi. Tüm değerlerin eşik değeri ROC analizi ile belirlendi. Sağkalım analizleri için Kaplan-Meier Sağkalım analizleri kullanıldı. Coxproportional-hazards modeli kullanılarak tüm sağkalım (TSK) ve progresyonsuz sağkalım (PSK)’ı etkileyen faktörlerin hazardratio (HR) ve güven aralıkları (CI) hesaplandı. Bulgular: Hastaların ortanca yaşı 63,5±11,9 (28-80) yıl. Hastaların 69 (%60,5)’u metastatik evredeydi. Yüzaltı (%93,0) hastanın histolojisi az differasiye karsinomdu. Hastaların %88,6’sında (101) progresyon gelişti ve 98 hasta (%86) vefat etti. Tüm grupta mPSK 9,4+0,9 (%95CI 7,7-11,0) ay ve mOS 14,1+1,6 (%95CI 10,8-17,2) ay saptandı. Coxproportional-hazards modeli kullanıldığında TSK’i etkileyen faktörler ileri yaş, metastatik evre, nötrofil lenfosit oranı (NLO), platelet lenfosit oranı (PLO), derive nötrofil lenfosit oranı (dNLO) ve laktak dehidrogenaz (LDH) iken; PSK’yi etkileyen faktörler ileri yaş, metastatik evre, NLO, dNLO ve LDH olarak bulundu. Sonuç: Tedavi öncesi inflamasyon yanıtı belirteçlerinden NLO, PLO, dNLO ve LDH OS’yi etkilerken; LDH PSK’yi etkilemektedir. Lokal ileri rezeke edilemeyen ve metastatik evre mide kanserlerinin kemoterapi öncesi sistemik inflamatuvar belirteçleri prognozu öngörmede kullanılabilir.

Anahtar Kelimeler:

Mide kanseri, nötrofil-lenfosit oranı, platelet-lenfosit oranı, prognoz

The effect of pre-treatment inflammatory response markers on survival in locally advanced unresectable and metastatic gastric cancer: a retrospective cross-sectional study

Purpose: We evaluated the effect of pre-treatment inflammation response markers on overall survival (OS) and progression-free survival (PFS) in patients with locally advanced unresectable and metastatic gastric cancer. Material and method: Patients with locally advanced unresectable and metastatic gastric cancer between January 2016 and December 2021 were included. Among these patients, 114 patients with ECOG (Eastern Cooperative Oncology Group) Performance status 0-2, who received at least one line of chemotherapy, had no comorbidities and brain metastases were included in the study. Pre-treatment platelet, lymphocyte, leukocyte, neutrophil, monocyte, albumin, C-reactive protein (CRP), lactatedehydrogenase (LDH) levels, histology types, age, surgical history, treatment history and ECOG Performance status were retrospectively analysed from their records. Threshold values were determined by ROC analysis. Kaplan-Meier survival analyses were used for survival analyses. Hazard ratio (HR) and confidence intervals (CI) of the factors affecting overall survival (OS) and progression-free survival (PFS) were calculated using Coxproportional-hazards model. Results: The median age of the patients was 63.5±11.9 (28-80). Among the patients, 69 (60.5%) were in metastatic stage. One hundred and six (93.0%) patients had poorly differentiated carcinoma histology. Progression developed in 88.6% (101) of patients and 98 patients (86%) were deceased. In the whole group, mPFS was 9.4±0.9 (95%CI 7.7-11.0) months and mOS was 14.1±1.6 (95%CI 10.8-17.2) months. When the Coxproportional-hazards model was used, the factors affecting OS were advanced age, metastatic stage, neutrophil lymphocyte ratio (NLR), platelet lymphocyte ratio (PLR), derived neutrophil lymphocyte ratio (dNLR) and lactate dehydrogenase (LDH), while the factors affecting PFS were advanced age, metastatic stage, NLR, dNLR and LDH. Conclusion: While NLR, PLR, dNLR, dNLR and LDH affect OS, LDH affects PFS. Systemic inflammatory markers of locally advanced unresectable and metastatic gastric cancers before chemotherapy can be used to predict prognosis.

Keywords:

Gastric cancer, neutrophil-lymphocyte ratio, platelet-lymphocyte ratio, prognosis,

PDF

___

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;71:209-249. https://doi.org/10.3322/caac.21660
2. Maconi G, Manes G, Porro GB. Role of symptoms in diagnosis and outcome of gastric cancer. World J Gastroenterol 2008;14:1149-1155. https://doi.org/10.3748/wjg.14.1149
3. Murad AM, Santiago FF, Petroianu A, Rocha PR, Rodrigues MA, Rausch M. Modified therapy with 5-fluorouracil, doxorubicin, and methotrexate in advanced gastric cancer. Cancer 1993;72:37-41. https://doi.org/10.1002/1097-0142(19930701)72:1<37::aid-cncr2820720109>3.0.co;2-p
4. Pyrhönen S, Kuitunen T, Nyandoto P, Kouri M. Randomised comparison of fluorouracil, epidoxorubicin and methotrexate (FEMTX) plus supportive care with supportive care alone in patients with non-resectable gastric cancer. Br J Cancer 1995;71:587-591. https://doi.org/10.1038/bjc.1995.114
5. Sexton RE, Al Hallak MN, Diab M, Azmi AS. Gastric cancer: a comprehensive review of current and future treatment strategies. Cancer Metastasis Rev 2020;39:1179-1203. https://doi.org/10.1007/s10555-020-09925-3
6. GASTRIC (Global Advanced/Adjuvant Stomach Tumor Research International Collaboration) Group; Oba K, Paoletti X, Bang YJ, et al. Role of chemotherapy for advanced/recurrent gastric cancer: an individual-patient-data meta-analysis. Eur J Cancer 2013;49:1565-1577. https://doi.org/10.1016/j.ejca.2012.12.016
7. Colotta F, Allavena P, Sica A, Garlanda C, Mantovani A. Cancer-related inflammation, the seventh hallmark of cancer: links to genetic instability. Carcinogenesis 2009;30:1073-1081. https://doi.org/10.1093/carcin/bgp127
8. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell 2011;144:646-674. https://doi.org/10.1016/j.cell.2011.02.013
9. Mantovani A, Allavena P, Sica A, Balkwill F. Cancer-related inflammation. Nature 2008;454:436-444. https://doi.org/10.1038/nature07205
10. De Larco JE, Wuertz BRK, Furcht LT. The potential role of neutrophils in promoting the metastatic phenotype of tumors releasing interleukin-8. Clin Cancer Res 2004;10:4895-4900. https://doi.org/10.1158/1078-0432.CCR-03-0760
11. Ghasemzadeh M, Hosseini E. Platelet-leukocyte crosstalk: linking proinflammatory responses to procoagulant state. Thromb Res 2013;131:191-197. https://doi.org/10.1016/j.thromres.2012.11.028
12. Fridman WH, Pagès F, Sautès Fridman C, Galon J. The immune contexture in human tumours: impact on clinical outcome. Nat Rev Cancer 2012;12:298-306. https://doi.org/10.1038/nrc3245
13. Tecchio C, Scapini P, Pizzolo G, Cassatella MA. On the cytokines produced by human neutrophils in tumors. Semin Cancer Biol 2013;23:159-170. https://doi.org/10.1016/j.semcancer.2013.02.004
14. Goubran HA, Stakiw J, Radosevic M, Burnouf T. Platelets effects on tumor growth. Semin Oncol 2014;41:359-369. https://doi.org/10.1053/j.seminoncol.2014.04.006
15. Wilcox RA, Wada DA, Ziesmer SC, et al. Monocytes promote tumor cell survival in T-cell lymphoproliferative disorders and are impaired in their ability to differentiate into mature dendritic cells. Blood 2009;114:2936-2944. https://doi.org/10.1182/blood-2009-05-220111
16. Oh BS, Jang JW, Kwon JH, et al. Prognostic value of C-reactive protein and neutrophil-to-lymphocyte ratio in patients with hepatocellular carcinoma. BMC Cancer 2013;13:78. https://doi.org/10.1186/1471-2407-13-78
17. Sarraf KM, Belcher E, Raevsky E, Nicholson AG, Goldstraw P, Lim E. Neutrophil/lymphocyte ratio and its association with survival after complete resection in non-small cell lung cancer. J Thorac Cardiovasc Surg 2009;137:425-428. https://doi.org/10.1016/j.jtcvs.2008.05.046
18. Al Murri AM, Wilson C, Lannigan A, et al. Evaluation of the relationship between the systemic inflammatory response and cancer-specific survival in patients with primary operable breast cancer. Br J Cancer 2007;96:891-895. https://doi.org/10.1038/sj.bjc.6603682
19. Zhang LX, Wei ZJ, Xu AM, Zang JH. Can the neutrophil-lymphocyte ratio and platelet-lymphocyte ratio be beneficial in predicting lymph node metastasis and promising prognostic markers of gastric cancer patients? Tumor maker retrospective study. Int J Surg 2018;56:320-327. https://doi.org/10.1016/j.ijsu.2018.06.037
20. Chen L, Hao Y, Zhu L, et al. Monocyte to lymphocyte ratio predicts survival in patients with advanced gastric cancer undergoing neoadjuvant chemotherapy. Onco Targets Ther 2017;10:4007-4016. https://doi.org/10.2147/OTT.S140118
21. Najmeh S, Cools Lartigue J, Rayes RF, et al. Neutrophil extracellular traps sequester circulating tumor cells via β1-integrin mediated interactions. Int J Cancer 2017;140:2321-2330. https://doi.org/10.1002/ijc.30635
22. Zhao QT, Yuan Z, Zhang H, et al. Prognostic role of platelet to lymphocyte ratio in non-small cell lung cancers: a meta-analysis including 3,720 patients. Int J Cancer 2016;139:164-170. https://doi.org/10.1002/ijc.30060
23. Lu C, Gao P, Yang Y, et al. Prognostic evaluation of platelet to lymphocyte ratio in patients with colorectal cancer. Oncotarget 2017;8:86287-86295. https://doi.org/10.18632/oncotarget.21141
24. Mori M, Shuto K, Kosugi C, et al. An increase in the neutrophil-to-lymphocyte ratio during adjuvant chemotherapy indicates a poor prognosis in patients with stage II or III gastric cancer. BMC Cancer 2018;18:1261. https://doi.org/10.1186/s12885-018-5171-2
25. Pan YC, Jia ZF, Cao DH, et al. Preoperative lymphocyte-to-monocyte ratio (LMR) could independently predict overall survival of resectable gastric cancer patients. Medicine (Baltimore) 2018;97:e13896. https://doi.org/10.1097/MD.0000000000013896
26. Szor DJ, Dias AR, Pereira MA, et al. Prognostic role of neutrophil/lymphocyte ratio in resected gastric cancer: a systematic review and meta-analysis. Clinics (Sao Paulo) 2018;73:e360. https://doi.org/10.6061/clinics/2018/e360
27. Miyamoto R, Inagawa S, Sano N, Tadano S, Adachi S, Yamamoto M. The neutrophil-to-lymphocyte ratio (NLR) predicts short-term and long-term outcomes in gastric cancer patients. Eur J Surg Oncol 2018;44:607-612. https://doi.org/10.1016/j.ejso.2018.02.003
28. Tanaka H, Tamura T, Toyokawa T, et al. Clinical relevance of postoperative neutrophil-lymphocyte ratio (NLR) to recurrence after adjuvant chemotherapy of S-1 for gastric cancer. Anticancer Res 2018;38:3745-3751. https://doi.org/10.21873/anticanres.12655
29. Murakami Y, Saito H, Shimizu S, et al. Neutrophil-to-lymphocyte ratio as a prognostic indicator in patients with unresectable gastric cancer. Anticancer Res 2019;39:2583-2589. https://doi.org/10.21873/anticanres.13381
30. Li Z, Li S, Ying X, et al. The clinical value and usage of inflammatory and nutritional markers in survival prediction for gastric cancer patients with neoadjuvant chemotherapy and D2 lymphadenectomy. Gastric Cancer 2020;23:540-549. https://doi.org/10.1007/s10120-019-01027-6
31. Gong W, Zhao L, Dong Z, et al. After neoadjuvant chemotherapy platelet/lymphocyte ratios negatively correlate with prognosis in gastric cancer patients. J Clin Lab Anal 2018;32:22364.e1-10. https://doi.org/10.1002/jcla.22364
32. Wang W, Tong Y, Sun S, et al. Predictive value of NLR and PLR in response to preoperative chemotherapy and prognosis in locally advanced gastric cancer. Front Oncol 2022;12:936206.e1-13. https://doi.org/10.3389/fonc.2022.936206
33. Hirahara T, Arigami T, Yanagita S, et al. Combined neutrophil-lymphocyte ratio and platelet-lymphocyte ratio predicts chemotherapy response and prognosis in patients with advanced gastric cancer. BMC Cancer 20198;19:672.e1-7. https://doi.org/10.1186/s12885-019-5903-y
34. Gonda K, Shibata M, Sato Y, et al. Elevated neutrophil-to-lymphocyte ratio is associated with nutritional impairment, immune suppression, resistance to S-1 plus cisplatin, and poor prognosis in patients with stage IV gastric cancer. Mol Clin Oncol 2017;7:1073-1078. https://doi.org/10.3892/mco.2017.1438
35. Gou M, Qu T, Wang Z, et al. Neutrophil-to-Lymphocyte Ratio (NLR) Predicts PD-1 inhibitor survival in patients with metastatic gastric cancer. J Immunol Res 2021;2021:2549295.e1-9. https://doi.org/10.1155/2021/2549295
36. Gregory AD, Houghton AM. Tumor-associated neutrophils: new targets for cancer therapy. Cancer Res 2011;71:2411-2416. https://doi.org/10.1158/0008-5472.CAN-10-2583
37. Gambardella V, Castillo J, Tarazona N, et al. The role of tumor-associated macrophages in gastric cancer development and their potential as a therapeutic target. Cancer Treat Rev 2020;86:102015. https://doi.org/10.1016/j.ctrv.2020.102015
38. Xing X, Guo J, Ding G, et al. Analysis of PD1, PDL1, PDL2 expression and T cells infiltration in 1014 gastric cancer patients. Oncoimmunology. 2017;7:e1356144. https://doi.org/10.1080/2162402X.2017.1356144
39. Lin JX, Lin JP, Xie JW, et al. Prognostic value and association of sarcopenia and systemic inflammation for patients with gastric cancer following radical gastrectomy. Oncologist 2019;24:1091-1101. https://doi.org/10.1634/theoncologist.2018-0651
40. Deng Q, He B, Liu X, et al. Prognostic value of pre-operative inflammatory response biomarkers in gastric cancer patients and the construction of a predictive model. J Transl Med 2015;13:66.e1-16. https://doi.org/10.1186/s12967-015-0409-0
41. Lieto E, Galizia G, Auricchio A, et al. Preoperative neutrophil to lymphocyte ratio and lymphocyte to monocyte ratio are prognostic factors in gastric cancers undergoing surgery. J Gastrointest Surg 2017;21:1764-1774. https://doi.org/10.1007/s11605-017-3515-x
42. Ma JY, Liu Q. Clinicopathological and prognostic significance of lymphocyte to monocyte ratio in patients with gastric cancer: a meta-analysis. Int J Surg 2018;50:67-71. https://doi.org/10.1016/j.ijsu.2018.01.002
43. Ilhan N, Ilhan N, Ilhan Y, Akbulut H, Kucuksu M. C-reactive protein, procalcitonin, interleukin-6, vascular endothelial growth factor and oxidative metabolites in diagnosis of infection and staging in patients with gastric cancer. World J Gastroenterol 200415;10:1115-1120. https://doi.org/10.3748/wjg.v10.i8.1115
44. Sohda M, Sakai M, Yamaguchi A, et al. Pre-treatment CRP and albumin determines prognosis for unresectable advanced oesophageal cancer. In Vivo 2022;36:1930-1936. https://doi.org/10.21873/invivo.12914
45. Arakawa Y, Miyazaki K, Yoshikawa M et al. Value of the CRP-albumin ratio in patients with resectable pancreatic cancer. J Med Invest 2021;68:244-255. https://doi.org/10.2152/jmi.68.244
46. Yu Q, Li KZ, Fu YJ, et al. Clinical significance and prognostic value of C-reactive protein/albumin ratio in gastric cancer. Ann Surg Treat Res 2021;100:338-346. https://doi.org/10.4174/astr.2021.100.6.338
47. Ouyang X, Dang Y, Zhang F, Huang Q. Low serum albumin correlates with poor survival in gastric cancer patients. Clin Lab 20181;64:239-245. https://doi.org/10.7754/Clin.Lab.2017.170804
48. Alkurt EG, Durak D, Turhan VB, Sahiner IT. Effect of C-reactive protein-to-albumin ratio on prognosis in gastric cancer patients. Cureus 2022;14:e23972. https://doi.org/10.7759/cureus.23972
49. Lu J, Xu BB, Xue Z, et al. Perioperative CRP: a novel inflammation-based classification in gastric cancer for recurrence and chemotherapy benefit. Cancer Med 2021;10:34-44. https://doi.org/10.1002/cam4.3514
50. Zhao Z, Han F, Yang S, Hua L, Wu J, Zhan W. The clinicopathologic importance of serum lactic dehydrogenase in patients with gastric cancer. Dis Markers 2014;2014:140913.e1-7. https://doi.org/10.1155/2014/140913