Original StudyEffect of Systemic Inflammation on Survival in Patients With Metastatic Renal Cell Carcinoma Receiving Second-line Molecular-targeted Therapy
Introduction
The current treatment strategy for metastatic renal cell carcinoma (mRCC) consists of molecular-targeted therapy (mTT) to improve and prolong patient survival.1 To further improve treatment strategy and, consequently, patient survival, identifying the predictive factors or risk classifications is necessary.
The functional relationship between systemic inflammation and cancer is well recognized.2, 3 The tumor microenvironment, which is orchestrated by inflammatory cells, is an indispensable factor in the neoplastic process, fostering cell proliferation, survival, and migration.4 In RCC, an association between systemic inflammation and prognosis has been demonstrated. C-reactive protein (CRP) has been identified as an independent predictive biomarker for survival in patients with RCC with or without metastasis.5, 6, 7, 8, 9 Moreover, the neutrophil/lymphocyte ratio (NLR) has been identified as an effective predictor in patients with mRCC receiving mTT.10, 11 These relationships have been attributed to the mechanism by which RCC cells produce inflammatory cytokines, such as interleukin-6, inducing CRP, and neutrophils.12, 13, 14, 15 Furthermore, the platelet/lymphocyte ratio (PLR) has been identified as a predictive biomarker in patients with cancer, including RCC.16, 17, 18 Several platelet-derived cytokines related to tumor angiogenesis regulation, such as vascular endothelial growth factor, basic fibroblast growth factor, and platelet-derived growth factor, have been found to be elevated in patients with cancer.19, 20
In a recent retrospective largescale study, the neutrophil and platelet levels were independent predictive factors of the prognosis in patients with mRCC who had received second-line mTT after progression during first-line therapy.21 Therefore, we hypothesized that the NLR and/or PLR would also be associated with patient survival after second-line mTT. To the best of our knowledge, the effect of the NLR or PLR in predicting survival in the second-line setting remains unclear, although this has been demonstrated in first-line therapy.10, 18 Moreover, the association among systematic inflammatory markers, including CRP, NLR, and PLR, in the second-line setting is unknown.
Thus, we investigated the correlation among systemic inflammatory markers (CRP, NLR, and PLR) and the influence of these biomarkers in predicting the survival of patients with mRCC receiving second-line mTT after first-line tyrosine kinase inhibitor (TKI) failure.
Section snippets
Patient and Study Design
Of the 115 patients who had received second-line mTT at our department from January 2007 to August 2016, 52 were excluded. The reasons for exclusion were previous cytokine therapy (n = 23), previous dialysis therapy (n = 6), second-line mTT because of adverse events during first-line therapy (n = 11), mammalian target of rapamycin inhibitor (mTORi) as a first-line agent (n = 7), and missing data (n = 5). The remaining 63 patients were evaluated. The clinical and laboratory data were obtained
Patient Background
The patient characteristics are listed in Table 1. Of the 63 patients, 36 were ≥ 65 years old (57.1%), and 44 were men (69.8%). Clear cell carcinoma (CCC) was observed in 48 patients (76.2%), and non-CCC, including papillary RCC, CCC with spindle cells, Bellini duct carcinoma, medullary carcinoma, mucinous tubular and spindle cell carcinoma, and unknown, was observed in 5 (7.94%), 4 (6.35%), 1 (1.59%), 1 (1.59%), 1 (1.59%), and 3 (4.76%) patients, respectively. Previous nephrectomy had been
Discussion
A close relationship between systemic inflammation and prognosis in RCC has been recognized. Chronic systemic inflammation caused by CRP or neutrophils produced by cancer cells can affect the host's nutritional condition, resulting in a poor prognosis, by directly accelerating tumor growth and dissemination or impairing treatment tolerability.24, 25 Moreover, lymphocytes play a role in the host's immunity against cancer and are thought to possess an antitumor effect by inducing cell apoptosis,
Conclusion
Systemic inflammatory markers (specifically, CRP, NLR, and PLR) have prognostic value for PFS and OS in patients with mRCC receiving second-line mTT after first-line TKI failure. Furthermore, CRP was demonstrated to be a strong independent predictive biomarker. Patients with systemic inflammation have a poor prognosis despite second-line therapy initiation. Therefore, careful follow-up must be performed for such high-risk patients. In addition, these markers could be used to determine the best
Disclosure
T. Kondo has received honoraria from Pfizer, Bayer, and Novartis. The remaining authors declare that they have no competing interests.
Acknowledgments
We thank Nobuko Hata (Tokyo Women's Medical University) for secretarial support and Editage for English language editing.
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