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Characterizing the Impact of Lymph Node Metastases on the Survival Outcome for Metastatic Renal Cell Carcinoma Patients Treated with Targeted Therapies

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Kroeger N., Pantuck A.J., Wells J.C., Lawrence N., Broom R., Kim J.J., Srinivas S., Yim J., Bjarnason G.A., Templeton A., Knox J., Bernstein E., Smoragiewicz M., Lee J., Rini B.I., Vaishampayan U.N., Wood L.A., Beuselinck B., Donskov F., Choueiri T.K., Heng D.Y.

European Urology 2015 68:3 (506-515) Article Number 5988

Background It is unknown whether lymph node metastases (LNM) and their localization negatively affect clinical outcome in metastatic renal cell carcinoma (mRCC) patients. Objective To evaluate the clinicopathological features, survival outcome, and treatment response in mRCC patients with LNM versus those without LNM after treatment with targeted therapies (TT). Design, setting, and participants Patients (n = 2996) were first analyzed without consideration of lymph node (LN) localization or histologic subtype. Additional analyses (n = 1536) were performed in subgroups of patients with supradiaphragmatic (SPD) LNM, subdiaphragmatic (SBD) LNM, and patients with LNM in both locations (SPD+/SBD+) without histologic considerations, and then separately in clear cell RCC (ccRCC) and non-clear cell RCC (nccRCC) patients, respectively. Outcome measurements and statistical analysis The primary outcome was overall survival (OS) and the secondary outcome was progression-free survival (PFS). Results and limitations All patients with LNM had worse PFS (p = 0.001) and OS (p < 0.001) compared to those without LNM. Compared to patients without LNM (PFS 8.8 mo; OS 25.1 mo), any SBD LNM involvement was associated with worse PFS (SBD, 6.8 mo; p = 0.003; SPD+/SBD+, 5.5 mo; p < 0.001) and OS (SBD, 16.2 mo; p < 0.001; SPD+/SBD+, 11.5 mo; p < 0.001). Both SBD and SPD+/SBD+ LNM were retained as independent prognostic factors in multivariate analyses (MVA) for PFS (p = 0.006 and p = 0.022, respectively) and OS (both p < 0.001), while SPD LNM was not an independent risk factor. Likewise, in ccRCC, SBD LNM (19.8 mo) and SPD+/SBD+ LNM (12.85 mo) patients had the worst OS. SPD+/SBD+ LNM (p = 0.006) and SBD LNM (p = 0.028) were independent prognostic factors for OS in MVA, while SPD LNM was not significant (p = 0.301). The study is limited by its retrospective design and the lack of pathologic evaluation of LNM in all cases. Conclusions The metastatic spread of RCC to SBD lymph nodes is associated with poor prognosis in mRCC patients treated with TT. Patient summary The presence of lymph node metastases below the diaphragm is associated with shorter survival outcome when metastatic renal cell carcinoma (mRCC) patients are treated with targeted therapies. Clinical trials should evaluate whether surgical removal of regional lymph nodes at the time of nephrectomy may improve outcomes in high-risk RCC patients.

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