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Impact of neoadjuvant chemotherapy on short-term complications and survival following radical cystectomy

  • Uros Milenkovic
  • Murat Akand
  • Lisa Moris
  • Liesbeth Demaegd
  • Tim Muilwijk
  • Youri Bekhuis
  • Annouschka Laenen
  • Ben Van Cleynenbreugel
  • Wouter Everaerts
  • Hein Van Poppel
  • Herlinde Dumez
  • Maarten Albersen
  • Steven Joniau
Original Article

Abstract

Objectives

To compare perioperative and short-term postoperative complication rates between patients receiving radical cystectomy (RC) after neoadjuvant chemotherapy (NAC) and patients undergoing RC alone. Secondary objectives were to compare overall survival (OS) and cancer-specific survival (CSS).

Materials and methods

Clinico-pathological data of all patients who received RC between 1996 and 2015 were retrospectively collected. Only patients with RC for muscle-invasive bladder cancer were included in the final analysis. Short-term (30-day) postoperative complications were assessed by registering the Clavien–Dindo classification (CDC) and dividing into sub-groups: low-grade (LGC) CDC 1–2 and high-grade (HGC) CDC 3–5. To compare populations with similar age, comorbidities and preoperative creatinine, we used a propensity score-adjusted statistical model. Pre- and perioperative predictors of short-term complications were identified using uni- and multivariable models. Survival was assessed using Kaplan–Meier analysis.

Results

A total of 491 patients undergoing RC were included, of whom 102 (20.8%) received NAC. After propensity score covariate adjustment, there was no significant difference in postoperative complications between patients undergoing NAC plus RC and RC alone with an overall complication rate of 69% and 66%, respectively. No significant differences in the 30-day HGC rates (11.76% and 11.83%, respectively) were observed. NAC plus RC patients had worse prognostic factors at baseline; nevertheless, after correction for group differences OS and CSS did not differ from RC only group (5-year OS 61.3% vs. 50.2%, and 5-year CSS 61.8% vs. 57.9% respectively, p > 0.05 for all).

Conclusion

In appropriately selected patients, exposure to NAC is not associated with increased short-term complications.

Keywords

Radical cystectomy Bladder cancer Neoadjuvant chemotherapy Complications Short term 

Abbreviations

BC

Bladder cancer

NMIBC

Non-muscle-invasive bladder cancer

MIBC

Muscle-invasive bladder cancer

RC

Radical cystectomy

PLND

Pelvic lymph node dissection

UD

Urinary diversion

NAC

Neoadjuvant chemotherapy

OS

Overall survival

BCG

Bacillus Calmette–Guérin

CIS

Carcinoma in situ

CCI

Charlson comorbidity index

ACCI

Age-adjusted Charlson comorbidity index

BMI

Body mass index

TNM

Tumor-node-metastasis

EBL

Estimated blood loss

LoS

Length of stay

CDC

Clavien–Dindo Classification

HGC

High-grade complication

LGC

Low-grade complication

CSS

Cancer-specific survival

SD

Standard deviation

IQR

Interquartile range

CIF

Cumulative incidence function

IPTW

Inverse probability of treatment weighting

OR

Odds ratio

CI

Confidence interval

HR

Hazard ratio

OCS

Other-cause survival

UTI

Urinary tract infection

MVAC

Methotrexate–Vinblastine–Adriamycin–Cisplatin

GC

Gemcitabine–Cisplatin

Notes

Acknowledgments

Akand M is supported by a clinical scholarship from the European Urologic Scholarship Program (EUSP).Joniau S is a senior clinical researcher of the research foundation of Flanders (FWO).

Authors’ contributions

UM: Data collection, data analysis, manuscript writing. MA: Data analysis, manuscript writing, manuscript editing. LM: Data collection, data analysis. LD: Data collection, data analysis. TM: Data analysis, manuscript editing. YB: Data collection, data analysis. AL: Data analysis, manuscript editing. BVC: Data collection, data analysis. WE: Data collection, data analysis. HVP: Project development, data analysis, manuscript editing. HD: Project development, data analysis, manuscript editing. MA: Project development, data analysis, manuscript editing. SJ: Project development, data analysis, manuscript editing.

Funding

None declared.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest related to this manuscript.

Ethical approval

All procedures performed in this study involving human participants were in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. For this type of study, formal consent is not required.

Supplementary material

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Supplementary material 7 (DOCX 18 kb)

References

  1. 1.
    GLOBOCAN 2012 v1.0, cancer incidence and mortality worldwide: IARC CancerBase No. 11. International Agency for Research on Cancer Web site. http://globocan.iarc.fr
  2. 2.
    Clark PE, Agarwal N, Biagioli MC, Eisenberger MA, Greenberg RE, Herr HW, National Comprehensive Cancer Network (NCCN) et al (2013) Bladder cancer. J Natl Compr Canc Netw 11:446–475CrossRefPubMedGoogle Scholar
  3. 3.
    Witjes JA, Comperat E, Cowan NC, De Santis M, Gakis G, Lebret T, Ribal MJ, Van der Heijden AG, Sherif A, European Association of Urology (2014) EAU guidelines on muscle-invasive and metastatic bladder cancer: summary of the 2013 guidelines. Eur Urol 65:778–792CrossRefPubMedGoogle Scholar
  4. 4.
    Meeks JJ, Bellmunt J, Bochner BH, Clarke NW, Daneshmand S, Galsky MD, Hahn NM, Lerner SP, Mason M, Powles T, Sternberg CN, Sonpavde G (2012) A systematic review of neoadjuvant and adjuvant chemotherapy for muscle-invasive bladder cancer. Eur Urol 62:523–533CrossRefPubMedGoogle Scholar
  5. 5.
    Sternberg CN, Bellmunt J, Sonpavde G, Siefker-Radtke AO, Stadler WM, Bajorin DF, Dreicer DF, George DJ, Milowsky MI, Theodorescu D, Vaughn DJ, Galsky MD, Soloway MS, Quinn DI, International Consultation on Urologic Disease-European Association of Urology Consultation on Bladder Cancer 2012 (2013) ICUD–EAU International Consultation on Bladder Cancer 2012: chemotherapy for urothelial carcinoma—neoadjuvant and adjuvant settings. Eur Urol 63:58–66CrossRefPubMedGoogle Scholar
  6. 6.
    Grossman HB, Natale RB, Tangen CM, Speights VO, Vogelzang NJ, Trump DL, deVere White RW, Sarosdy MF, Wood DP Jr, Raghavan D, Crawford ED (2003) Neoadjuvant chemotherapy plus cystectomy compared with cystectomy alone for locally advanced bladder cancer. N Engl J Med 349:859–866CrossRefPubMedGoogle Scholar
  7. 7.
    Sherif A, Holmberg L, Rintala E, Mestad O, Nilsson J, Nilsson S, Malmström PU, Nordic Urothelial Cancer Group (2004) Neoadjuvant cisplatinum based combination chemotherapy in patients with invasive bladder cancer: a combined analysis of two Nordic studies. Eur Urol 45:297–303CrossRefPubMedGoogle Scholar
  8. 8.
    International Collaboration of Trialists, Medical Research Council Advanced Bladder Cancer Working Party (now the National Cancer Research Institute Bladder Cancer Clinical Studies Group), European Organisation for Research and Treatment of Cancer Genito-Urinary Tract Cancer Group, Australian Bladder Cancer Study Group, National Cancer Institute of Canada Clinical Trials Group, Finnbladder; Norwegian Bladder Cancer Study Group, Club Urologico Espanol de Tratamiento Oncologico Group, Griffiths G, Hall R, Sylvester R, Raghavan D, Parmar MK (2011) International phase III trial assessing neoadjuvant cisplatin, methotrexate, and vinblastine chemotherapy for muscle-invasive bladder cancer: long-term results of the BA06 30894 trial. J Clin Oncol 29:2171–2177CrossRefPubMedCentralGoogle Scholar
  9. 9.
    Malmström PU, Rintala E, Wahlqvist R, Hellström P, Hellsten S, Hannisdal E (1996) Five-year follow-up of a prospective trial of radical cystectomy and neoadjuvant chemotherapy: nordic Cystectomy Trial I. The Nordic Cooperative Bladder Cancer Study Group. J Urol 155:1903–1906CrossRefPubMedGoogle Scholar
  10. 10.
    Advanced Bladder Cancer (ABC), Meta-analysis Collaboration (2005) Neoadjuvant chemotherapy in invasive bladder cancer: update of a systematic review and meta-analysis of individual patient data: advanced Bladder Cancer (ABC) Meta-analysis Collaboration. Eur Urol 48:202–205CrossRefGoogle Scholar
  11. 11.
    Dash A, Pettus JA 4th, Herr HW, Bochner BH, Dalbagni G, Donat SM, Russo P, Boyle MG, Milowsky MI, Bajorin DF (2008) A role for neoadjuvant gemcitabine plus cisplatin in muscle-invasive urothelial carcinoma of the bladder: a retrospective experience. Cancer 113:2471–2477CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Plimack ER, Hoffman-Censits JH, Viterbo R, Trabulsi EJ, Ross EA, Greenberg RE, Chen DY, Lallas CD, Wong YN, Lin J, Kutikov A, Dotan E, Brennan TA, Palma N, Dulaimi E, Mehrazin R, Boorjian SA, Kelly WK, Uzzo RG, Hudes GR (2014) Accelerated methotrexate, vinblastine, doxorubicin, and cisplatin is safe, effective, and efficient neoadjuvant treatment for muscle-invasive bladder cancer: results of a multicenter phase II study with molecular correlates of response and toxicity. J Clin Oncol 32:1895–1901CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Choueiri TK, Jacobus S, Bellmunt J, Qu A, Appleman LJ, Bubley GJ, Stack EC, Signoretti S, Walsh M, Steele G, Hirsch M, Sweeney CJ, Taplin ME, Kibel AS, Krajewski KM, Kantoff PW, Ross RW, Rosenberg JE (2014) Neoadjuvant dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin with pegfilgrastim support in muscle-invasive urothelial cancer: pathologic, radiologic, and biomarker correlates. J Clin Oncol 32:1889–1894CrossRefPubMedGoogle Scholar
  14. 14.
    Rehman S, Crane A, Din R, Raza SJ, Shi Y, Wilding G, Levine EG, George S, Pili R, Trump DL, Guru KA (2013) Understanding avoidance, refusal, and abandonment of chemotherapy before and after cystectomy for bladder cancer. Urology 82:1370–1375CrossRefPubMedGoogle Scholar
  15. 15.
    Liew MS, Azad A, Tafreshi A, Eapen R, Bolton D, Davis ID, Sengupta S (2013) USANZ: time-trends in use and impact on outcomes of perioperative chemotherapy in patients treated with radical cystectomy for urothelial bladder cancer. BJU Int 112(Suppl 2):74–82CrossRefPubMedGoogle Scholar
  16. 16.
    Zaid HB, Patel SG, Stimson CJ, Resnick MJ, Cookson MS, Barocas DA, Chang SS (2014) Trends in the utilization of neoadjuvant chemotherapy in muscle-invasive bladder cancer: results from the National Cancer Database. Urology 83:75–80CrossRefPubMedGoogle Scholar
  17. 17.
    Reardon ZD, Patel SG, Zaid HB, Stimson CJ, Resnick MJ, Keegan KA, Barocas DA, Chang SS, Cookson MS (2015) Trends in the use of perioperative chemotherapy for localized and locally advanced muscle-invasive bladder cancer: a sign of changing tides. Eur Urol 67:165–170CrossRefPubMedGoogle Scholar
  18. 18.
    Cowan NG, Chen Y, Downs TM, Bochner BH, Apolo AB, Poster MP, La Rochelle JC, Amling CL, Koppie TM (2014) Neoadjuvant chemotherapy use in bladder cancer: a survey of current practice and opinions. Adv Urol 2014:746298CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Thompson RH, Boorjian SA, Kim SP, Cheville JC, Thapa P, Dronca R, Costello B, Frank I (2014) Eligibility for neoadjuvant/adjuvant cisplatin-based chemotherapy among radical cystectomy patients. BJU Int 113:E17–21CrossRefPubMedGoogle Scholar
  20. 20.
    Rosenbaum PR, Rubin DB (1983) The central role of the propensity score in observational studies for causal effects. Biometrika 70:41–55CrossRefGoogle Scholar
  21. 21.
    Austin PC, Stuart EA (2015) Moving towards best practice when using inverse probability of treatment weighting (IPTW) using the propensity score to estimate causal treatment effects in observational studies. Stat Med 34:3661–3679CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Bassi P, Ferrante GD, Piazza N, Spinadin R, Carando R, Pappagallo G, Pagano F (1999) Prognostic factors of outcome after radical cystectomy for bladder cancer: a retrospective study of a homogeneous patient cohort. J Urol 161:1494–1497CrossRefPubMedGoogle Scholar
  23. 23.
    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 23:4602–4608CrossRefPubMedGoogle Scholar
  24. 24.
    Lee C, Madii R, Daignault S, Dunn RL, Zhang Y, Montie JE, Wood DP Jr (2006) Cystectomy delay more than 3 months from initial bladder cancer diagnosis results in decreased disease specific and overall survival. J Urol 175:1262–1267CrossRefPubMedGoogle Scholar
  25. 25.
    Alva AS, Tallman CT, He C, Hussain MH, Hafez K, Montie JE, Smith DC, Weizer AZ, Wood D, Lee CT (2012) Efficient delivery of radical cystectomy after neoadjuvant chemotherapy for muscle-invasive bladder cancer: a multidisciplinary approach. Cancer 118:44–53CrossRefPubMedGoogle Scholar
  26. 26.
    Donat SM, Shabsigh A, Savage C, Cronin AM, Bochner BH, Dalbagni G, Herr HW, Milowsky MI (2009) Potential impact of postoperative early complications on the timing of adjuvant chemotherapy in patients undergoing radical cystectomy: a high-volume tertiary cancer center experience. Eur Urol 55:177–185CrossRefPubMedGoogle Scholar
  27. 27.
    Johnson DC, Nielsen ME, Matthews J, Woods ME, Wallen EM, Pruthi RS, Milowsky MI, Smith AB (2014) Neoadjuvant chemotherapy for bladder cancer does not increase risk of perioperative morbidity. BJU Int 114:221–228CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Gandaglia G, Popa I, Abdollah F, Schiffmann J, Shariat SF, Briganti A, Montorsi F, Trinh QD, Karakiewicz PI, Sun M (2014) The effect of neoadjuvant chemotherapy on perioperative outcomes in patients who have bladder cancer treated with radical cystectomy: a population-based study. Eur Urol 66:561–568CrossRefPubMedGoogle Scholar
  29. 29.
    Meyer V, Flechon A, Tartas S, Fassi-Fehri H, Ruffion A, Martin X, Colombel M (2015) Impact of neoadjuvant chemotherapy on therapeutic management of muscle-invasive bladder cancer. Prog Urol 25:83–89CrossRefPubMedGoogle Scholar
  30. 30.
    Tully CM, Iyer G, Bajorin DF (2013) Neoadjuvant chemotherapy in bladder cancer. J Clin Invest 3:991–1002CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Uros Milenkovic
    • 1
    • 2
  • Murat Akand
    • 1
    • 3
  • Lisa Moris
    • 1
  • Liesbeth Demaegd
    • 1
  • Tim Muilwijk
    • 1
  • Youri Bekhuis
    • 1
  • Annouschka Laenen
    • 1
  • Ben Van Cleynenbreugel
    • 1
  • Wouter Everaerts
    • 1
    • 2
  • Hein Van Poppel
    • 1
  • Herlinde Dumez
    • 4
  • Maarten Albersen
    • 1
    • 2
  • Steven Joniau
    • 1
  1. 1.Department of UrologyUniversity Hospitals LeuvenLouvainBelgium
  2. 2.Laboratory of Experimental Urology, Department of Development and RegenerationCatholic University of LeuvenLouvainBelgium
  3. 3.School of Medicine, Department of UrologySelcuk UniversityKonyaTurkey
  4. 4.University Hospitals Leuven, Department of General Medical Oncology, Leuven Cancer InstituteKU LeuvenLouvainBelgium

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