Abstract
Purpose
For many malignancies, considerable divergence between the efficacy found in clinical trials and effectiveness in routine practice have been reported (efficacy–effectiveness gap). The purpose of this study was to evaluate the efficacy–effectiveness gap in palliative first-line (1L) chemotherapy treatment (CTx) for urothelial carcinoma of the bladder.
Methods
From seven Dutch teaching hospitals, all patients diagnosed with unresectable stage III (cT2-4aN1-3M0) and IV (cT4b and/or cM1) disease, who received 1L-CTx (for both primary as recurrent disease after radical cystectomy) between 2008 and 2016, were captured. Results were compared with data from seven randomised trials that investigated 1L gemcitabine + cisplatin (GemCis) and/or gemcitabine + carboplatin (GemCarbo).
Results
Of the 835 included patients, 191 received 1L-CTx. Median overall survival (mOS) of GemCis patients (N = 88) was 10.4 months [95% CI 7.9–13.0], which was shorter compared to clinical trial findings (range mOS: 12.7–14.3 months) despite comparable clinical characteristics. The mOS of GemCarbo patients (N = 92) was 9.3 months [95% CI 7.5–11.1]. Patients who received GemCarbo had worse prognostic characteristics (higher age, impaired renal function and worse performance status (all P-values < 0.001)) compared to GemCis patients, but were equal in occurrence of dose reductions (24.4% vs. 29.5%, P-value = 0.453), early termination (55.7% vs. 54.1%, P-value = 0.839), clinical best response (P-value = 0.733), and toxicity (68.1% vs. 63.3%, P-value = 0.743). In multivariable regression, GemCis was not superior to GemCarbo (HR 0.90 [95% CI 0.55–1.47], P-value = 0.674).
Conclusion
There seems to be an efficacy–effectiveness gap in 1L GemCis treatment, despite patients having similar baseline characteristics. Early termination of treatment occurred more often and dose reduction less often compared to clinical trials, hinting towards abandonment of treatment in case of adverse events. Patients treated with 1L GemCis did not have superior survival compared to GemCarbo patients, even though GemCarbo patients had worse baseline characteristics.
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References
Sternberg CN, Vogelzang NJ (2003) Gemcitabine, paclitaxel, pemetrexed and other newer agents in urothelial and kidney cancers. Crit Rev Oncol Hematol 46(Suppl):S105–S115. https://doi.org/10.1016/s1040-8428(03)00068-4
Witjes JA, Bruins HM, Cathomas R, Compérat EM, Cowan NC, Gakis G et al (2021) European association of urology guidelines on muscle-invasive and metastatic bladder cancer: summary of the 2020 guidelines. Eur Urol 79:82–104. https://doi.org/10.1016/j.eururo.2020.03.055
von der Maase H, Hansen SW, Roberts JT, Dogliotti L, Oliver T, Moore MJ et al (2000) Gemcitabine and cisplatin versus methotrexate, vinblastine, doxorubicin, and cisplatin in advanced or metastatic bladder cancer: results of a large, randomized, multinational, multicenter, phase III study. J Clin Oncol 18:3068–3077. https://doi.org/10.1200/JCO.2000.18.17.3068
von der Maase H, Sengelov L, Roberts JT, Ricci S, Dogliotti L, Oliver T et al (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 23:4602–4608. https://doi.org/10.1200/JCO.2005.07.757
Dogliotti L, Cartenì G, Siena S, Bertetto O, Martoni A, Bono A et al (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 52:134–141. https://doi.org/10.1016/j.eururo.2006.12.029
De Santis M, Bellmunt J, Mead G, Kerst JM, Leahy M, Maroto P et al (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 30:191–199. https://doi.org/10.1200/JCO.2011.37.3571
De Santis M, Bellmunt J, Mead G, Kerst JM, Leahy M, Maroto P et al (2009) Randomized phase II/III trial assessing gemcitabine/ carboplatin and methotrexate/carboplatin/vinblastine in patients with advanced urothelial cancer “unfit” for cisplatin-based chemotherapy: phase II–results of EORTC study 30986. J Clin Oncol 27:5634–5639. https://doi.org/10.1200/JCO.2008.21.4924
Bellmunt J, Von Der Maase H, Mead GM, Skoneczna I, De Santis M, Daugaard G et al (2012) Randomized phase III study comparing paclitaxel/cisplatin/ gemcitabine and gemcitabine/cisplatin in patients with locally advanced or metastatic urothelial cancer without prior systemic therapy: EORTC intergroup study 30987. J Clin Oncol 30:1107–1113. https://doi.org/10.1200/JCO.2011.38.6979
Dash A, Galsky MD, Vickers AJ, Serio AM, Koppie TM, Dalbagni G et al (2006) Impact of renal impairment on eligibility for adjuvant cisplatin-based chemotherapy in patients with urothelial carcinoma of the bladder. Cancer 107:506–513. https://doi.org/10.1002/cncr.22031
Nogué-Aliguer M, Carles J, Arrivi A, Juan O, Alonso L, Font A et al (2003) Gemcitabine and carboplatin in advanced transitional cell carcinoma of the urinary tract. Cancer 97:2180–2186. https://doi.org/10.1002/cncr.10990
Sonpavde G, Watson D, Tourtellott M, Cowey CL, Hellerstedt B, Hutson TE et al (2012) Administration of cisplatin-based chemotherapy for advanced urothelial carcinoma in the community. Clin Genitourin Cancer 10:1–5. https://doi.org/10.1016/j.clgc.2011.11.005
Pfail JL, Small AC, Cumarasamy S, Galsky MD (2021) Real World Outcomes of patients with bladder cancer: effectiveness versus efficacy of modern treatment paradigms. Hematol Oncol Clin North Am 35:597–612. https://doi.org/10.1016/j.hoc.2021.01.005
Galsky MD, Hahn NM, Rosenberg J, Sonpavde G, Hutson T, Oh WK et al (2011) A consensus definition of patients with metastatic urothelial carcinoma who are unfit for cisplatin-based chemotherapy. Lancet Oncol 12:211–214. https://doi.org/10.1016/S1470-2045(10)70275-8
Sobin LH, Gospodarowicz MK, Wittekind C (2010) TNM Classification of Malignant Tumours, 7th Edition. Wiley-Blackwell
Ma C, Bandukwala S, Burman D, Bryson J, Seccareccia D, Banerjee S et al (2010) Interconversion of three measures of performance status: An empirical analysis. Eur J Cancer 46:3175–3183. https://doi.org/10.1016/j.ejca.2010.06.126
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R et al (2009) New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 45:228–47. https://doi.org/10.1016/j.ejca.2008.10.026
Kaufman D, Raghavan D, Carducci M, Levine EG, Murphy B, Aisner J et al (2000) Phase II trial of gemcitabine plus cisplatin in patients with metastatic urothelial cancer. J Clin Oncol 18:1921–1927. https://doi.org/10.1200/JCO.2000.18.9.1921
Bamias A, Moulopoulos LA, Koutras A, Aravantinos G, Fountzilas G, Pectasides D et al (2006) The combination of gemcitabine and carboplatin as first-line treatment in patients with advanced urothelial carcinoma. A Phase II study of the Hellenic Cooperative Oncology Group. Cancer 106:297–303. https://doi.org/10.1002/cncr.21604
Nordon C, Karcher H, Groenwold RHH, Ankarfeldt MZ, Pichler F, Chevrou-Severac H et al (2016) The “efficacy-effectiveness gap”: historical background and current conceptualization. Value Health 19:75–81. https://doi.org/10.1016/j.jval.2015.09.2938
Galsky MD, Chen GJ, Oh WK, Bellmunt J, Roth BJ, Petrioli R et al (2012) Comparative effectiveness of cisplatin-based and carboplatin-based chemotherapy for treatment of advanced urothelial carcinoma. Ann Oncol Off J Eur Soc Med Oncol 23:406–410. https://doi.org/10.1093/annonc/mdr156
Ferry D, Billingham L, Jarrett H, Dunlop D, Woll PJ, Nicolson M et al (2017) Carboplatin versus two doses of cisplatin in combination with gemcitabine in the treatment of advanced non-small-cell lung cancer: Results from a British Thoracic Oncology Group randomised phase III trial. Eur J Cancer 83:302–312. https://doi.org/10.1016/j.ejca.2017.05.037
Griesinger F, Korol EE, Kayaniyil S, Varol N, Ebner T, Goring SM (2019) Lung Cancer Efficacy and safety of first-line carboplatin-versus cisplatin-based chemotherapy for non-small cell lung cancer : a meta-analysis. Lung Cancer 135:196–204. https://doi.org/10.1016/j.lungcan.2019.07.010
Flannery K, Cao X, He J, Zhong Y, Shah AY, Kamat AM (2018) Survival rates and health care costs for patients with advanced bladder cancer treated and untreated with chemotherapy. Clin Genitourin Cancer 16:e909–e917. https://doi.org/10.1016/j.clgc.2018.03.002
Acknowledgements
The authors thank the registration team of the Netherlands Comprehensive Cancer Organisation (IKNL) for the collection of data for the Netherlands Cancer Registry as well as IKNL staff for scientific advice. The authors thank Roche Nederland B.V. for funding for this research project.
*The Santeon MIBC Study Group (collaborators) are: D.H. Biesma, P.E.F. Stijns, J. Lavalaye, P.C. De Bruin, B.J.M. Peters, St. Antonius Hospital, Utrecht/Nieuwegein, The Netherlands. D.M. Somford, M. Berends, Canisius Wilhelmina Hospital (CWZ), Nijmegen, The Netherlands. R. Richardson, Catharina Hospital, Eindhoven, The Netherlands. G. Van Andel, Onze Lieve Vrouwe Gasthuis (OLVG), Amsterdam, The Netherlands. O.S. Klaver, B.C.M. Haberkorn, Maasstad Hospital, Rotterdam, The Netherlands. J.M. Van Rooijen, Martini Hospital, Groningen, The Netherlands. R.A. Korthorst, Medisch Spectrum Twente (MST), Enschede, The Netherlands. R.P. Meijer, J.R.N. Van der Voort Van Zyp, University Medical Center Utrecht (UMCU), Utrecht, The Netherlands.
Funding
This research received a grant from Roche Nederland B.V. to perform this study (Grant number: ML40374).
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The study has been approved by the local research ethics committee of the St. Antonius Hospital Utrecht/Nieuwegein (W17.087) and was conducted in accordance with Good Clinical Practice Guidelines.
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Reesink, D.J., van Melick, H.H.E., van der Nat, P.B. et al. Real-world outcomes of first-line chemotherapy for unresectable stage III and IV bladder cancer. World J Urol 41, 1551–1562 (2023). https://doi.org/10.1007/s00345-023-04408-w
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DOI: https://doi.org/10.1007/s00345-023-04408-w