Advertisement

Changes in skeletal muscle area and lean body mass during pazopanib vs sunitinib therapy for metastatic renal cancer

  • Osman KöstekEmail author
  • Erdem Yılmaz
  • Muhammet Bekir Hacıoğlu
  • Nazım Can Demircan
  • Ali Gökyer
  • Sernaz Uzunoğlu
  • Nermin Tunçbilek
  • İrfan Çiçin
  • Bülent Erdoğan
Original Article
  • 36 Downloads

Abstract

Purpose

To evaluate whether sunitinib and pazopanib treatments are associated with change in skeletal muscle area (SMA) and total lean body mass (LBM) as well as to compare their efficacies and safety profiles in patients with metastatic renal cell cancer (mRCC).

Methods

Thirty-six patients treated with a tyrosine kinase inhibitor were included. Eighteen of them received sunitinib and the rest/remaining received pazopanib in the first line of mRCC treatment. Baseline and follow-up computed tomography studies of the patients were performed to measure cross-sectional areas (cm2) of muscle tissues.

Results

About 69% of patients were male and median age was 60 (49–68) years. Median time interval between two CT imagings was 6.1 (3.1–7.7) months and it was similar between the two groups (for sunitinib, 4.9 (2.5–6.9) months vs for pazopanib, 7.3 (3.2–9.5) months, p = 0.16, respectively). Disease control rate was 77.7% in all patients. Of these, 66.6% in sunitinib group was consisted of four partial responses and eight stable diseases. In addition, 88.8% in pazopanib group was consisted of three partial responses and 13 stable diseases. A significant decrease in SMA and LBM was observed after sunitinib therapy, whereas SMA and LBM values of pazopanib group did not change significantly (p = 0.02 and p = 0.70, respectively). No significant differences were observed between patients with sunitinib, and pazopanib group median PFS [11.9 (95% CI 6.1–17.6) vs 8.1 months (95% CI 7.2–9.1), respectively; p = 0.28] and median OS [28.6 (95% CI 24.3–32.9) vs 25.5 months (95% CI 18.9–52.7), respectively; p = 0.42]. Dose-limiting toxicities were significantly more frequent in sunitinib group than in pazopanib group (66.7% vs 22.2%, p = 0.02, respectively).

Conclusions

Loss of SMA and LBM with sunitinib was more substantial than with pazopanib. Treatment efficacies of both drugs were similar, but dose-limiting toxicity was more frequent in sunitinib group. Loss of SMA had no significant association with prognosis. Further studies are needed to clarify the possible association between SMA and prognosis in mRCC patients who receive sunitinib or pazopanib.

Keywords

Skeletal muscle area Lean body mass Sunitinib Pazopanib Renal cell cancer 

Notes

Funding

There is no financial support in this study.

Compliance with ethical standards

Conflict of interest

All authors declare that they have no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

For this type of study formal consent is not required.

References

  1. 1.
    Siegel RL, Miller KD, Jemal A (2018) Cancer statistics 2018. CA 68(1):7–30.  https://doi.org/10.3322/caac.21442 Google Scholar
  2. 2.
    Moch H, Gasser T, Amin MB, Torhorst J, Sauter G, Mihatsch MJ (2000) Prognostic utility of the recently recommended histologic classification and revised TNM staging system of renal cell carcinoma: a Swiss experience with 588 tumors. Cancer 89(3):604–614Google Scholar
  3. 3.
    Howlader N, Noone A, Krapcho M, Miller D, Bishop K, Kosary C, Yu M, Ruhl J, Tatalovich Z, Mariotto A (2017) SEER Cancer Statistics Review, 1975–2014. National Cancer Institute, Bethesda (Based on November 2016 SEER data submission, posted to the SEER web site, April 2017) Google Scholar
  4. 4.
    Chang SF, Lin PL (2016) Systematic literature review and meta-analysis of the association of sarcopenia with mortality. Worldviews Evid Based Nurs 13(2):153–162Google Scholar
  5. 5.
    Chang KV, Chen JD, Wu WT, Huang KC, Hsu CT, Han DS (2018) Association between loss of skeletal muscle mass and mortality and tumor recurrence in hepatocellular carcinoma: a systematic review and meta-analysis. Liver Cancer 7(1):90–103.  https://doi.org/10.1159/000484950 Google Scholar
  6. 6.
    Shachar SS, Williams GR, Muss HB, Nishijima TF (2016) Prognostic value of sarcopenia in adults with solid tumours: a meta-analysis and systematic review. Eur J Cancer 57:58–67.  https://doi.org/10.1016/j.ejca.2015.12.030 Google Scholar
  7. 7.
    Antoun S, Baracos VE, Birdsell L, Escudier B, Sawyer MB (2010) Low body mass index and sarcopenia associated with dose-limiting toxicity of sorafenib in patients with renal cell carcinoma. Ann Oncol 21(8):1594–1598.  https://doi.org/10.1093/annonc/mdp605 Google Scholar
  8. 8.
    Mitsiopoulos N, Baumgartner RN, Heymsfield SB, Lyons W, Gallagher D, Ross R (1998) Cadaver validation of skeletal muscle measurement by magnetic resonance imaging and computerized tomography. J Appl Physiol (Bethesda Md 1985) 85(1):115–122.  https://doi.org/10.1152/jappl.1998.85.1.115 Google Scholar
  9. 9.
    Mourtzakis M, Prado CM, Lieffers JR, Reiman T, McCargar LJ, Baracos VE (2008) A practical and precise approach to quantification of body composition in cancer patients using computed tomography images acquired during routine care. Appl Physiol Nutr Metab 33(5):997–1006.  https://doi.org/10.1139/h08-075 Google Scholar
  10. 10.
    Huillard O, Mir O, Peyromaure M, Tlemsani C, Giroux J, Boudou-Rouquette P, Ropert S, Delongchamps NB, Zerbib M, Goldwasser F (2013) Sarcopenia and body mass index predict sunitinib-induced early dose-limiting toxicities in renal cancer patients. Br J Cancer 108(5):1034–1041.  https://doi.org/10.1038/bjc.2013.58 Google Scholar
  11. 11.
    Fukushima H, Nakanishi Y, Kataoka M, Tobisu K, Koga F (2016) Prognostic significance of sarcopenia in patients with metastatic renal cell carcinoma. J Urol 195(1):26–32.  https://doi.org/10.1016/j.juro.2015.08.071 Google Scholar
  12. 12.
    Lange AM, Lo HW (2018) Inhibiting TRK proteins in clinical cancer therapy. Cancers.  https://doi.org/10.3390/cancers10040105 Google Scholar
  13. 13.
    Faivre S, Demetri G, Sargent W, Raymond E (2007) Molecular basis for sunitinib efficacy and future clinical development. Nat Rev Drug Discov 6(9):734–745.  https://doi.org/10.1038/nrd2380 Google Scholar
  14. 14.
    Sun L, Liang C, Shirazian S, Zhou Y, Miller T, Cui J, Fukuda JY, Chu JY, Nematalla A, Wang X, Chen H, Sistla A, Luu TC, Tang F, Wei J, Tang C (2003) Discovery of 5-[5-fluoro-2-oxo-1,2- dihydroindol-(3Z)-ylidenemethyl]-2,4- dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)amide, a novel tyrosine kinase inhibitor targeting vascular endothelial and platelet-derived growth factor receptor tyrosine kinase. J Med Chem 46(7):1116–1119.  https://doi.org/10.1021/jm0204183 Google Scholar
  15. 15.
    Mendel DB, Laird AD, Xin X, Louie SG, Christensen JG, Li G, Schreck RE, Abrams TJ, Ngai TJ, Lee LB (2003) In vivo antitumor activity of SU11248, a novel tyrosine kinase inhibitor targeting vascular endothelial growth factor and platelet-derived growth factor receptors: determination of a pharmacokinetic/pharmacodynamic relationship. Clin Cancer Res 9(1):327–337Google Scholar
  16. 16.
    Motzer RJ, Michaelson MD, Redman BG, Hudes GR, Wilding G, Figlin RA, Ginsberg MS, Kim ST, Baum CM, DePrimo SE (2006) Activity of SU11248, a multitargeted inhibitor of vascular endothelial growth factor receptor and platelet-derived growth factor receptor, in patients with metastatic renal cell carcinoma. J Clin oncol 24(1):16–24Google Scholar
  17. 17.
    Motzer RJ, Rini BI, Bukowski RM, Curti BD, George DJ, Hudes GR, Redman BG, Margolin KA, Merchan JR, Wilding G (2006) Sunitinib in patients with metastatic renal cell carcinoma. JAMA 295(21):2516–2524Google Scholar
  18. 18.
    Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski RM, Rixe O, Oudard S, Negrier S, Szczylik C, Kim ST, Chen I, Bycott PW, Baum CM, Figlin RA (2007) Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med 356(2):115–124.  https://doi.org/10.1056/NEJMoa065044 Google Scholar
  19. 19.
    Motzer RJ, Figlin RA, Hutson TE, Tomczak P, Bukowski RM, Rixe O, Bjarnason GA, Kim ST, Chen I, Michaelson D (2007) Sunitinib versus interferon-alfa (IFN-α) as first-line treatment of metastatic renal cell carcinoma (mRCC): updated results and analysis of prognostic factors. J Clin Oncol 25(18_suppl):5024–5024.  https://doi.org/10.1200/jco.2007.25.18_suppl.5024 Google Scholar
  20. 20.
    Motzer RJ, Hutson TE, Cella D, Reeves J, Hawkins R, Guo J, Nathan P, Staehler M, de Souza P, Merchan JR, Boleti E, Fife K, Jin J, Jones R, Uemura H, De Giorgi U, Harmenberg U, Wang J, Sternberg CN, Deen K, McCann L, Hackshaw MD, Crescenzo R, Pandite LN, Choueiri TK (2013) Pazopanib versus sunitinib in metastatic renal-cell carcinoma. N Engl J Med 369(8):722–731.  https://doi.org/10.1056/NEJMoa1303989 Google Scholar
  21. 21.
    Rousseau B, Kempf E, Desamericq G, Boissier E, Chaubet-Houdu M, Joly C, Saldana C, Boussion H, Neuzillet C, Macquin-Mavier I (2016) First-line antiangiogenics for metastatic renal cell carcinoma: a systematic review and network meta-analysis. Crit Rev Oncol Hematol 107:44–53Google Scholar
  22. 22.
    Escudier B, Porta C, Bono P, Powles T, Eisen T, Sternberg CN, Gschwend JE, De Giorgi U, Parikh O, Hawkins R, Sevin E, Negrier S, Khan S, Diaz J, Redhu S, Mehmud F, Cella D (2014) Randomized, controlled, double-blind, cross-over trial assessing treatment preference for pazopanib versus sunitinib in patients with metastatic renal cell carcinoma: PISCES study. J Clin Oncol 32(14):1412–1418.  https://doi.org/10.1200/jco.2013.50.8267 Google Scholar
  23. 23.
    Laguna MP (2017) Re: First-line sunitinib versus pazopanib in metastatic renal cell carcinoma: results from the International Metastatic Renal Cell Carcinoma Database Consortium. J Urol 197(3 Pt 1):603.  https://doi.org/10.1016/j.juro.2016.12.059 Google Scholar
  24. 24.
    Kim JH, Park I, Lee JL (2016) Pazopanib versus sunitinib for the treatment of metastatic renal cell carcinoma patients with poor-risk features. Cancer Chemother Pharmacol 78(2):325–332Google Scholar
  25. 25.
    MacLean E, Mardekian J, Cisar LA, Hoang CJ, Harnett J (2016) Real-world treatment patterns and costs for patients with renal cell carcinoma initiating treatment with sunitinib and pazopanib. J Manag Care Spec Pharm 22(8):979–990Google Scholar
  26. 26.
    Motzer RJ, Hutson TE, McCann L, Deen K, Choueiri TK (2014) Overall survival in renal-cell carcinoma with pazopanib versus sunitinib. N Engl J Med 370(18):1769–1770Google Scholar
  27. 27.
    Fernandez-Pello S, Hofmann F, Tahbaz R, Marconi L, Lam TB, Albiges L, Bensalah K, Canfield SE, Dabestani S, Giles RH, Hora M, Kuczyk MA, Merseburger AS, Powles T, Staehler M, Volpe A, Ljungberg B, Bex A (2017) A systematic review and meta-analysis comparing the effectiveness and adverse effects of different systemic treatments for non-clear cell renal cell carcinoma. Eur Urol 71(3):426–436.  https://doi.org/10.1016/j.eururo.2016.11.020 Google Scholar
  28. 28.
    Cohen S, Nathan JA, Goldberg AL (2015) Muscle wasting in disease: molecular mechanisms and promising therapies. Nat Rev Drug Discov 14(1):58–74.  https://doi.org/10.1038/nrd4467 Google Scholar
  29. 29.
    Schmidinger M, Wittes J (2015) First-line treatment of metastatic renal cell carcinoma after COMPARZ and PISCES. Curr Opin Urol 25(5):395–401.  https://doi.org/10.1097/mou.0000000000000207 Google Scholar
  30. 30.
    Makhov P, Naito S, Haifler M, Kutikov A, Boumber Y, Uzzo RG, Kolenko VM (2018) The convergent roles of NF-kappaB and ER stress in sunitinib-mediated expression of pro-tumorigenic cytokines and refractory phenotype in renal cell carcinoma. Cell Death Dis 9(3):374.  https://doi.org/10.1038/s41419-018-0388-1 Google Scholar
  31. 31.
    Argiles JM, Lopez-Soriano FJ, Busquets S (2012) Counteracting inflammation: a promising therapy in cachexia. Crit Rev Oncog 17(3):253–262.  https://doi.org/10.1615/CritRevOncog.v17.i3.30 Google Scholar
  32. 32.
    Fanzani A, Conraads VM, Penna F, Martinet W (2012) Molecular and cellular mechanisms of skeletal muscle atrophy: an update. J Cachexia Sarcopenia Muscle 3(3):163–179Google Scholar
  33. 33.
    Spirina LV, Usynin EA, Yurmazov ZA, Slonimskaya EM, Kondakova IV (2017) Effect of targeted therapy with pazopanib on expression levels of transcription, growth factors and components of AKT/m-TOR signaling pathway in patients with renal cell carcinoma. Asian Pac J Cancer Prev 18(11):2977–2983.  https://doi.org/10.22034/APJCP.2017.18.11.2977 Google Scholar
  34. 34.
    Ishibashi K, Koguchi T, Matsuoka K, Onagi A, Tanji R, Takinami-Honda R, Hoshi S, Onoda M, Kurimura Y, Hata J, Sato Y, Kataoka M, Ogawsa S, Haga N, Kojima Y (2018) Interleukin-6 induces drug resistance in renal cell carcinoma. Fukushima J Med Sci 64(3):103–110.  https://doi.org/10.5387/fms.2018-15 Google Scholar
  35. 35.
    Tran HT, Liu Y, Zurita AJ, Lin Y, Baker-Neblett KL, Martin AM, Figlin RA, Hutson TE, Sternberg CN, Amado RG, Pandite LN, Heymach JV (2012) Prognostic or predictive plasma cytokines and angiogenic factors for patients treated with pazopanib for metastatic renal-cell cancer: a retrospective analysis of phase 2 and phase 3 trials. Lancet Oncol 13(8):827–837.  https://doi.org/10.1016/S1470-2045(12)70241-3 Google Scholar
  36. 36.
    Carmichael C, Yuh BE, Sun V, Lau C, Hsu J, Saikia J, Liu X, Wilson T, Ferrell B, Pal SK (2013) Quality of life in patients with metastatic renal cell carcinoma: assessment of long-term survivors. Clin Genitourin Cancer 11(2):149–154Google Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Osman Köstek
    • 1
    Email author
  • Erdem Yılmaz
    • 2
  • Muhammet Bekir Hacıoğlu
    • 1
  • Nazım Can Demircan
    • 1
  • Ali Gökyer
    • 1
  • Sernaz Uzunoğlu
    • 1
  • Nermin Tunçbilek
    • 2
  • İrfan Çiçin
    • 1
  • Bülent Erdoğan
    • 1
  1. 1.Division of Medical Oncology, Department of Internal MedicineTrakya University School of MedicineEdirneTurkey
  2. 2.Department of RadiologyTrakya University School of MedicineEdirneTurkey

Personalised recommendations