Bladder research

Quality of care

Every patient expects optimal quality of oncological care. Wherever it is performed. But how optimal is it? Are there (major) differences between departments, hospitals and settings? In a very close collaboration with the Netherlands Cancer Registry (held by IKNL), we identify practice variation and (non)-adherence to guidelines as well as factors underlying such variation and (non)adherence. The ultimate goal of our research is to optimize survival and quality of life of bladder cancer patients by improving quality of care.

Publications

• Insight into bladder cancer care: Study protocol of a large nationwide prospective cohort study (BlaZIB). Ripping, T.M., Kiemeney, L.A., van Hoogstraten, L.M.C., Witjes, J.A. & Aben, K.K.H (BlaZIB study group). BMC Cancer. 2020, May 20;20(1):455. doi: 10.1186/s12885-020-06954-7.PMID: 32434491.
• Hospital-specific probability of cystectomy affects survival from muscle-invasive bladder cancer. Ripping, T.M., Witjes, J.A., Meijer, R.P., van Rhijn, B.W.G., Oddens, J.R., Goossens-Laan, C.A., Mulder, S.F., van Moorselaar, R.J.A., Kiemeney, L.A. & Aben, K.K.H. Urol Oncol. 2020 Dec;38(12):935.e9-935.e16. doi: 10.1016/j.urolonc.2020.08.014. Epub 2020 Sep 8.PMID: 32917503.
• Utilization of systemic treatment for metastatic bladder cancer in everyday practice: Results of a nation-wide population-based cohort study. Richters, A., Mehra, N., Meijer, R.P., Boormans, J.L., van der Heijden, A.G., Smilde, T.J., van der Heijden, M.S., Kiemeney, L.A. & Aben, K.K. Cancer Treat Res Commun. 2020;25:100266. doi: 10.1016/j.ctarc.2020.100266. Epub 2020 Dec 8.PMID: 33316557.
• Hospital volume is associated with postoperative mortality after radical cystectomy for treatment of bladder cancer. Richters, A., Ripping, T.M., Kiemeney, L.A., Leliveld, A.M., van Rhijn, B.W.G., Oddens, J.R., van Moorselaar, R.J.A., Goossens-Laan, C.A., Meijer, R.P. & Boormans, J.L. (BlaZIB Study Group), Witjes J.A. & Aben, K.K.H. BJU Int. 2021 Jan 6. doi: 10.1111/bju.15334. Online ahead of print.PMID: 33404154.

Comparative effectiveness research

With new treatment options becoming available for muscle invasive and metastatic bladder cancer, the landscape of systemic options has been broadened significantly. A multitude of clinical trials are currently assessing efficacy of these immunotherapeutic agents. These trials are crucial to determine superior efficacy of new agents compared to current standard of care.

However, estimated efficacy does not translate directly to routine clinical practice effectiveness due to well established differences among patient populations. Therefore, the ideal evolution of evidence involves well-designed RCTs evaluating efficacy, complemented with subsequent population-based observational studies to evaluate effectiveness and cost-effectiveness in routine practice. This complementary research approach mitigates limitations of clinical trials, including strict patient selection, limited external validity, and difficulty to reach recruitment goals. Furthermore, it can be used to support health-care decisions and development of guidelines, to provide insight into subpopulations lacking evidence-based treatment options, to link effectiveness to expenses and to support clinical trial designs, when based on high-quality, well-designed observational studies.

Publications

• Prospective bladder cancer infrastructure for experimental and observational research on bladder cancer: Study protocol for the 'trials within cohorts' study ProBCI. Richters, A., Meijer, R.P., Mehra, N., Boormans, J.L., van der Heijden, A.G., van der Heijden, M.S., Kiemeney, L.A. & Aben, K.K. BMJ Open. 2021 May 18;11(5):e047256. doi: 10.1136/bmjopen-2020-047256.PMID: 34006553.
• Utilization of systemic treatment for metastatic bladder cancer in everyday practice: Results of a nation-wide population-based cohort study. Richters, A., Mehra, N., Meijer, R.P., Boormans, J.L., van der Heijden, A.G., Smilde, T.J., van der Heijden, M.S., Kiemeney, L.A. & Aben, K.K. Cancer Treat Res Commun. 2020;25:100266. doi: 10.1016/j.ctarc.2020.100266. Epub 2020 Dec 8.PMID: 33316557.

Transcriptome and proteome research

Biomarkers are aimed at optimizing diagnosis, improving assessment of prognosis, and better predicting outcome to intravesical and systemic therapies. Current standard methods used to detect and monitor bladder cancer, such as cystoscopy and urine cytology, are invasive or have low sensitivity. Molecular uroscopy, or measurement of genetic abnormalities in urine, could circumvent or supplement classical detection methods.

The urology research laboratory, in collaboration with other research groups around the world, is researching cancer-associated messenger RNAs and methylation of cancer-related genes in urine. Gene classifiers are tested in prospective multicenter trials in which the urine collection of the Radboud Biobank is of utmost importance. New avenues to monitor bladder cancer recurrence, and predict early therapy response, based on the presence and nature of circulating tumor DNA, are being explored. With focus on systemic immunotherapy, predictive signatures are being sought from within the whole blood transcriptome, the mononuclear cell proteome and T-cell repertoire.

Within the European PRECISE consortium Radboudumc is leading the path towards an improved response prediction for checkpoint immunotherapy through validation of a multi-modality predictive liquid biomarkers panel. For BCG immunotherapy, response signatures are being sought in immune-related proteins in blood and urine, as well as the tumor genome and transcriptome. In collaboration with the biotechnology industry, we aim to introduce new molecular tests for bladder cancer in clinical practice. Viable tissue is stored at -80 °C for the development of an organoid biobank within the PIONEER study, with aim to facilitate drug discovery and translational research.

Clinical studies

Besides fundamental and translational research, we initiate and participate in several clinical trials in the field of non-muscle-invasive, muscle-invasive and metastatic bladder cancer. In non-muscle-invasive bladder cancer our focus is on new treatment modalities, i.e. oral metformin for intravesical treatment or the application of a gemcitabine-releasing intravesical drug delivery system (GemRIS). Furthermore, we have extensive experience in clinical trials on radiofrequency-induced intravesical hyperthermia (Synergo).

In muscle invasive and metastatic bladder cancer, several immunotherapy studies with pembrolizumab, ipilimumab and nivolumab are recruiting patients for neoadjuvant or palliative treatment. Within the nationwide DRUP study we are actively including urothelial cancer patients for molecular-matched targeted therapies. Since we are convinced that physical fitness improves patients’ outcome after major surgery such as cystectomy, we also participate in a multimodal rehabilitation study (Fit4Surgery).

Publications

• Trained immunity as a molecular mechanism for BCG immunotherapy in bladder cancer. van Puffelen, J.H., Keating, S.T., Oosterwijk, E., van der Heijden, A.G., Netea, M.G., Joosten, L.A.B. & Vermeulen, S.H. Nat Rev Urol. 2020 Sep;17(9):513-525. doi: 10.1038/s41585-020-0346-4. Epub 2020 Jul 16.PMID: 32678343.

Tumor genomics and genetics

Tumor genetic profiling to individualize patient therapy is being performed by the Molecular Tumor Board. Here next-generation sequencing and RNA sequencing is utilized to identify molecular drivers, such as FGFR mutations and fusions, for targeted treatment within clinical studies. In addition, tumor and germline genetic research into bladder cancer predisposition is being performed.

The MOTIEF study is specifically aimed at identifying germline mutations underlying early-onset bladder cancer (i.e. up to 30 years of age) through whole genome sequencing of germline DNA and targeted sequencing of tumor DNA. We have an extensive research line that is aimed at identification of germline DNA variation for prognostic outcomes in non-muscle invasive bladder cancer, with a special interest in BCG response. Furthermore, we perform genome-wide association studies in our large bladder cancer biorepositories (Nijmegen Bladder Cancer Study and UroLife) and combine our results with the data from our international collaborators to increase the power to identify new genetic variants. We apply high-standard genetic epidemiological research methods and contribute to method evaluation and optimization, e.g. into statistical genetic analysis of recurrent events.

Publications

• Independent Replication of Published Germline Polymorphisms Associated with Urinary Bladder Cancer Prognosis and Treatment Response. Grotenhuis, A.J., Dudek, A.M., Verhaegh, G.W., Aben, K.K., Witjes, J.A., Kiemeney, L.A. & Vermeulen, S.H. Bladder Cancer. 2016 Jan 7;2(1):77-89. doi: 10.3233/BLC-150027. PMID: 27376129; PMCID: PMC4927992.
• A comparison of multivariate genome-wide association methods. Galesloot. T.E., van Steen, K., Kiemeney, L.A., Janss, L.L. & Vermeulen, S.H. PLoS One. 2014 Apr 24;9(4):e95923. doi: 10.1371/journal.pone.0095923. PMID: 24763738; PMCID: PMC3999149.
• Identification of an enhancer region within the TP63/LEPREL1 locus containing genetic variants associated with bladder cancer risk. Dudek, A.M., Vermeulen, S.H., Kolev, D., Grotenhuis, A.J., Kiemeney, L.A. & Verhaegh, G.W. Cell Oncol (Dordr). 2018 Oct;41(5):555-568. doi: 10.1007/s13402-018-0393-5. Epub 2018 Jun 28. PMID: 29956121; PMCID: PMC6153957.

Lifestyle and prognosis

Lifestyle factors are known to be related to increased cancer risk, but evidence for their role in cancer prognosis is still limited. We aim to investigate whether lifestyle-related factors (e.g. diet, smoking, physical activity) are related to cancer recurrence and progression and health-related quality of life in patients with non-muscle-invasive bladder cancer (NMIBC).

Hereto, we are conducting a multicentre prospective cohort study including around 1,500 patients with NMIBC recruited from 22 hospitals in The Netherlands (UroLife). At several time points after diagnosis, participants fill out a general questionnaire, and questionnaires about their lifestyle habits and HRQOL. Information about fluid intake and micturition is collected repeatedly with a 4-day diary. Patients also donate blood samples for DNA extraction and (dietary) biomarker analysis. Tumor samples are collected from all patients with T1 disease to assess molecular subtypes. Information about disease characteristics and therapy for the primary tumor and subsequent recurrences is collected from the medical records by the Netherlands Cancer Registry.

Publications

• The UroLife study: protocol for a Dutch prospective cohort on lifestyle habits in relation to non-muscle-invasive bladder cancer prognosis and health-related quality of life. de Goeij, L., Westhoff, E., Witjes, J.A., Aben, K.K.H., Kampman, E., Lambertus, A.L.M., Kiemeney, L.A. & Vrieling, A.BMJ Open. 2019;9(10):e030396. doi:10.1136/bmjopen-2019-030396.

Tailored and personalized dosing

Cancer pharmacology can be used to optimize and personalize the treatment of patients with cancer. Over the past decade broad knowledge has been gained on the pharmacology of oral targeted anticancer drugs. Additionally multiple pharmacological approaches have been implemented to optimize drug exposure of this group of anticancer drugs with the aim at improving the treatment outcomes for patients with cancer.

True personalized medicine is within reach. Over the next few years the selection of the right drug for the right person with a unique tumor type will be driven by preclinical tumor model information. In these models cancer biology and anticancer drug activity can be investigated leading to the most potent drug for the individual patient. For translation of the preclinical findings to the required optimal clinical exposure, cancer pharmacology is essential.

The discovery of specific biomarkers with which treatment response can be monitored will facilitate true personalized treatment of patients with cancer. With cancer pharmacology the relation between biomarker dynamics and anticancer drug exposure can be described which enables individualized anticancer treatment.

Publications

• Wide variation in tissue, systemic, and drain fluid exposure after oxaliplatin-based HIPEC: results of the GUTOX study. de Jong, L.A.W., Elekonawo, F.M.K., Lambert, M., de Gooyer, J.M., Verheul, H.M.W., Burger, D.M., de Wilt, J.H.W., Chatelut, E., ter Heine, R., de Reuver, P.R., Bremers, A.J.A. & van Erp, N.P. Cancer Chemother Pharmacol. 2020 Jul;86(1):141-50.
• Prognostic Value of Novel Liquid Biomarkers in Patients with Metastatic Castration-Resistant Prostate Cancer Treated with Enzalutamide: A Prospective Observational Study. Benoist, G.E., van Oort, I.M., Boerrigter, E., Verhaegh, G.W., van Hooij, O., Groen, L., Smit, F., de Mol, P., Hamberg, P., Dezentjé, V.O., Mehra, N., Gerritsen, W., Somford, D.M., van Erp, N.P.H. & Schalken, J.A. Clin Chem. 2020;66(6):842-51.
• Dose recommendations for anticancer drugs in patients with renal or hepatic impairment. Krens, S.D., Lassche, G., Jansman, F.G.A., Desar, I.M.E., Lankheet, N.A.G., Burger, D.M., van Herpen, C.M.L. & van Erp, N.P. Lancet Oncol, 2019 Apr;20(4);e200-e207.
• The Effect of using pazopanib with food vs fasted on the pharmacokinetics, patient safety and preference (DIET study). Lubberman, F.J.E., Gelderblom, H., Hamberg, P., Vervenne, W.L., Mulder, S.F., Jansman, F.G.A., Colbers, A., van der Graaf, W.T.A., Burger, D.M., Luelmo, S., Moes, D.J.A.R., van Herpen, C.M.L. & van Erp, N.P. Clin Pharm Ther 2019 Nov; 106(5):1076-1082.
• Clinical utility of emerging biomarkers in prostate cancer liquid biopsies. Boerrigter, E., Groen, L.N., van Erp, N.P., Verhaegh, G.W. & Schalken, J.A. Expert Rev Mol Diagn. 2020;20(2):219-30.

Biobank Urological Tumors

In the Radboudumc Biobank for Urological Tumors tissue, blood, and urine from patients is collected and stored ('biobanked’) over the course of their disease. Research performed with this material uses innovative genetic screening methods, advanced visualization of the tumor-tissue and immune system, and complementing functional models (e.g. in vitro organoid culture). The department of Medical Oncology and the Laboratory of Experimental Urology work together to group large numbers of patients based on their tumor profile, and to link these to data on treatment outcome. This allows them to improve diagnosis accuracy and to predict the optimal treatment for each individual patient, which will greatly improve clinical outcome.