Analysis of the influence of prognostic factors in patients with renal cancer metastases to the brain

Brain metastases are an unfavourable manifestation of renal cell cancer. Currently, we have limited understanding of the tumour and immune biology of brain metastases and resistance factors to systemic therapy. The optimal approach to comprehensive treatment of brain metastases in renal cancer remains unclear. That is why it is important to search for additional prognostic factors in this category of patients.
The aim of the study was to analyse prognostic predictors in patients with renal cancer metastases to the brain affecting survival rates.
Materials and methods. We retrospectively analysed the data of 56 patients with brain metastases of RCC treated at the Moscow City Oncological Hospital No. 62 in Moscow and the City Clinical Oncological Dispensary (St. Petersburg) from 2006 to 2022, with a median follow-up of 45,6 months. 48 (85,7%) men prevailed in the study. Solitary brain metastases were detected in 19 (33,9%), and more than 2 metastases in 21 (37,5%). Intermediate and poor prognosis according to IMDC was established in 21 (37,5%) and 25 (44,6%), respectively, with low-differentiated tumours in the primary kidney tumour detected in 28 (50%) patients. Radiation therapy was given to 32 (57,1%) and metastasectomy to 33 (58,9%) patients. The study investigated clinical and morphological prognostic factors influencing survival rates in patients with brain metastases of RCC. Statistical analysis was performed using Statistica 10.0 software packages (StatSoft, USA) by constructing Kaplan-Meier curves and survival tables, building a mathematical model of survival.
Results. The 3- and 5-year OS in patients with brain metastases of RCC (n=56) was 43% and 22%, respectively, with a median OS of 22,3 months. In single factor analysis in patients with renal cancer brain metastases, ECOG status (p=0,0047), number of brain metastases (p<0,001), liver metastases (p=0,028), IMDC prognosis (p=0,024), nephrectomy (p<0,001) and radiotherapy (p=0,05) were found to have a negative impact on survival rates. In multivariate analysis, gender (p<0,001), ECOG status (p<0,001), degree of tumour differentiation (p=0,001), type and number of brain metastases (p<0,001), IMDC prognosis (p<0,001), metastases to lung (p<0,001), bone (p<0,001), liver (p=0,001) and lymph nodes (p<0,001), as well as nephrectomy (p=0,001) and radiotherapy (p<0,001) were additional predictors affecting AE rates in patients with brain metastases of RCC.
Conclusion. In our study, sex, ECOG status, tumour differentiation, type and number of brain metastases, IMDC prognosis, metastases to lung, bone, liver and lymph nodes, as well as nephrectomy and radiotherapy were additional independent prognostic factors affecting OS in patients with brain metastases of RCC. 

1. Achrol A.S., Rennert R.C., Anders C. et al. Brain metastases // Nat. Rev. Dis. Primers. 2019. Vol. 5. Р. 5. https://doi.org/10.1038/s41572-018-0055-y.

2. Dudani S., de Velasco G., Wells J.C. et al. Evaluation of clear cell, papillary, and chromophobe renal cell carcinoma metastasis sites and association with survival // JAMA Netw Open. 2021. Vol. 4. Р. e2021869. https://doi.org/10.1001/jamanetworkopen.2020.21869.

3. Schouten L.J., Rutten J., Huveneers H.A. et al. Incidence of brain metastases in a cohort of patients with carcinoma of the breast, colon, kidney, and lung and melanoma // Cancer. 2002. Vol. 94. Р. 2698–2705. https://doi.org/10.1002/cncr.10541.

4. Bowman I.A., Le T., Christie A. et al. Incidence of brain metastases in metastatic renal cell carcinoma in the era of targeted therapies // J. Clin. Oncol. 2016. Vol. 34. https://doi.org/10.1200/jco.2016.34.15_suppl.e16103.

5. Daugherty M., Daugherty E., Jacob J. et al. Renal cell carcinoma and brain metastasis: Questioning the dogma of role for cytoreductive nephrectomy // Urol. Oncol. 2019. Vol. 37, No. 3. Р. 182 e189–182. e115. https://doi.org/10.1016/j.urolonc.2018.10.021.

6. Hanzly M., Abbotoy D., Creighton T. et al. Early identification of asymptomatic brain metastases from renal cell carcinoma // Clin. Exp. Metastasis. 2015. Vol. 32, No. 8. Р. 783–788. https://doi.org/10.1007/s10585-015-9748-8.

7. Motzer R.J., Tannir N.M., McDermott D.F. et al. Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma // N. Engl. J. Med. 2018. Vol. 378. Р. 1277–1290. https://doi.org/10.1056/NEJMoa1712126.

8. Motzer R.J., Penkov K. Haanen J. et al. Avelumab plus axitinib versus sunitinib for advanced renal-cell carcinoma // N. Engl. J. Med. 2019. Vol. 380. Р. 1103–1115. https://doi.org/10.1056/NEJMoa1816047.

9. Rini B.I., Plimack E.R., Stus V. et al. Pembrolizumab plus axitinib versus sunitinib for advanced renal-cell carcinoma // N. Engl. J. Med. 2019. Vol. 380. Р. 1116–1127. https://doi.org/10.1056/NEJMoa1816714.

10. Choueiri TK, Powles T., Burotto M. et al. Nivolumab plus cabozantinib versus sunitinib for advanced renal-cell carcinoma // N. Engl. J. Med. 2021. Vol. 384. Р. 829–841. https://doi.org/10.1056/NEJMoa2026982.

11. Motzer R., Alekseev B., Rha S.Y. et al. Lenvatinib plus pembrolizumab or everolimus for advanced renal cell carcinoma // N. Engl. J. Med. 2021. Vol. 384. Р. 1289–1300. https://doi.org/10.1056/NEJMoa2035716.

12. Hasanov E., Gao J., Tannir N.M. et al. The immunotherapy revolution in kidney cancer treatment: scientific rationale and first-generation results // Cancer J. 2020. Vol. 26. Р. 419–431. https://doi.org/10.1097/PPO.0000000000000471.

13. Flippot R., Dalban C., Laguerre B. et al. Safety and efficacy of nivolumab in brain metastases from renal cell carcinoma: results of the GETUG-AFU 26 NIVOREN multicenter phase II study // J. Clin. Oncol. 2019. Vol. 37. Р. 2008–2016. https://doi.org/10.1200/jco.18.02218.

14. Jonasch E., Hasanov E., Motzer R.J. et al. Evaluation of brain metastasis in JAVELIN Renal 101: efficacy of avelumab + axitinib (A+Ax) versus sunitinib (S) [abstract] // J. Clin. Oncol. 2020. Vol. 38, No. 6, suppl. Р. 687. https://doi.org/10.1200/jco.2020.38.6_suppl.687.

15. Patchell R.A., Tibbs P.A., Walsh J.W. et al. A randomized trial of surgery in the treatment of single metastases to the brain // N. Engl. J. Med. 1990. Vol. 322. Р. 494–500. https://doi.org/10.1056/nejm199002223220802.

16. Lamba N., Muskens I.S., DiRisio A.C. et al. Stereotactic radiosurgery versus whole-brain radiotherapy after intracranial metastasis resection: a systematic review and meta-analysis // Radiat. Oncol. 2017. Vol. 12. Р. 106. https://doi.org/10.1186/s13014-017-0840-x.

17. Yomo S., Oda K., Oguchi K. et al. Effectiveness of immune checkpoint inhibitors in combination with stereotactic radiosurgery for patients with brain metastases from renal cell carcinoma: inverse probability of treatment weighting using propensity scores // J. Neurosurg. 2022. Vol. 138. Р. 1591–1599. https://doi.org/10.3171/2022.9.jns221215.

18. Huntoon K., Damante M., Wang J. et al. Survival benefit with resection of brain metastases from renal cell carcinoma in the setting of molecular targeted therapy and/or immune therapy // Curr. Probl. Cancer. 2022. Vol. 46. Р. 100805. https://doi.org/10.1016/j.currproblcancer.2021.100805.

19. Tannir N.M., Motzer R.J., Albiges L. et al. Patterns of progression in patients treated with nivolumab plus ipilimumab (NIVO + IPI) versus sunitinib (SUN) for first-line treatment of advanced renal cell carcinoma (aRCC) in CheckMate 214 [abstract] // J. Clin. Oncol. 2021. Vol. 39, No. 6, suppl. 313. https://doi.org/10.1200/JCO.2021.39.6_suppl.313.

20. Crisman C.M., Patel A.R., Winston G. et al. Clinical Outcomes in Patients with Renal Cell Carcinoma Metastases to the Choroid Plexus // World Neurosurg. 2020. Vol. 140. Р. e7–e13. https://doi.org/10.1016/j.wneu.2020.03.125.

21. Vornicova O., Bar-Sela G. et al. Do we have a «game changer» in treating patients with brain metastasis from renal cell carcinoma? // Ann. Transl. Med. 2019. Vol. 7, Suppl. S8. Р. S360. https://doi.org/10.21037/atm.2019.09.50.

22. Internò V., De Santis P., Stucci L.S. et al. Prognostic Factors and Current Treatment Strategies for Renal Cell Carcinoma Metastatic to the Brain: An Overview // Cancers. 2021. Vol. 13. Р. 2114. https://doi.org/10.3390/cancers13092114.

23. Zapata Laguado M., Paez Quintero H., Gomez A. et al. Retrospective Study of Metastatic Renal Cell Carcinoma Patients with Brain Metastases // Cureus. 2023. Vol. 15. Р. e34014. https://doi.org/10.7759/cureus.34014.

24. Sperduto P.W., Deegan B.J., Li J. et al. Estimating survival for renal cell carcinoma patients with brain metastases: An update of the Renal Graded Prognostic Assessment tool // Neuro-Oncology. 2018. Vol. 20. Р. 1652–1660. https://doi.org/10.1093/neuonc/noy099.

25. Shuch B., La Rochelle J.C., Klatte T. et al. Brain metastasis from renal cell carcinoma: presentation, recurrence, and survival // Cancer. 2008. Vol. 113, No. 7. Р. 1641–1648. https://doi.org/10.1002/cncr.23769.

26. Ljungberg B., Albiges L., Abu-Ghanem Y. et al. European Association of Urology Guidelines on Renal Cell Carcinoma: The 2019 Update // Eur. Urol. 2019. Vol. 75, No. 5. Р. 799–810. https://doi.org/10.1016/j.eururo.2022.05.038.

27. Escudier B., Porta C., Schmidinger M. et al. Renal cell carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up // Ann. Oncol. 2019. Vol. 30, No. 5. Р. 706–720. https://doi.org/10.1093/annonc/mdz056.

28. de Velasco G., Bex A., Albiges L. et al. Sequencing and Combination of Systemic Therapy in Metastatic Renal Cell Carcinoma // Eur. Urol. Oncol. 2019. Vol. 2, No. 5. Р. 505–514. https://doi.org/10.1016/j.euo.2019.06.022.

29. Parmar A., Chan K.K. еt al. Health technology assessment methodology in metastatic renal cell carcinoma // Nat. Rev. Urol. 2020. Vol. 17. Р. 3–5. https://doi.org/10.1038/s41585–019–0257–4.

30. Kotecha R.R., Flippot R., Nortman T. et al. Prognosis of incidental brain metastases in patients with advanced renal cell carcinoma // J. Natl. Compr. Canc. Netw. 2021. 19. Р. 432–438. https://doi.org/10.6004/jnccn.2020.7634.

31. Sun M., De Velasco G., Brastianos P.K. et al. The development of brain metastases in patients with renal cell carcinoma: epidemiologic trends, survival, and clinical risk factors using a population-based cohort // Eur. Urol. Focus. 2019. Vol. 5. Р. 474–481. http://10.1016/j.euf.2017.12.007.

32. Ferrel E.A., Roehrig A.T., Kaya E.A. et al. Retrospective study of metastatic melanoma and renal cell carcinoma to the brain with multivariate analysis of prognostic pre-treatment clinical factors // Int. J. Mol Sci. 2016. Vol. 17. Р. 400. https://doi.org/10.3390/ijms17030400.

33. Ratnayake G., Challapalli A., McGrane K. et al. A UK multicentre retrospective review of metastatic renal cell carcinoma (mRCC) patients (pts) outcomes with brain metastases (BM) in the modern era // Ann. Oncol. 2022. Vol. 33. Р. S1211 https://doi.org/10.1016/j.annonc.2022.07.1560.

34. Hasanov E., Yeboa D.N., Tucker M.D. et al. An interdisciplinary consensus on the management of brain metastases in patients with renal cell carcinoma // CA Cancer J. Clin. 2022. Vol. 72. Р. 454–489. https://doi.org/10.3322/caac.21729.