Bladder Cancer in a Population-Based Cohort from Stockholm County with Long-Term Follow-Up; a Comparative Analysis of Prediction Models for Recurrence and Progression, Including External Validation of the Updated 2021 EAU Model - Beyond the Abstract

One of the great challenges for Uro-Oncologists caring for patients with non-muscle invasive bladder cancer (NMIBC) Is advising them at diagnosis regarding the right treatment options to potentially minimize their visits to the hospital for those with low risk disease but at the same time optimize their long term survival for those with higher risk disease. This is particularly challenging for the later, some of whom may safely be offered intravesical treatment and cystoscopic surveillance in contrast to other high risk patients who should be encouraged to undergo “timely” cystectomy. Contributing to the decision making process are a number of models predicting rates of recurrence and progression, although the landscape for these tools has become increasingly complex, notwithstanding the relatively recent introduction of the updated WHO 2004/2016 pathological grading system.1

There are two established models using the old WHO 1973 pathology system which have been externally validated by a number of studies; the CUETO model and EORTC 2006 model. The CUETO model was designed from over 1000 trial patients, none of whom received single shot intravesical chemotherapy at diagnostic TURBT or underwent 2nd TURBT but who were all treated with intravesical BCG treatment for a period of up to 6 months.2 The model scoring system is built on 7 different clinical factors including age at diagnosis, gender, tumor WHO ’73 grade, stage and number, history of recurrence, and the presence of carcinoma-in-situ (CIS), and predicts recurrence and progression of disease at 1, 2 and 5 years. By contrast, the EORTC 2006 model was built from nearly 3000 trial patients, with no 2nd TURBTs in the cohort, close to 80% having intravesical chemotherapy, only 6.5% receiving intravesical BCG (but not maintenance treatment), and 4.4 % having CIS at diagnosis.3 Their scoring system was based on 6 clinical factors (tumor number, size, stage, and grade according to WHO ’73 classification as well as rate of recurrence and presence of CIS), predicting tumor recurrence and progression at 1 and 5 years. Comparing the two models, the CUETO model tends to predict lower rates of recurrence for all risk groups and lower rates of progression for higher risk groups.2

In addition to these, following publication of the revised WHO pathological classification, an updated EAU model was recently developed to predict progression which allows clinicians to use both the older and newer grading systems. The new EAU model was expanded to include a novel 4 tier risk stratification predicting progression at 1, 5 and 10 years and is based on a cohort of 3401 patients who had undergone diagnostic TURBT and chemotherapy but no additional BCG.4 There are also AUA guidelines that describe risk groups for clinical decision making, but limited to only 3 tiers.5 By contrast to the four tier EAU groups, the AUA guidelines suggest high grade Ta disease should be intermediate risk and propose 3 years of BCG for maintenance schedules for high risk patients as opposed to 1-3 years advocated by the EAU.6 Other options for clinicians to aid in decision making are the National Institute of Clinical Excellence (NICE) from the U.K which also provide risk groups and the National Comprehensive Cancer Network (NCCN) in the U.S.A. that use pathological grade and stage.4

With all of these models in mind, a recent paper published in Urologic Oncology used a unique prospective cohort of 535 patients from Stockholm, Sweden to externally validate EORTC 2006 and CUETO models, the AUA risk categories, and the more recent EAU risk progression model with 4 tier risk categories using both the WHO 2004/16 and 1973 pathology grading systems (Dovey et al., 2021). The cohort included all patients diagnosed with NMIBC across all hospitals in Stockholm County between 1995-1996 with up to 25 years follow up and is first study to externally validate the updated EAU 2021 model.4 All patients received the standard of care (SOC) at the time, including intravesical chemotherapy, although no single shot chemotherapy at diagnostic TURBT or office fulguration.

The study findings for the Stockholm cohort were both CUETO and EORTC 2006 models underestimated recurrence and progression rates at 1 and 5 years, although this was more marked for the CUETO model (Cis 0.68;0.67; 0.82; 0.84 respectively). The only exception was the EORTC high risk group tended to have higher predicted rates of progression than those observed. Predicted progression rates in the updated EAU 2021 model were lower than those observed in the study group for both the WHO 1973 and 2004/16 pathology classifications (CIs 0.83;0.83 respectively), although this difference flattened over 10 years follow up. The A.U.A. risk groups showed reasonable performance for predicting recurrence and progression at up to 5 years follow up, although interestingly approximately one third of high risk patients for recurrence and one half at high risk of progression were free of disease at the end of this period. The authors remarked underestimations of predicted rates of both recurrence and progression seen may have resulted from the SOC at the time, with variations in BCG dosing schedules and the use of intravesical chemotherapies as well as a paucity of single shot chemotherapy at diagnostic TURBT. Another finding of note from this study was the use of a simplified model devised by the authors incorporating only tumor size, grade, stage and multifocality showed similar performance to the established models for both recurrence and progression using both 1973 and 2004/16 WHO pathology systems (Cis 0.65;0.65;0.81;0.82 respectively).

All of these models are extremely important in clinical practice and are widely used to plan treatment strategies for patients presenting with NMIBC. However, challenges remain regarding advising specific patient groups who, for example, may be discharged early for those with low risk disease, or for those with high risk disease who are undecided between major surgery in the form of radical cystectomy or the less invasive option of maintenance BCG. Treatment choices for the latter group are tempered by the risk of delaying surgery in patients who may not respond to BCG with the risk of missing the opportunity for cure and significantly reducing life expectancy. From the results of this study, it seems unlikely that models based on clinical variables will answer these questions, and the authors suggest genomic classification may improve our predictive accuracy. Unfortunately for those clinicians who are advocates of early cystectomy for high grade T1 disease, there is no “number needed to treat” data which may give insight into how many patients it would require to operate on to save one life. As we understand more about the genetics of bladder cancer, genetic biomarkers may reveal themselves, and help guide these important clinical decisions.

Written by: Zachary Dovey, MBBS, John P. Sfakianos, MD, & Peter Wiklund, MD, PhD, Icahn School of Medicine at Mount Sinai, New York, NY.

References:

  1. Compérat EM, Burger M, Gontero P, Mostafid AH, Palou J, Rouprêt M, van Rhijn BWG, Shariat SF, Sylvester RJ, Zigeuner R, Babjuk M. Grading of Urothelial Carcinoma and The New "World Health Organisation Classification of Tumours of the Urinary System and Male Genital Organs 2016". Eur Urol Focus. 2019 May;5(3):457-466. doi: 10.1016/j.euf.2018.01.003. Epub 2018 Jan 20. PMID: 29366854.
  2. Fernandez-Gomez J, Madero R, Solsona E, Unda M, Martinez-Piñeiro L, Gonzalez M et al (2009) Predicting nonmuscle invasive bladder cancer recurrence and progression in patients treated with Bacillus Calmette-Guerin: the Cueto Scoring Model. J Urol 182(5):2195–2203. https ://doi.org/10.1016/j.juro.2009.07.016
  3. Sylvester RJ, van der Meijden AP, Oosterlinck W, Witjes JA, Bouffioux C, Denis L et al (2006) Predicting recurrence and progression in individual patients with stage Ta T1 bladder cancer using EORTC risk tables: a combined analysis of 2596 patients from seven EORTC trials. Eur Urol 49(3):466–477. https ://doi.org/10.1016/j.eurur o.2005.12.031
  4. Sylvester RJ, Rodríguez O, Hernández V et al. European Association of Urology (EAU) Prognostic Factor Risk Groups for Non-muscle-invasive Bladder Cancer (NMIBC) Incorporating the WHO 2004/2016 and WHO 1973 Classification Systems for Grade: An Update from the EAU NMIBC Guidelines Panel. Eur Urol. 2021 Apr;79(4):480-488. doi: 10.1016/j.eururo.2020.12.033. Epub 2021 Jan 6. PMID: 33419683.
  5. Chang SS, Boorjian SA, Chou R, Clark PE, Daneshmand S, Konety BR, Pruthi R, Quale DZ, Ritch CR, Seigne JD, Skinner EC, Smith ND, McKiernan JM. Diagnosis and Treatment of Non-Muscle Invasive Bladder Cancer: AUA/SUO Guideline. J Urol. 2016 Oct;196(4):1021-9. doi: 10.1016/j.juro.2016.06.049. Epub 2016 Jun 16. PMID: 27317986.
  6. Matulewicz RS, Steinberg GD. Non-muscle-invasive Bladder Cancer: Overview and Contemporary Treatment Landscape of Neoadjuvant Chemoablative Therapies. Rev Urol. 2020;22(2):43-51.

Read the Abstract