Skip to main content

Advertisement

Log in

Gemcitabine plus split-dose cisplatin could be a promising alternative to gemcitabine plus carboplatin for cisplatin-unfit patients with advanced urothelial carcinoma

  • Original Article
  • Published:
Cancer Chemotherapy and Pharmacology Aims and scope Submit manuscript

Abstract

Purpose

Cisplatin-based chemotherapies are standard treatment regimens of advanced urothelial cell carcinoma. But a significant proportion of patients are unsuitable for cisplatin due to impaired renal function. Carboplatin-based regimens such as gemcitabine and carboplatin regimen (GCb) were applied due to less nephrotoxicity and side effects in these patients. However, it is known that clinical outcome of carboplatin-based regimens was unsatisfactory compared to cisplatin-based regimens. We compared the nephrotoxicity and response to treatment between GCb and gemcitabine plus split-dose cisplatin regimen (GC-S).

Methods

GC-S consists of cisplatin 35 mg/m2 given on day 1, 2 and gemcitabine 1000 mg/m2 on day 1, 8 every 3 weeks. GCb consists of carboplatin (AUC 4.5) on day 1 and gemcitabine 1000 mg/m2 on day 1, 8 every 3 weeks. Patient demographics, serum creatinine and calculated GFR, adverse events, and radiologic response were retrospectively reviewed.

Results

Forty-four patients with advanced urothelial carcinoma treated with GCb (n = 22) or GC-S (n = 22) in our institution. There was no difference at deterioration of serum creatinine or GFR between GCb and GC-S (p = 0.442, p = 0.345). For patients who had GFR < 60 mL/min/1.73 m2 subgroup, similar results were produced (p = 0.292, p = 0.186). In addition, GC-S (68.4 %) showed improved response compared to GCb (31.6 %) (p = 0.023). Both treatments were well tolerated, and there were no unexpected serious adverse events.

Conclusions

Based on preserved renal function, favorable response, and tolerability, GC-S could be a promising alternative to GCb for cisplatin-unfit patients with advanced urothelial carcinoma.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Siegel R, Ma J, Zou Z, Jemal A (2014) Cancer statistics. CA Cancer J Clin 64(1):9–29. doi:10.3322/caac.21208

    Article  PubMed  Google Scholar 

  2. Sternberg CN, de Mulder P, Schornagel JH, Theodore C, Fossa SD, van Oosterom AT, Witjes JA, Spina M, van Groeningen CJ, Duclos B, Roberts JT, de Balincourt C, Collette L, Group EG-UC (2006) Seven year update of an EORTC phase III trial of high-dose intensity M-VAC chemotherapy and G-CSF versus classic M-VAC in advanced urothelial tract tumours. Eur J Cancer 42(1):50–54. doi:10.1016/j.ejca.2005.08.032

    Article  CAS  PubMed  Google Scholar 

  3. von der Maase H, Sengelov L, Roberts JT, Ricci S, Dogliotti L, Oliver T, Moore MJ, Zimmermann A, Arning M (2005) Long-term survival results of a randomized trial comparing gemcitabine plus cisplatin, with methotrexate, vinblastine, doxorubicin, plus cisplatin in patients with bladder cancer. J Clin Oncol 23(21):4602–4608. doi:10.1200/JCO.2005.07.757

    Article  PubMed  Google Scholar 

  4. De Santis M, Bellmunt J, Mead G, Kerst JM, Leahy M, Maroto P, Gil T, Marreaud S, Daugaard G, Skoneczna I, Collette S, Lorent J, de Wit R, Sylvester R (2012) Randomized phase II/III trial assessing gemcitabine/carboplatin and methotrexate/carboplatin/vinblastine in patients with advanced urothelial cancer who are unfit for cisplatin-based chemotherapy: EORTC study 30986. J Clin Oncol 30(2):191–199. doi:10.1200/JCO.2011.37.3571

    Article  PubMed Central  PubMed  Google Scholar 

  5. Vaughn DJ (2008) Chemotherapeutic options for cisplatin-ineligible patients with advanced carcinoma of the urothelium. Cancer Treat Rev 34(4):328–338

    Article  CAS  PubMed  Google Scholar 

  6. Bellmunt J, Ribas A, Eres N, Albanell J, Almanza C, Bermejo B, Sole LA, Baselga J (1997) Carboplatin-based versus cisplatin-based chemotherapy in the treatment of surgically incurable advanced bladder carcinoma. Cancer 80(10):1966–1972

    Article  CAS  PubMed  Google Scholar 

  7. Dogliotti L, Carteni G, Siena S, Bertetto O, Martoni A, Bono A, Amadori D, Onat H, Marini L (2007) Gemcitabine plus cisplatin versus gemcitabine plus carboplatin as first-line chemotherapy in advanced transitional cell carcinoma of the urothelium: results of a randomized phase 2 trial. Eur Urol 52(1):134–141. doi:10.1016/j.eururo.2006.12.029

    Article  CAS  PubMed  Google Scholar 

  8. Hotta K, Matsuo K, Ueoka H, Kiura K, Tabata M, Tanimoto M (2004) Meta-analysis of randomized clinical trials comparing Cisplatin to Carboplatin in patients with advanced non-small-cell lung cancer. J Clin Oncol 22(19):3852–3859. doi:10.1200/JCO.2004.02.109

    Article  CAS  PubMed  Google Scholar 

  9. Klastersky J, Sculier JP, Lacroix H, Dabouis G, Bureau G, Libert P, Richez M, Ravez P, Vandermoten G, Thiriaux J et al (1990) A randomized study comparing cisplatin or carboplatin with etoposide in patients with advanced non-small-cell lung cancer: European Organization for Research and Treatment of Cancer Protocol 07861. J Clin Oncol 8(9):1556–1562

    CAS  PubMed  Google Scholar 

  10. Rosell R, Gatzemeier U, Betticher DC, Keppler U, Macha HN, Pirker R, Berthet P, Breau JL, Lianes P, Nicholson M, Ardizzoni A, Chemaissani A, Bogaerts J, Gallant G (2002) Phase III randomised trial comparing paclitaxel/carboplatin with paclitaxel/cisplatin in patients with advanced non-small-cell lung cancer: a cooperative multinational trial. Ann Oncol 13(10):1539–1549

    Article  CAS  PubMed  Google Scholar 

  11. Hussain SA, Palmer DH, Swinson DE, Riley P, Wills A, Brown C, Draycott C, El-Modir A, Peake DR, Rea DW, Chetiyawardana AD, Cullen MH (2008) A phase II clinical trial of gemcitabine and split dose cisplatin in advanced non-small cell lung cancer in an outpatient setting. Oncol Rep 20(1):233–237

    CAS  PubMed  Google Scholar 

  12. Hussain SA, Stocken DD, Riley P, Palmer DH, Peake DR, Geh JI, Spooner D, James ND (2004) A phase I/II study of gemcitabine and fractionated cisplatin in an outpatient setting using a 21-day schedule in patients with advanced and metastatic bladder cancer. Br J Cancer 91(5):844–849. doi:10.1038/sj.bjc.6602112

    CAS  PubMed Central  PubMed  Google Scholar 

  13. Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D (1999) A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease Study Group. Ann Intern Med 130(6):461–470

    Article  CAS  PubMed  Google Scholar 

  14. De Santis M, Bellmunt J, Mead G, Kerst JM, Leahy M, Maroto P, Gil T, Marreaud S, Daugaard G, Skoneczna I (2012) Randomized phase II/III trial assessing gemcitabine/carboplatin and methotrexate/carboplatin/vinblastine in patients with advanced urothelial cancer who are unfit for cisplatin-based chemotherapy: EORTC study 30986. J Clin Oncol 30(2):191–199

    Article  PubMed Central  PubMed  Google Scholar 

  15. Arany I, Safirstein RL (2003) Cisplatin nephrotoxicity. Semin Nephrol 23(5):460–464

    Article  CAS  PubMed  Google Scholar 

  16. Meijer S, Mulder NH, Sleijfer DT, de Jong PE, Sluiter WJ, Schraffordt Koops H, van der Hem GK (1982) Nephrotoxicity of cis-diamminedichloride platinum (CDDP) during remission-induction and maintenance chemotherapy of testicular carcinoma. Cancer Chemother Pharmacol 8(1):27–30

    Article  CAS  PubMed  Google Scholar 

  17. Bournakis E, Dimopoulos MA, Bamias A (2011) Management of advanced bladder cancer in patients with impaired renal function. Expert Rev Anticancer Ther 11(6):931–939. doi:10.1586/era.10.197

    Article  CAS  PubMed  Google Scholar 

  18. Pabla N, Dong Z (2008) Cisplatin nephrotoxicity: mechanisms and renoprotective strategies. Kidney Int 73(9):994–1007. doi:10.1038/sj.ki.5002786

    Article  CAS  PubMed  Google Scholar 

  19. Yao X, Panichpisal K, Kurtzman N, Nugent K (2007) Cisplatin nephrotoxicity: a review. Am J Med Sci 334(2):115–124. doi:10.1097/MAJ.0b013e31812dfe1e

    Article  PubMed  Google Scholar 

  20. Bamias A, Lainakis G, Kastritis E, Antoniou N, Alivizatos G, Koureas A, Chrisofos M, Skolarikos A, Karayiotis E, Dimopoulos MA (2007) Biweekly carboplatin/gemcitabine in patients with advanced urothelial cancer who are unfit for cisplatin-based chemotherapy: report of efficacy, quality of life and geriatric assessment. Oncology 73(5–6):290–297. doi:10.1159/000132394

    Article  CAS  PubMed  Google Scholar 

  21. Bellmunt J, De Wit R, Albanell J, Baselga J (2001) A feasibility study of carboplatin with fixed dose of gemcitabine in ‘unfit’ patients with advanced bladder cancer. Eur J Cancer 37(17):2212–2215

    Article  CAS  PubMed  Google Scholar 

  22. Linardou H, Aravantinos G, Efstathiou E, Kalofonos C, Anagnostopoulos A, Deliveliotis C, Bafaloukos D, Athanasios Dimopoulos M, Bamias A, Phase IIsoHC-oOG (2004) Gemcitabine and carboplatin combination as first-line treatment in elderly patients and those unfit for cisplatin-based chemotherapy with advanced bladder carcinoma: phase II study of the Hellenic Co-operative Oncology Group. Urology 64(3):479–484. doi:10.1016/j.urology.2004.04.024

    Article  PubMed  Google Scholar 

  23. Small EJ, Lew D, Redman BG, Petrylak DP, Hammond N, Gross HM, Eastham JA, Crawford ED (2000) Southwest Oncology Group Study of paclitaxel and carboplatin for advanced transitional-cell carcinoma: the importance of survival as a clinical trial end point. J Clin Oncol 18(13):2537–2544

    CAS  PubMed  Google Scholar 

  24. Vaughn DJ, Manola J, Dreicer R, See W, Levitt R, Wilding G (2002) Phase II study of paclitaxel plus carboplatin in patients with advanced carcinoma of the urothelium and renal dysfunction (E2896): a trial of the Eastern Cooperative Oncology Group. Cancer 95(5):1022–1027. doi:10.1002/cncr.10782

    Article  CAS  PubMed  Google Scholar 

  25. Carles J, Esteban E, Climent M, Font A, Gonzalez-Larriba JL, Berrocal A, Garcia-Ribas I, Marfa X, Fabregat X, Albanell J, Bellmunt J (2007) Gemcitabine and oxaliplatin combination: a multicenter phase II trial in unfit patients with locally advanced or metastatic urothelial cancer. Ann Oncol 18(8):1359–1362. doi:10.1093/annonc/mdm160

    Article  CAS  PubMed  Google Scholar 

  26. Culine S, Flechon A, Guillot A, Le Moulec S, Pouessel D, Rolland F, Ravaud A, Houede N, Mignot L, Joly F, Oudard S, Gourgou S (2011) Gemcitabine or gemcitabine plus oxaliplatin in the first-line treatment of patients with advanced transitional cell carcinoma of the urothelium unfit for cisplatin-based chemotherapy: a randomized phase 2 study of the French Genitourinary Tumor Group (GETUG V01). Eur Urol 60(6):1251–1257. doi:10.1016/j.eururo.2011.08.072

    Article  CAS  PubMed  Google Scholar 

  27. Dimopoulos MA, Deliveliotis C, Moulopoulos LA, Papadimitriou C, Mitropoulos D, Anagnostopoulos A, Athanassiades P, Dimopoulos C (1998) Treatment of patients with metastatic urothelial carcinoma and impaired renal function with single-agent docetaxel. Urology 52(1):56–60

    Article  CAS  PubMed  Google Scholar 

  28. Ricci S, Galli L, Chioni A, Iannopollo M, Antonuzzo A, Francesca F, Vocaturo V, Selli C, Orlandini C, Conte P (2002) Gemcitabine plus epirubicin in patients with advanced urothelial carcinoma who are not eligible for platinum-based regimens. Cancer 95(7):1444–1450. doi:10.1002/cncr.10860

    Article  CAS  PubMed  Google Scholar 

  29. Turkolmez K, Beduk Y, Baltaci S, Gogus C, Gogus O (2003) Gemcitabine plus vinorelbine chemotherapy in patients with advanced bladder carcinoma who are medically unsuitable for or who have failed cisplatin-based chemotherapy. Eur Urol 44(6):682–686

    Article  PubMed  Google Scholar 

  30. Carles J, Suarez C, Mesia C, Nogue M, Font A, Domenech M, Suarez M, Tusquets I, Gallen M, Albanell J, Fabregat X (2006) Feasibility study of gemcitabine and cisplatin administered every two weeks in patients with advanced urothelial tumors and impaired renal function. Clin Transl Oncol 8(10):755–757

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This study was supported by a Grant (HI12C1788, HI14C1931, HI14C1731) from the Korean Health Technology R&D Project, Ministry of Health and Welfare, Korea.

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical standard

This study was reviewed and approved by the Institutional Review Board of Asan Medical Center. For this type of study, formal consent is not required.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Jae Lyun Lee.

Appendices

Appendix 1

See Fig. 3a, b.

Fig. 3
figure 3

Percentage changes in renal function in patients who received six cycles or more. Due to insufficient number of patients, p value could not be obtained. Error bars indicate the standard error of the mean

Appendix 2

Statistical data about changes of renal function and response to treatments (see Tables 3, 4 and 5).

Table 3 Baseline characteristics (absolute value)
Table 4 Baseline characteristics (percentile change)
Table 5 Treatment comparison

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kim, Y.R., Lee, J.L., You, D. et al. Gemcitabine plus split-dose cisplatin could be a promising alternative to gemcitabine plus carboplatin for cisplatin-unfit patients with advanced urothelial carcinoma. Cancer Chemother Pharmacol 76, 141–153 (2015). https://doi.org/10.1007/s00280-015-2774-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00280-015-2774-z

Keywords

Navigation