Lokal İleri Rektal Kanserin Neoadjuvan Kemoradyoterapisinde, Tümör Regresyonunu ve Sağkalımı Tahmin Edebilecek Yeni Parametreler

Abstract

Amaç: Lokal ileri rektal kanser (locally advanced rectal cancer, LARC) yüksek mortaliteye sahiptir. Neoadjuvan kemoradyoterapi (nCRT) tedavinin temelini oluştursa da, beklenen patolojik yanıt yetersizdir. Total neoadjuvan tedavi (TNT) ile ilgili araştırmalar devam etmektedir. Bu çalışmanın amacı, tedavi yanıtını ve sağkalımı tahmin etmede belirli inflamatuar ve metabolik parametrelerin önemini araştırmaktır. Gereç ve Yöntemler: 2010 ve 2023 yılları arasında nCRT veya TNT uygulanan 57 LARC hastasına ait veriler geriye dönük analiz edildi. Sistemik immün-inflamasyon indeksi (SII), prognostik beslenme indeksi (PNI), nötrofil-lenfosit oranı (NLR), trombosit-lenfosit oranı (PLR), lenfosit-monosit oranı (LMR) ve eritrosit dağılım genişliği (RDW)-lenfosit oranı (RLR) tedavi başlanmadan önce toplanan kan örneklerinin sonuçlarından hesaplandı. Bulgular: Hastaların 52'sinde (%91,2) adenokarsinom, 5'inde (%8,8) ise müsinöz veya taşlı yüzük histoloji vardı. Verileri mevcut olan 55 hastadan 42'si (%76,4) klinik olarak N+ idi. Yedi (%12,3) hasta TNT aldı. Dworak regresyon skoruna göre 48 (%84,2) hastada zayıf yanıt, 9 (%15,8) hastada iyi yanıt vardı. Altı hastada (%10,5) patolojik tam yanıt vardı. Tek değişkenli analizde 100 ünite başına SII'de (HR=1,081, %95 CI: 1,005-1,162, p=0,036) ve RLR'de (HR=1,197, %95 CI: 1,025-1,398, p=0,023) artış hastalıksız sağkalım (disease-free survival, DFS) ile anlamlı şekilde ilişkiliydi, ancak çoklu modelde böyle bir ilişki yoktu. Sonuç: LARC'de nCRT'ye yanıt olarak Dworak regresyon skoru ile inflamatuar ve metabolik parametreler arasında anlamlı bir ilişki saptanmadı. Yeni bir parametre olan RLR ile DFS arasındaki ilişkiyi belirlemek için daha ileri çalışmalara ihtiyaç vardır.

Keywords

• Kan glikozu
• eritrosit indeksleri
• neoadjuvant tedavi
• rektum neoplazileri
• sistemik immün-inflamatuar indeks

New Parameters That May Predict Tumor Regression and Survival in Neoadjuvant Chemoradiotherapy in Locally Advanced Rectal Cancer

Abstract

Aim: Locally advanced rectal cancer (LARC) is associated with high mortality. Although neoadjuvant chemoradiotherapy (nCRT) is the mainstay of treatment, the expected pathological response is inadequate. Research on total neoadjuvant treatment (TNT) is ongoing. This study aimed to investigate the significance of certain inflammatory and metabolic parameters in predicting treatment response and survival. Material and Methods: Data from 57 patients with LARC who underwent nCRT or TNT between 2010 and 2023 were retrospectively analyzed. The systemic immune-inflammation index (SII) and prognostic nutritional index (PNI) were calculated from the results of the blood samples collected before the initiation of treatment, along with the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), lymphocyte-to-monocyte ratio (LMR), and erythrocyte distribution width (RDW)-to-lymphocyte ratio (RLR). Results: Of the patients, 52 (91.2%) had adenocarcinoma, while 5 (8.8%) had mucinous or signet-ring histology. Among 55 patients with available data, 42 (76.4%) were clinically N+. Seven (12.3%) received TNT. According to the Dworak regression score, 48 (84.2%) had a poor, and 9 (15.8%) had a good response. Six (10.5%) patients had a pathological complete response. An increase in SII per 100 units (HR=1.081, 95% CI: 1.005-1.162, p=0.036) and in RLR (HR=1.197, 95% CI: 1.025-1.398, p=0.023) was significantly associated with disease-free survival (DFS) in univariate analysis, but not in the multiple model. Conclusion: There was no significant association between the Dworak regression score and the inflammatory and metabolic parameters in response to nCRT in LARC. Further studies are needed to determine the relationship between the RLR, a novel parameter, and DFS.

Keywords

• Blood glucose
• erythrocyte indices
• neoadjuvant therapy
• rectal neoplasms
• systemic immune-inflammation index

References

1. Bray F, Laversanne M, Sung H, Ferlay J, Siegel RL, Soerjomataram I, 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):229-63.
2. Paul S, Arya S, Mokul S, Baheti A, Kumar S, Ramaswamy A, et al. Extramural vascular invasion as an independent prognostic marker in locally advanced rectal cancer: propensity score match pair analysis. Abdom Radiol (NY). 2022;47(11):3671-8.
3. Bosset JF, Collette L, Calais G, Mineur L, Maingon P, Radosevic-Jelic L, et al. Chemotherapy with preoperative radiotherapy in rectal cancer. N Engl J Med. 2006;355(11):1114-23.
4. Guillem JG, Chessin DB, Cohen AM, Shia J, Mazumdar M, Enker W, et al. Long-term oncologic outcome following preoperative combined modality therapy and total mesorectal excision of locally advanced rectal cancer. Ann Surg. 2005;241(5):829-36; discussion 836-8.
5. Sauer R, Becker H, Hohenberger W, Rödel C, Wittekind C, Fietkau R, et al. Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med. 2004;351(17):1731-40.
6. Mendis S, To YH, Tie J. Biomarkers in locally advanced rectal cancer: a review. Clin Colorectal Cancer. 2022;21(1):36-44.
7. Mawdsley S, Glynne-Jones R, Grainger J, Richman P, Makris A, Harrison M, et al. Can histopathologic assessment of circumferential margin after preoperative pelvic chemoradiotherapy for T3-T4 rectal cancer predict for 3-year disease-free survival? Int J Radiat Oncol Biol Phys. 2005;63(3):745-52.
8. Beresford M, Glynne-Jones R, Richman P, Makris A, Mawdsley S, Stott D, et al. The reliability of lymph-node staging in rectal cancer after preoperative chemoradiotherapy. Clin Oncol (R Coll Radiol). 2005;17(6):448-55.

9. Dudani S, Marginean H, Tang PA, Monzon JG, Raissouni S, Asmis TR, et al. Neutrophil-to-lymphocyte and platelet-to-lymphocyte ratios as predictive and prognostic markers in patients with locally advanced rectal cancer treated with neoadjuvant chemoradiation. BMC Cancer. 2019;19(1):664.
10. Cercek A, Roxburgh CSD, Strombom P, Smith JJ, Temple LKF, Nash GM, et al. Adoption of total neoadjuvant therapy for locally advanced rectal cancer. JAMA Oncol. 2018;4(6):e180071.
11. Shin JK, Huh JW, Lee WY, Yun SH, Kim HC, Cho YB, et al. Clinical prediction model of pathological response following neoadjuvant chemoradiotherapy for rectal cancer. Sci Rep. 2022;12(1):7145.
12. Diakos CI, Charles KA, McMillan DC, Clarke SJ. Cancer-related inflammation and treatment effectiveness. Lancet Oncol. 2014;15(11):e493-503.
13. McMillan DC. Systemic inflammation, nutritional status and survival in patients with cancer. Curr Opin Clin Nutr Metab Care 2009;12(3):223-6.
14. McMillan DC, Crozier JE, Canna K, Angerson WJ, McArdle CS. Evaluation of an inflammation-based prognostic score (GPS) in patients undergoing resection for colon and rectal cancer. Int J Colorectal Dis. 2007;22(8):881-6.
15. Roxburgh C, McDonald A, Salmond J, Oien K, Anderson J, McKee R, et al. Adjuvant chemotherapy for resected colon cancer: comparison of the prognostic value of tumour and patient related factors. Int J Colorectal Dis. 2011;26(4):483-92.
16. Ishizuka M, Nagata H, Takagi K, Kubota K. Influence of inflammation-based prognostic score on mortality of patients undergoing chemotherapy for far advanced or recurrent unresectable colorectal cancer. Ann Surg. 2009;250(2):268-72.
17. Walsh SR, Cook EJ, Goulder F, Justin TA, Keeling NJ. Neutrophil-lymphocyte ratio as a prognostic factor in colorectal cancer. J Surg Oncol. 2005;91(3):181-4.
18. Kitayama J, Yasuda K, Kawai K, Sunami E, Nagawa H. Circulating lymphocyte number has a positive association with tumor response in neoadjuvant chemoradiotherapy for advanced rectal cancer. Radiat Oncol. 2010;5:47.
19. Özdemir DB, Karayiğit A, Dizen H, Ünal B. Evaluation of preoperative neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio for their predictive value in determining short-term mortality in patients with operable colorectal cancers. Duzce Med J. 2022;24(1):67-73.
20. Jun SY, Cho S, Kim MJ, Park JW, Ryoo SB, Jeong SY, et al. Glycemic traits and colorectal cancer survival in a cohort of South Korean patients: A Mendelian randomization analysis. Cancer Med. 2024;13(5):e7084.
21. Shim BY, Jung JH, Lee KM, Kim HJ, Hong S, Kim SH, et al. Glucose transporter 1 (GLUT1) of anaerobic glycolysis as predictive and prognostic values in neoadjuvant chemoradiotherapy and laparoscopic surgery for locally advanced rectal cancer. Int J Colorectal Dis. 2013;28(3):375-83.
22. Matsutani S, Shibutani M, Maeda K, Nagahara H, Fukuoka T, Nakao S, et al. Significance of tumor-infiltrating lymphocytes before and after neoadjuvant therapy for rectal cancer. Cancer Sci. 2018;109(4):966-79.
23. Hirahara N, Tajima Y, Fujii Y, Kaji S, Yamamoto T, Hyakudomi R, et al. Comprehensive analysis of red blood cell distribution width as a preoperative prognostic predictor in gastric cancer. Anticancer Res. 2019;39(6):3121-30.
24. Fukuokaya W, Kimura T, Onuma H, Mori K, Honda M, Inaba H, et al. Red cell distribution width predicts prostate-specific antigen response and survival of patients with castration-resistant prostate cancer treated with androgen receptor axis-targeted agents. Clin Genitourin Cancer. 2019;17(3):223-30.
25. Calle MC, Fernandez ML. Inflammation and type 2 diabetes. Diabetes Metab. 2012;38(3):183-91.
26. Lee YY, Choi CH, Kim CJ, Song TJ, Kim MK, Kim TJ, et al. Glucose as a prognostic factor in non-diabetic women with locally advanced cervical cancer (IIB-IVA). Gynecol Oncol. 2010;116(3):459-63.
27. Kohl VKB, Weber K, Brunner M, Geppert CI, Fietkau R, Grützmann R, et al. Factors influencing downstaging after neoadjuvant long-course chemoradiotherapy in rectal carcinoma. Int J Colorectal Dis. 2022;37(6):1355-65.
28. Sun Y, Xu Z, Lin H, Lu X, Huang Y, Huang S, et al. Impact of body mass index on treatment outcome of neoadjuvant chemoradiotherapy in locally advanced rectal cancer. Eur J Surg Oncol. 2017;43(10):1828-34.
29. Toiyama Y, Inoue Y, Saigusa S, Kawamura M, Kawamoto A, Okugawa Y, et al. C-reactive protein as predictor of recurrence in patients with rectal cancer undergoing chemoradiotherapy followed by surgery. Anticancer Res. 2013;33(11):5065-74.
30. Andras D, Crisan D, Craciun R, Nemes A, Caziuc A, Drasovean R, et al. Neutrophil-to-lymphocyte ratio: a hidden gem in predicting neoadjuvant treatment response in locally advanced rectal cancer? J BUON. 2020;25(3):1436-42.
31. Li A, He K, Guo D, Liu C, Wang D, Mu X, et al. Pretreatment blood biomarkers predict pathologic responses to neo-CRT in patients with locally advanced rectal cancer. Future Oncol. 2019;15(28):3233-42.
32. Cheong C, Shin JS, Suh KW. Prognostic value of changes in serum carcinoembryonic antigen levels for preoperative chemoradiotherapy response in locally advanced rectal cancer. World J Gastroenterol. 2020;26(44):7022-35.
33. Lai S, Huang L, Luo S, Liu Z, Dong J, Wang L, et al. Systemic inflammatory indices predict tumor response to neoadjuvant chemoradiotherapy for locally advanced rectal cancer. Oncol Lett. 2020;20(3):2763-70.
34. Shen L, Zhang H, Liang L, Li G, Fan M, Wu Y, et al. Baseline neutrophil-lymphocyte ratio (≥2.8) as a prognostic factor for patients with locally advanced rectal cancer undergoing neoadjuvant chemoradiation. Radiat Oncol. 2014;9:295.
35. Wang Y, Chen L, Zhang B, Song W, Zhou G, Xie L, et al. Pretreatment inflammatory-nutritional biomarkers predict responses to neoadjuvant chemoradiotherapy and survival in locally advanced rectal cancer. Front Oncol. 2021;11:639909.
36. Ding Y, Liu Z, Li J, Niu W, Li C, Yu B. Predictive effect of the systemic inflammation response index (SIRI) on the efficacy and prognosis of neoadjuvant chemoradiotherapy in patients with locally advanced rectal cancer. BMC Surg. 2024;24(1):89.
37. Probst CP, Becerra AZ, Aquina CT, Tejani MA, Hensley BJ, González MG, et al. Watch and wait?--elevated pretreatment CEA is associated with decreased pathological complete response in rectal cancer. J Gastrointest Surg. 2016;20(1):43-52.
38. Colloca G, Venturino A, Vitucci P. Pre-treatment carcinoembryonic antigen and outcome of patients with rectal cancer receiving neo-adjuvant chemo-radiation and surgical resection: a systematic review and meta-analysis. Med Oncol. 2017;34(10):177.
39. Kim TH, Kwak Y, Song C, Lee HS, Kim DW, Oh HK, et al. GLUT-1 may predict metastases and death in patients with locally advanced rectal cancer. Front Oncol. 2023;13:1094480.
40. Wang PF, Song SY, Guo H, Wang TJ, Liu N, Yan CX. Prognostic role of pretreatment red blood cell distribution width in patients with cancer: A meta-analysis of 49 studies. J Cancer. 2019;10(18):4305-17.
41. Ma C, Liu Q, Li C, Cheng J, Liu D, Yang Z, et al. Novel blood indicators of progression and prognosis in renal cell carcinoma: red cell distribution width-to-lymphocyte ratio and albumin-to-fibrinogen ratio. J Oncol. 2020;2020:2895150.