Prognosis and treatment of invasive bladder cancer

Abstract

This thesis focuses on prognosis and treatment of invasive bladder cancer (BC). The concept “invasive BC” comprises two entities: muscle-invasive BC (MIBC) and T1 bladder cancer, which invades the lamina propria and not the muscularis propria. T1 bladder cancer T1 bladder cancer can either be treated with transurethral resection and intravesical instillations or with radical cystectomy. Treatment depends on the risk of progression to MIBC and/or metastases. We performed two multicenter studies aimed at identifying prognostic factors for T1 bladder cancer as these are currently lacking. We found that the “old” WHO1973 grade classification was prognostic for progression and cancer-specific mortality, while the “new” WHO2004 classification was not. This contradicts with current recommendations by the American Urological Association. We also explored the prognostic value of two substage classifications for T1 bladder cancer and found that Metric substage, based on the diameter of the invasive tumour component, was highly prognostic for progression and cancer-specific mortality. Combined with WHO1973 grade, this substage classification could aid in treatment decision making for T1 bladder cancer. Muscle-invasive bladder cancer: Systemic treatment For MIBC, standard treatment consists of radical cystectomy (RC) following neoadjuvant chemotherapy (NAC). A complete pathologic tumour response to NAC significantly improves survival. The second part of this thesis aimed at predicting pathologic MIBC response by means of response imaging and by means of genomic tumour marker analysis prior to NAC. We found that 18F-FDG-PET/CT imaging could be used to distinguish responders from non-responders. However, 18F-FDG-PET/CT could not be used to accurately identify complete pathologic response. Results on genomic tumour markers were more promising. We found that ERBB2 (HER2) missense mutations were highly predictive for a complete pathologic BC response to chemotherapy. If these findings are confirmed by future studies, they will ultimately aid in patient selection for NAC. Muscle-invasive bladder cancer: locoregional treatment RC comprises surgical resection of the bladder, prostate or uterus / anterior vaginal wall / ovaries, and pelvic lymph node dissection. It is associated with high morbidity, a long period for recovery and lasting functional impairment. The third part of this thesis included a study on organ-preserving therapy for a selected group of MIBC patients. Treatment comprised NAC, pelvic lymph node dissection and combined external beam radiation with panitumumab (an EGFR inhibitor) administration. Toxicity was non-inferior to the commonly used cisplatin/radiotherapy combination and response rates were promising. Prostate-sparing cystectomy (PSC) is an option for a selected group of patients who wish to preserve sexual function. PSC is debated for fear of incomplete resection and incidental prostate carcinoma. Our two-centre study in this thesis confirms that PSC oncologic outcomes are acceptable, provided that extensive work-up including preoperative prostatic urethral biopsies or per-operative frozen section analysis is performed. Future research should validate the patient’s perception of functional advantages by means of quality of life questionnaires. Conclusion The work presented in this thesis may aid in risk stratification, therapy selection and ultimately survival of bladder cancer patients. Organ-preserving therapies and critical appraisal of surgical boundaries should reduce morbidity and functional loss