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Impact of Concomitant Cardiovascular Medication on Survival of Metastatic Renal Cell Carcinoma Patients Treated with Sunitinib or Pazopanib in the First Line

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Abstract

Background

Patients with metastatic renal cell carcinoma (mRCC) are often elderly and have various comorbidities, including cardiovascular diseases. Although these patients have extensive co-exposure to targeted therapy and cardiovascular drugs, the impact of this co-exposure on outcomes for patients with mRCC remains unclear.

Objective

Our objective was to evaluate the association between the use of cardiovascular medication and survival of patients with mRCC.

Methods

The study included 343 consecutive patients with mRCC treated with sunitinib or pazopanib in the first line. Clinical data obtained from the Renal Cell Carcinoma Information System (RENIS) clinical registry and hospital information systems were retrospectively analyzed. Progression-free survival (PFS) and overall survival (OS) were compared according to the use of common medications, including antihypertensives (i.e., β-blockers [BBs], angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, calcium channel blockers, and diuretics), acetylsalicylic acid (aspirin), statins, and proton pump inhibitors.

Results

The univariate Cox analysis evaluating the impact of the assessed comedications on patient survival revealed that only BBs were significantly associated with PFS (hazard ratio [HR] 0.533, p < 0.001) and OS (HR 0.641, p = 0.006). The median PFS and OS for users of BBs was 18.39 and 37.60 months versus 8.16 and 20.4 months for patients not using BBs (p < 0.001 and p < 0.001, respectively). The Cox multivariate analysis showed that the use of BBs was a significant factor for both PFS (HR 0.428, p = 0.001) and OS (HR 0.518, p = 0.001).

Conclusions

The results of this retrospective study suggest that the use of BBs is associated with favorable outcomes for patients with mRCC treated with sunitinib or pazopanib in the first line.

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References

  1. Padala SA, Barsouk A, Thandra KC, Saginala K, Mohammed A, Vakiti A, et al. Epidemiology of renal cell carcinoma. World J Oncol. 2020;11:79–87.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Di Lorenzo G, Autorino R, Bruni G, Cartenì G, Ricevuto E, Tudini M, et al. Cardiovascular toxicity following sunitinib therapy in metastatic renal cell carcinoma: a multicenter analysis. Ann Oncol. 2009;20:1535–42.

    Article  PubMed  Google Scholar 

  3. Rini BI, Cohen DP, Lu DR, Chen I, Hariharan S, Gore ME, et al. Hypertension as a biomarker of efficacy in patients with metastatic renal cell carcinoma treated with sunitinib. J Natl Cancer Inst. 2011;103:763–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Szmit S, Zaborowska M, Waśko-Grabowska A, Żołnierek J, Nurzyński P, Filipiak KJ, et al. Cardiovascular comorbidities for prediction of progression-free survival in patients with metastatic renal cell carcinoma treated with sorafenib. Kidney Blood Press Res. 2012;35:468–76.

    Article  CAS  PubMed  Google Scholar 

  5. Telli ML, Witteles RM, Fisher GA, Srinivas S. Cardiotoxicity associated with the cancer therapeutic agent sunitinib malate. Ann Oncol. 2008;19:1613–8.

    Article  CAS  PubMed  Google Scholar 

  6. Weikert S, Boeing H, Pischon T, Weikert C, Olsen A, Tjonneland A, et al. Blood pressure and risk of renal cell carcinoma in the European prospective investigation into cancer and nutrition. Am J Epidemiol. 2008;167:438–46.

    Article  PubMed  Google Scholar 

  7. Hamnvik OP, Choueiri TK, Turchin A. Clinical risk factors for the development of hypertension in patients treated with inhibitors of the VEGF signaling pathway. Cancer. 2015;121:311–9.

    Article  CAS  PubMed  Google Scholar 

  8. Izzedine H, Derosa L, Le Teuff G, Albiges L, Escudier B. Hypertension and angiotensin system inhibitors: impact on outcome in sunitinib-treated patients for metastatic renal cell carcinoma. Ann Oncol. 2015;26:1128–33.

    Article  CAS  PubMed  Google Scholar 

  9. Keizman D, Huang P, Eisenberger MA, Pili R, Kim JJ, Antonarakis ES, et al. Angiotensin system inhibitors and outcome of sunitinib treatment in patients with metastatic renal cell carcinoma: a retrospective examination. Eur J Cancer. 2011;47:1955–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Patel VG, Oh WK, Galsky MD, Liaw BCH, Tsao CK. Effect of concurrent beta-blocker (BB) use in patients receiving immune checkpoint inhibitors for metastatic urothelial (mUC) and renal cell carcinomas (mRCC). J Clin Oncol. 2019;37:467–467.

    Article  Google Scholar 

  11. Larochelle P, Kollmannsberger C, Feldman RD, Schiffrin EL, Poirier L, Patenaude F, et al. Hypertension management in patients with renal cell cancer treated with anti-angiogenic agents. Curr Oncol. 2012;19:202–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Buchler T, Klapka R, Melichar B, Brabec P, Dusek L, Vyzula R, et al. Sunitinib followed by sorafenib or vice versa for metastatic renal cell carcinoma—data from the Czech registry. Ann Oncol. 2012;23:395–401.

    Article  CAS  PubMed  Google Scholar 

  13. Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, et al. New guidelines to evaluate the response to treatment in solid tumours. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst. 2000;92:205–16.

    Article  CAS  PubMed  Google Scholar 

  14. Schuller HM. Beta-adrenergic signaling, a novel target for cancer therapy? Oncotarget. 2010;1:466–9.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Sastry KS, Karpova Y, Prokopovich S, Smith AJ, Essau B, Gersappe A, et al. Epinephrine protects cancer cells from apoptosis via activation of cAMP-dependent protein kinase and BAD phosphorylation. J Biol Chem. 2007;282:14094–100.

    Article  CAS  PubMed  Google Scholar 

  16. Wong HP, Ho JW, Koo MW, Yu L, Wu WK, Lam EK, et al. Effects of adrenaline in human colon adenocarcinoma HT-29 cells. Life Sci. 2011;88:1108–12.

    Article  CAS  PubMed  Google Scholar 

  17. Drell TL, Joseph J, Lang K, Niggemann B, Zaenker KS, Entschladen F. Effects of neurotransmitters on the chemokinesis and chemotaxis of MDA-MB-468 human breast carcinoma cells. Breast Cancer Res Treat. 2003;80:63–70.

    Article  CAS  PubMed  Google Scholar 

  18. Yang EV, Sood AK, Chen M, Li Y, Eubank TD, Marsh CB, et al. Norepinephrine up-regulates the expression of vascular endothelial growth factor, matrix metalloproteinase (MMP)-2, andMMP-9 in nasopharyngeal carcinoma tumor cells. Cancer Res. 2006;66:10357–64.

    Article  CAS  PubMed  Google Scholar 

  19. Nilsson MB, Armaiz-Pena G, Takahashi R, Lin YG, Trevino J, Li Y, et al. Stress hormonesregulate interleukin-6 expression by human ovarian carcinoma cells through a Src-dependent mechanism. J Biol Chem. 2007;282:29919–26.

    Article  CAS  PubMed  Google Scholar 

  20. Cole SW, Arevalo JM, Takahashi R, Sloan EK, Lutgendorf SK, Sood AK, et al. Computational identification of gene-social environment interaction at the human IL6 locus. Proc Natl AcadSci USA. 2010;107:5681–6.

    Article  CAS  Google Scholar 

  21. Shahzad MM, Arevalo JM, Armaiz-Pena GN, Lu C, Stone RL, Moreno-Smith M, et al. Stress effects on FosB and interleukin-8 (IL8) -driven ovarian cancer growth and metastasis. J Biol Chem. 2010;285:35462–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Thaker PH, Han LY, Kamat AA, Arevalo JM, Takahashi R, Lu C, et al. Chronic stress promotes tumor growth and angiogenesis in a mouse model of ovarian carcinoma. Nat Med. 2006;12:939–44.

    Article  CAS  PubMed  Google Scholar 

  23. Chakroborty D, Sarkar C, Basu B, Dasgupta PS, Basu S. Catecholamines regulate tumor angiogenesis. Cancer Res. 2009;69:3727–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Masur K, Niggemann B, Zanker KS, Entschladen F. Norepinephrine-induced migration of SW 480 colon carcinoma cells is inhibited by beta-blockers. Cancer Res. 2001;61:2866–9.

    CAS  PubMed  Google Scholar 

  25. Guo K, Ma Q, Wang L, Hu H, Li J, Zhang D, et al. Norepinephrine-induced invasion by pancreatic cancer cells is inhibited by propranolol. Oncol Rep. 2009;22:825–30.

    CAS  PubMed  Google Scholar 

  26. Stiles JM, Amaya C, Rains S, Diaz D, Pham R, Battiste J, et al. Targeting of beta adrenergic receptors results in therapeutic efficacy against models of hemangioendothelioma and angiosarcoma. PLoS ONE. 2013;8:e60021.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Grytli HH, Fagerland MW, Fossa SD, Tasken KA. Association between use of beta- blockers and prostate cancer-specific survival: a cohort study of 3561 prostate cancer patients with high-risk or metastatic disease. Eur Urol. 2014;65:635–41.

    Article  CAS  PubMed  Google Scholar 

  28. Barron TI, Connolly RM, Sharp L, Bennett K, Visvanathan K. Beta blockers and breast cancer mortality: a population-based study. J Clin Oncol. 2011;29:2635–44.

    Article  CAS  PubMed  Google Scholar 

  29. Botteri E, Munzone E, Rotmensz N, Cipolla C, De Giorgi V, Santillo B, et al. Therapeutic effect of β-blockers in triple-negative breast cancer postmenopausal women. Breast Cancer Res Treat. 2013;140:567–75.

    Article  CAS  PubMed  Google Scholar 

  30. Lemeshow S, Sorensen HT, Phillips G, Yang EV, Antonsen S, Riis AH, et al. β-blockers and survival among Danish patients with malignant melanoma: a population-based cohort study. Cancer Epidemiol Biomark Prev. 2011;20:2273–9.

    Article  CAS  Google Scholar 

  31. Beg MS, Gupta A, Sher D, Ali S, Khan S, Gao A, et al. Impact of concurrent medication use on pancreatic cancer survival-SEER-medicare analysis. Am J Clin Oncol. 2018;41:766–71.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Giampieri R, Scartozzi M, Del Prete M, Faloppi L, Bianconi M, Ridolfi F, et al. Prognostic value for incidental antihypertensive therapy with beta-blockers in metastatic colorectal cancer. Medicine. 2015;94:719.

    Article  CAS  Google Scholar 

  33. Diaz ES, Karlan BY, Li AJ. Impact of beta blockers on epithelial ovarian cancer survival. Gynecol Oncol. 2012;127:375–8.

    Article  CAS  PubMed  Google Scholar 

  34. Wang HM, Liao ZX, Komaki R, Welsh JW, Reilly MS, Chang JY, et al. Improved survival outcomes with the incidental use of beta-blockers among patients with non-small-cell lung cancer treated with definitive radiation therapy. Ann Oncol. 2013;24:1312–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Holmes S, Griffith EJ, Musto G, Minuk GY. Antihypertensive medications and survival in patients with cancer: a population-based retrospective cohort study. Cancer Epidemiol. 2013;37:881–5.

    Article  PubMed  Google Scholar 

  36. Heitz F, Hengsbach A, Harter P, Traut A, Ataseven B, Schneider S, et al. Intake of selective beta blockers has no impact on survival in patients with epithelial ovarian cancer. Gynecol Oncol. 2017;144:181–6.

    Article  CAS  PubMed  Google Scholar 

  37. Johannesdottir SA, Schmidt M, Phillips G, Glaser R, Yang EV, Blumenfeld M, et al. Use of ß-blockers and mortality following ovarian cancer diagnosis: a population-based cohort study. BMC Cancer. 2013;13:85.

    Article  PubMed  PubMed Central  Google Scholar 

  38. Choi CH, Song TJ, Kim TH, Choi JK, Park JY, Yoon A, et al. Meta-analysis of the effects of beta blocker on survival time in cancer patients. J Cancer Res Clin Oncol. 2014;140:1179–88.

    Article  CAS  PubMed  Google Scholar 

  39. Zhong S, Yu D, Zhang X, Chen X, Yang S, Tang J, et al. β-blocker use and mortality in cancer patients: systematic review and meta-analysis of observational studies. Eur J Cancer Prev. 2016;25:440–8.

    Article  CAS  PubMed  Google Scholar 

  40. Na Z, Qiao X, Hao X, Fan L, Xiao Y, Shao Y, et al. The effects of beta-blocker use on cancer prognosis: a meta-analysis based on 319,006 patients. Onco Targets Ther. 2018;11:4913–44.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Neumann E, Klaiber P, Freitag K, Schwab M, Schaeffeler E, Hennenlotter J, et al. Assessment of concomitant non-oncologic medication in patients with surgically treated renal cell carcinoma: impact on prognosis, cell-cycle progression and proliferation. J Cancer Res Clin Oncol. 2019;145:1835–43.

    Article  CAS  PubMed  Google Scholar 

  42. Parker WP, Lohse CM, Zaid HB, Cheville JC, Boorjian SA, Leibovich BC, et al. Evaluation of beta-blockers and survival among hypertensive patients with renal cell carcinoma. Urol Oncol. 2017;35(36):e1-36.e6.

    Google Scholar 

  43. Shyu KG, Liou JY, Wang BW, Fang WJ, Chang H. Carvedilol prevents cardiac hypertrophy and overexpression of hypoxia-inducible factor-1a and vascular endothelial growth factor in pressure-overloaded rat heart. J Biomed Sci. 2005;12:409–20.

    Article  CAS  PubMed  Google Scholar 

  44. Schiestl C, Neuhaus K, Zoller S, Subotic U, Forster-Kuebler I, Michels R, et al. Efficacy and safety of propranolol as first-line treatment for infantile hemangiomas. Eur J Pediatr. 2011;170:493–501.

    Article  CAS  PubMed  Google Scholar 

  45. Manunza F, Syed S, Laguna B, Linward J, Kennedy H, Gholam K, et al. Propranolol for complicated infantile haemangiomas: a case series of 30 infants. Br J Dermatol. 2010;162:466–8.

    Article  CAS  PubMed  Google Scholar 

  46. Deng GH, Liu J, Zhang J, Wang Y, Peng XC, Wei YQ, et al. Exogenous norepinephrine attenuates the efficacy of sunitinib in a mouse cancer model. J Exp Clin Cancer Res. 2014;33:21.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  47. Boegemann M, Schlack K, Rink M, Bernhardt S, Moran M, Hubbe M, et al. Effect of comorbidities/comedications on sunitinib outcomes for metastatic renal cell carcinoma: the STAR-TOR registry. Future Oncol. 2020;16:2939–48.

    Article  CAS  PubMed  Google Scholar 

  48. Lalani AA, McKay RR, Lin X, Simantov R, Kaymakcalan MD, Choueiri TK. Proton pump inhibitors and survival outcomes in patients with metastatic renal cell carcinoma. Clin Genitourin Cancer. 2017;15:724–32.

    Article  PubMed  Google Scholar 

  49. Chan KK, Oza AM, Siu LL. The statins as anticancer agents. Clin Cancer Res. 2003;9:10–9.

    CAS  PubMed  Google Scholar 

  50. Keyomarsi K, Sandoval L, Band V. Synchronization of tumor and normal cells from G1 to multiple cell cycles by lovastatin. Cancer Res. 2003;9:10–9.

    Google Scholar 

  51. Wong WW, Dimitroulakos J, Minden MD, Penn LZ. HMG-CoA reductase inhibitors and the malignant cell: the statin family of drugs as triggers of tumor-specific apoptosis. Leukemia. 2002;16:508–19.

    Article  CAS  PubMed  Google Scholar 

  52. McKay RR, Lin X, Albiges L, Fay AP, Kaymakcalan MD, Mickey SS, et al. Statins and survival outcomes in patients with metastatic renal cell carcinoma. Eur J Cancer. 2016;52:155–62.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The authors thank all patients who voluntarily took part in the study.

Author information

Authors and Affiliations

  1. Department of Oncology and Radiotherapy, Faculty of Medicine and University Hospital in Pilsen, Charles University, alej Svobody 80, 304 60, Pilsen, Czech Republic

    Ondřej Fiala, Ondřej Šorejs, Jan Šustr & Jindřich Fínek

  2. Laboratory of Cancer Treatment and Tissue Regeneration, Faculty of Medicine in Pilsen, Biomedical Center, Charles University, alej Svobody 76, Pilsen, Czech Republic

    Ondřej Fiala & Ondřej Šorejs

  3. Laboratory of Tumor Biology and Immunotherapy, Faculty of Medicine in Pilsen, Biomedical Center, Charles University, alej Svobody 76, Pilsen, Czech Republic

    Pavel Ostašov

  4. Department of Oncology, First Faculty of Medicine, Charles University and Thomayer Hospital, Videnska 800, Prague, Czech Republic

    Aneta Rozsypalová & Tomáš Büchler

  5. Department of Urology, Faculty of Medicine and University Hospital in Pilsen, Charles University, E. Beneše 13, Pilsen, Czech Republic

    Milan Hora, Barbora Bendová & Ivan Trávníček

  6. 2nd Department of Internal Medicine, Faculty of Medicine and University Hospital in Pilsen, Charles University, E. Beneše 13, Pilsen, Czech Republic

    Jan Filipovský

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  1. Ondřej Fiala
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  2. Pavel Ostašov
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  4. Milan Hora
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  9. Jan Filipovský
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  10. Jindřich Fínek
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  11. Tomáš Büchler
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Corresponding author

Correspondence to Ondřej Fiala.

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Funding

This study was supported by The Institutional Research Fund of University Hospital Plzen (FN 00669806), by the Charles University Research Fund (Progres Q39), by the European Regional Development Fund-Project “Application of Modern Technologies in Medicine and Industry” (No. CZ.02.1.01/0.0/0.0/17_048/0007280), by a grant from the Ministry of Health of the Czech Republic (AZV NV19-08-00250), and by the European Union's Horizon 2020 research and innovation program (Grant Agreement No. 856620).

Conflict of interest

OF has received honoraria from Roche, Janssen, GSK, and Pfizer for consultations and lectures unrelated to this project. MH has received honoraria for lecture, tutoring, clinical trials, or travel grants from Astellas, Janssen-Cilag, and Roche. J. Finek has received honoraria from Astra Zeneca, Roche, and Novartis for consultations and lectures unrelated to this project. TB has received lecture honoraria from Novartis, Ipsen, Pfizer, Bayer, Amgen, Servier, Bristol Myers Squibb, Astellas, Janssen, and Roche and research support from Roche, Servier, and Novartis, all unrelated to the presented work. PO, AR, OS, JS, BB, IT and J. Filipovsky have no conflicts of interest that are directly relevant to the content of this article.

Ethics approval

This study was performed in accordance with the study protocol, the ethical principles stated in the Declaration of Helsinki as well as those indicated in the International Conference on Harmonization Guidance on Good Clinical Practice (1995), and all applicable regulatory requirements.

Consent to participate

All patients signed written informed consent before study entry. Adequate information was given to eligible patients by the principal investigator or co-investigators at each participating center and in accordance with local regulations. The declaration of informed consent was personally signed and dated by the subject and by the investigator/person designated by the investigator to conduct the informed consent discussion.

Consent for publication

Patients signed informed consent regarding the publication of their data.

Availability of data and material

The datasets generated and/or analyzed during the current study are available from the corresponding author on reasonable request.

Code availability

Not applicable.

Author contributions

OF designed the study. OF and TB wrote the manuscript with support from PO, AR, MH, OS, JS, BB, IT, J. Finek and J. Filipovsky. PO performed statistical analyses.

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Fiala, O., Ostašov, P., Rozsypalová, A. et al. Impact of Concomitant Cardiovascular Medication on Survival of Metastatic Renal Cell Carcinoma Patients Treated with Sunitinib or Pazopanib in the First Line. Targ Oncol 16, 643–652 (2021). https://doi.org/10.1007/s11523-021-00829-y

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