Birinci Basamak Tirozin Kinaz İnhibitörü Alan Metastatik Berrak Hücreli Renal Karsinom Hastalarında Sistemik İnflamasyon ve Beslenme Göstergelerinin Progresyonsuz Sağkalım Üzerine Etkisi

Öz

Amaç: Sistemik inflamasyon ve beslenme durumu, metastatik berrak hücreli renal karsinomda (mccRCC) prognozun önemli belirleyicilerindendir. Sistemik immün-inflamasyon indeksi (SII) ve modifiye Glasgow prognostik skoru (mGPS) gibi basit biyobelirteçlerin prognostik değeri çeşitli kanserlerde gösterilmiş olsa da mccRCC’de gerçek yaşam verileri sınırlıdır. Yöntem: Bu retrospektif tek merkezli kohorta, Kasım 2022–Kasım 2024 arasında Etlik Şehir Hastanesi’nde birinci basamak tirozin kinaz inhibitörü (TKI) monoterapisi (sunitinib, pazopanib veya kabozantinib) alan histolojik olarak doğrulanmış mccRCC hastaları dâhil edildi. İnflamatuvar ve nutrisyonel indeksler (SII, mGPS) ile progresyonsuz sağkalım (PFS) arasındaki ilişkiler Kaplan–Meier ve çok değişkenli lojistik regresyon analizleriyle değerlendirildi. Bulgular: Toplam 55 hasta analize dâhil edildi. Medyan yaş 62 (İAS 52–71) yıl olup, hastaların %67’si erkekti. Medyan PFS 13,24 ay (%95 GA 7,75–19,12) iken, medyan genel sağkalıma ulaşılamamıştır. Yüksek SII (≥870) çok değişkenli analiz sonucunda daha kısa PFS ile bağımsız olarak ilişkiliydi (OR 5,05; %95 GA 1,14–15,77; p=0,039). mGPS (1–2) Kaplan–Meier analizinde daha kısa PFS ile anlamlı şekilde ilişkiliydi (HR 3,43; %95 GA 1,42–8,30; p=0,006; log-rank p=0,001), ancak çok değişkenli modelde bağımsızlığını yitirdi. Metformin kullanımı (OR 0,12; %95 GA 0,02–0,93; p=0,044), sunitinib tedavisi (OR 0,07; %95 GA 0,006–0,74; p=0,027) ve IMDC düşük/orta risk grubu (OR 0,17; %95 GA 0,06–0,96; p=0,047) daha düşük progresyon riskiyle bağımsız olarak ilişkili bulundu. Cabozantinib (n=15) grubunda medyan PFS 18,6 ay (%95 GA 13,8–23,3) olup, sunitinib ve pazopanib gruplarına göre daha uzun gözlendi; ancak fark istatistiksel olarak anlamlı değildi (log-rank p=0,152). Sonuç: Birinci basamak tirozin kinaz inhibitörü tedavisi alan mccRCC hastalarından oluşan bu gerçek yaşam kohortunda, konakla ilişkili inflamatuvar ve beslenme durumu progresyonsuz sağkalımla yakından ilişkili bulunmuştur. Ayrıca, IMDC düşük risk grubundaki hastalarda progresyon riskinin belirgin şekilde daha düşük olması, klinik risk sınıflamasının bu biyobelirteçlerle birlikte değerlendirilmesinin prognostik doğruluğu artırabileceğini göstermektedir. Bu kolay erişilebilir biyobelirteçlerin ve klinik risk skorlarının mevcut prognostik modellerle bütünleştirilmesi, bireyselleştirilmiş risk değerlendirmesi ve tedavi planlamasını güçlendirebilir. Bulguların doğrulanması için prospektif, çok merkezli, randomize kontrollü ve yapay zekâ destekli çalışmalara ihtiyaç vardır.

Anahtar Kelimeler

• Berrak hücreli metastatik renal karsinom
• Enflamasyon
• Prognoz
• Tirozin kinaz inhibitörleri
• Yapay zekâ

Destekleyen Kurum

Bu araştırma, kamu, ticari veya kâr amacı gütmeyen kuruluşlardan herhangi bir özel mali destek almamıştır.

Proje Numarası

AEŞH-BADEK2-2025-243

Etik Beyan

Çalışma protokolü, Etlik Şehir Hastanesi Etik Kurulu tarafından onaylanmıştır (Onay No: AEŞH-BADEK2-2025-243) ve Helsinki Bildirgesi’ne uygun olarak yürütülmüştür.

Teşekkür

Yazarlar, Etlik Şehir Hastanesi Onkoloji ve Veri Yönetim Ekiplerine, veri toplama ve hasta takibi sürecindeki değerli destekleri için teşekkür ederler.

The Impact of Systemic Inflammation and Nutritional Indicators on Progression-Free Survival in Patients with Metastatic Clear Cell Renal Carcinoma Receiving First-Line Tyrosine Kinase Inhibitor Therapy

Öz

Background: Systemic inflammation and nutritional status are key determinants of prognosis in metastatic clear-cell renal carcinoma (mccRCC). Composite indices such as the Systemic Immune–Inflammation Index (SII) and the Modified Glasgow Prognostic Score (mGPS) have demonstrated prognostic relevance across cancers, but real-world data in mccRCC remain limited. Methods: This retrospective, single-center cohort included patients with histologically confirmed mccRCC who received first-line tyrosine kinase inhibitor (TKI) monotherapy (sunitinib, pazopanib, or cabozantinib) between November 2022 and November 2024 at Etlik City Hospital (Ankara, Türkiye). Associations between inflammatory–nutritional indices (SII, mGPS) and progression-free survival (PFS) were evaluated using Kaplan–Meier and multivariable logistic regression analyses. Results: A total of 55 patients met eligibility criteria and were included in the analysis. The median age was 62 years (IQR 52–71), and 67% were male. Median PFS was 13.24 months (95% CI 7.75–19.12), while median OS was not reached. High SII (≥ 870) was independently associated with shorter PFS in multivariable analysis (OR 5.05; 95% CI 1.14–15.77; p = 0.039). mGPS (1–2) was significantly associated with inferior PFS in Kaplan–Meier analysis (HR 3.43; 95% CI 1.42–8.30; p = 0.006; log-rank p = 0.001), but lost significance in multivariable modeling. Metformin use (OR 0.12; 95% CI 0.02–0.93; p = 0.044), sunitinib therapy (OR 0.07; 95% CI 0.006–0.74; p = 0.027), and favorable/intermediate IMDC risk group (OR 0.17; 95% CI 0.06–0.96; p = 0.047) were independently associated with a lower progression risk. Patients treated with cabozantinib (n = 15) showed a numerically longer median PFS (18.6 months; 95% CI 13.8–23.3) compared with sunitinib (n = 25, 12.2 months; 95% CI 5.5–19.0) and pazopanib (n = 15, 12.1 months; 95% CI 6.7–17.5), although this difference was not statistically significant (log-rank p = 0.152). Conclusion: In this real-world cohort of patients with mccRCC treated with first-line TKI, host-related inflammatory and nutritional status were closely associated with progression-free survival. Additionally, patients classified within the favorable IMDC risk group exhibited a significantly lower risk of progression, highlighting the importance of integrating clinical risk stratification with systemic inflammatory and nutritional markers. Incorporating such easily measurable biomarkers and clinical risk scores into existing prognostic models may enhance individualized risk assessment and therapeutic decision-making. Future prospective, multicenter, randomized controlled, and artificial intelligence–assisted studies are warranted to validate these findings and refine precision oncology approaches in this population.

Anahtar Kelimeler

• Artificial intelligence
• Inflammation
• Metastatic clear-cell renal carcinoma
• Prognosis
• Tyrosine kinase inhibitors

Destekleyen Kurum

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Proje Numarası

AEŞH-BADEK2-2025-243

Etik Beyan

The study protocol was approved by the Etlik City Hospital Ethics Committee (Approval No: AEŞH-BADEK2-2025-243) and conducted in accordance with the Declaration of Helsinki.

Teşekkür

The authors thank the oncology and data management teams of Etlik City Hospital for their kind support during data collection and patient follow-up.

Kaynakça

1. Capitanio U, Montorsi F. Renal cancer. Lancet 2016; 387: 894-906.
2. Ljungberg B, Albiges L, Abu-Ghanem Y, Bedke J, Capitanio U, Dabestani S et al. European Asso-ciation of Urology Guidelines on Renal Cell Carcinoma: The 2022 Update. Eur Urol 2022; 82: 399-410.
3. Choueiri TK, Motzer RJ. Systemic Therapy for Metastatic Renal-Cell Carcinoma. N Engl J Med 2017; 376: 354-66.
4. Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski RM, Rixe O et al. Sunitinib ver-sus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med 2007; 356: 115-24.
5. Motzer RJ, Hutson TE, Cella D, Reeves J, Hawkins R, Guo J et al. Pazopanib versus sunitinib in metastatic renal-cell carcinoma. N Engl J Med 2013; 369: 722-31.
6. Choueiri TK, Escudier B, Powles T, Tannir NM, Mainwaring PN, Rini BI et al. Cabozantinib ver-sus everolimus in advanced renal cell carcinoma (METEOR): final results from a randomised, open-label, phase 3 trial. Lancet Oncol 2016; 17: 917-27.
7. Motzer RJ, Tannir NM, McDermott DF, Arén Frontera O, Melichar B, Choueiri TK et al. Nivolu-mab plus Ipilimumab versus Sunitinib in Advanced Renal-Cell Carcinoma. N Engl J Med 2018; 378: 1277-90.
8. Choueiri TK, Powles T, Burotto M, Escudier B, Bourlon MT, Zurawski B et al. Nivolumab plus Cabozantinib versus Sunitinib for Advanced Renal-Cell Carcinoma. N Engl J Med 2021; 384: 829-41.

9. Jo JK, Seo SI, Kang M, Chung J, Kwak C, Hong SH et al. Optimal sequential therapy using tyrosi-ne kinase inhibitors as the first-line treatment in patients with metastatic renal cell carcinoma: A na-tionwide multicenter study. Asian J Urol 2024; 11: 450-9.
10. Hou Z, Lai L, Wu H, Zou B, Xu N, Zhu D et al. Administering immunotherapy after anti-vascular targeted therapy improves overall survival of patients with metastatic clear cell renal cell carcinoma. J Cancer 2024; 15: 4527-33.
11. Zhao Z, Yan M, Pang H, Chen L, Tang X, Chen Z et al. Significance of Nutritional-Inflammatory Index as Predictors for Total Neoadjuvant Therapy-Induced Tumor Regression in Locally Advanced Rectal Cancer Patients. J Inflamm Res 2024; 17: 3865-78.
12. Uyar GC, Başaran BN, Başkurt K, Yeşilbaş E, Özkan E, Yücel KB et al. Predicting Pathologic Response in Locally Advanced Rectal Cancer Using Inflammatory, Nutritional, and Sarcopenia-Based Markers: A Regression and AI-Based Analysis (CINR-AI Study). Clin Colorectal Cancer 2025; doi: 10.1016/j.clcc.2025.10.002.
13. Grivennikov SI, Greten FR, Karin M. Immunity, inflammation, and cancer. Cell 2010; 140: 883-99.
14. Douglas E, McMillan DC. Towards a simple objective framework for the investigation and tre-atment of cancer cachexia: the Glasgow Prognostic Score. Cancer Treat Rev 2014; 40: 685-91.
15. McMillan DC. An inflammation-based prognostic score and its role in the nutrition-based mana-gement of patients with cancer. Proc Nutr Soc 2008; 67: 257-62.
16. Sen V, Ozer MS, Sarıkaya AE, Irer B, Bozkurt O. Inflammation-based prognostic markers in renal cell carcinoma: insights from a 15-year experience. BMC Urol 2025; 25: 220.
17. Yıldız Çeltek N, Süren M, Demir O, Okan İ. Karnofsky Performance Scale validity and reliability of Turkish palliative cancer patients. Turk J Med Sci 2019; 49: 894-8.
18. Uyar GC, Kılıç MK. Evaluation of the effects of thyroid functions on frailty in geriatric patients using the Edmonton, SOF and FRAIL Scales. BMC Geriatr 2024; 24: 1051.
19. Maiorano BA, Catalano M, Mercinelli C, Roviello G, Maruzzo M, De Giorgi U et al. Prognostic Impact of IMDC Category Shift From Baseline to Nivolumab Initiation in Metastatic Renal Cell Car-cinoma: A Sub-Analysis of the MEET-URO 15 Study. Clin Genitourin Cancer 2025; 23: 102267.
20. Wu TH, Tsai YT, Chen KY, Yap WK, Luan CW. Utility of High-Sensitivity Modified Glasgow Prognostic Score in Cancer Prognosis: A Systemic Review and Meta-Analysis. Int J Mol Sci 2023; 24: 213.
21. Nøst TH, Alcala K, Urbarova I, Byrne KS, Guida F, Sandanger TM et al. Systemic inflammation markers and cancer incidence in the UK Biobank. Eur J Epidemiol 2021; 36: 841-8.
22. Schwartz LH, Litière S, de Vries E, Ford R, Gwyther S, Mandrekar S et al. RECIST 1.1-Update and clarification: From the RECIST committee. Eur J Cancer 2016; 62: 132-7.
23. Xu J, Chen P, Cao S, Hu X, Li X. Prognostic value of systemic immune-inflammation index in patients with metastatic renal cell carcinoma treated with systemic therapy: a meta-analysis. Front Oncol 2024; 14: 1404753.
24. Stühler V, Herrmann L, Rausch S, Stenzl A, Bedke J. Role of the Systemic Immune-Inflammation Index in Patients with Metastatic Renal Cell Carcinoma Treated with First-Line Ipili-mumab plus Nivolumab. Cancers (Basel) 2022; 14: 2972.
25. Fiala O, Ostašov P, Rozsypalová A, Hora M, Šorejs O, Šustr J et al. Metformin Use and the Out-come of Metastatic Renal Cell Carcinoma Treated with Sunitinib or Pazopanib. Cancer Manag Res 2021; 13: 4077-86.
26. Liu M, Zhang Z, Wang H, Chen X, Jin C. Activation of AMPK by metformin promotes renal cancer cell proliferation under glucose deprivation through its interaction with PKM2. Int J Biol Sci 2019; 15: 617-27.
27. Li Y, Hu L, Xia Q, Yuan Y, Mi Y. The impact of metformin use on survival in kidney cancer patients with diabetes: a meta-analysis. Int Urol Nephrol 2017; 49: 975-81.
28. Choueiri TK, Halabi S, Sanford BL, Hahn O, Michaelson MD, Walsh MK et al. Cabozantinib Versus Sunitinib As Initial Targeted Therapy for Patients With Metastatic Renal Cell Carcinoma of Poor or Intermediate Risk: The Alliance A031203 CABOSUN Trial. J Clin Oncol 2017; 35: 591-7.
29. Kim MS, Chung HS, Hwang EC, Jung SI, Kwon DD, Hwang JE et al. Efficacy of First-Line Tar-geted Therapy in Real-World Korean Patients with Metastatic Renal Cell Carcinoma: Focus on Suni-tinib and Pazopanib. J Korean Med Sci 2018; 33: e325.
30. Rini BI, Plimack ER, Stus V, Gafanov R, Hawkins R, Nosov D et al. Pembrolizumab plus Axiti-nib versus Sunitinib for Advanced Renal-Cell Carcinoma. N Engl J Med 2019; 380: 1116-27.
31. Motzer R, Alekseev B, Rha SY, Porta C, Eto M, Powles T et al. Lenvatinib plus Pembrolizumab or Everolimus for Advanced Renal Cell Carcinoma. N Engl J Med 2021; 384: 1289-300.
32. Chakiryan NH, Jiang DD, Gillis KA, Green E, Hajiran A, Hugar L et al. Real-World Survival Outcomes Associated With First-Line Immunotherapy, Targeted Therapy, and Combination Therapy for Metastatic Clear Cell Renal Cell Carcinoma. JAMA Netw Open 2021; 4: e2111329.
33. Gan CL, Dudani S, Wells JC, Donskov F, Pal SK, Dizman N et al. Cabozantinib real-world effec-tiveness in the first-through fourth-line settings for the treatment of metastatic renal cell carcinoma: Results from the International Metastatic Renal Cell Carcinoma Database Consortium. Cancer Med 2021; 10: 1212-21.
34. McKay RR, Kroeger N, Xie W, Lee JL, Knox JJ, Bjarnason GA et al. Impact of bone and liver metastases on patients with renal cell carcinoma treated with targeted therapy. Eur Urol 2014; 65: 577-84.
35. Prado CM, Purcell SA, Laviano A. Nutrition interventions to treat low muscle mass in cancer. J Cachexia Sarcopenia Muscle 2020; 11: 366-80.
36. Hess DL, Harmon C, Bhatia S, Williams GR, Giri S. SARC-F as a screening tool to detect compu-ted tomography-based sarcopenia and myosteatosis among older adults with cancer. Cancer Med 2023; 12: 20690-8.
37. Fukushima H, Nakanishi Y, Kataoka M, Tobisu K, Koga F. Prognostic Significance of Sarcope-nia in Patients with Metastatic Renal Cell Carcinoma. J Urol 2016; 195: 26-32.