Improving chemotherapy in advanced urothelial cancer : real-world data studies and prospective clinical trials

Advanced urothelial cancer (UC) is an aggressive disease with high morbidity and mortality. The primary aim of this thesis was to improve chemotherapy with respect to treatment efficacy, safety, and health-related quality of life (HRQoL) in advanced UC. The recently introduced chemotherapeutical drug vinflunine was investigated as monotherapy and in novel treatment combinations for metastatic UC (mUC). Further, two different neoadjuvant chemotherapy regimens were evaluated in muscle-invasive bladder cancer (MIBC). Platinum-based combination chemotherapy have been standard treatment in mUC patients since the late 1980s. Vinflunine, approved in 2009, show a small but important improvement in survival when given as second line treatment. In Paper I, patients treated with vinflunine were evaluated in a retrospective real-world data study. The results confirmed that vinflunine is an active drug in an unselected cohort of routine patients. Further, patients with poor performance status had short survival and a high frequency of adverse events. With the aim of further improving the efficacy of second-line treatment of mUC, vinflunine was combined with sorafenib in the dose-finding phase I trial VINSOR (Paper II). A recommended phase II dose could be identified. The adverse events generally agreed with those previously reported for vinflunine and sorafenib as monotherapy. The novel combination generated clinically meaningful disease stabilisation and tumour responses. There is an unmet medical need for new treatment options for cisplatin-ineligible patients in first-line mUC, which was addressed in the randomised phase II trial VINGEM (Paper III) that compared the experimental combination of vinflunine and gemcitabine (VG) and standard treatment with gemcitabine and carboplatin. Compared to standard treatment, VG did not improve the primary endpoint progression-free survival. However, patients treated with VG did show a notably high overall response rate that was similar to the best data reported for any systemic therapy for mUC. The toxicity profile for VG was generally manageable, although high rates of neutropenia and febrile neutropenia were observed. No significant differences in HRQoL were found between the two treatment arms. For patients with MIBC, neoadjuvant cisplatin-combination chemotherapy prior to cystectomy improves overall survival, but the optimal regimen is still unknown. A more cisplatin-dose- intense 3-week schedule was compared with a 4-week schedule of gemcitabine and cisplatin (GC) as neoadjuvant treatment in a retrospective study (Paper IV). Compared to the 4-week schedule, the 3-week schedule led to a significantly higher degree of pathological complete response, although this was associated with more frequent neutropenia. Despite the differences in downstaging, no differences in survival were observed between the two schedules. In summary, vinflunine is an active drug for second-line treatment of mUC patients in a real- world setting. The novel combination of vinflunine and sorafenib can be safely combined in second-line treatment. In cisplatin-ineligible patients, compared to standard first-line treatment, the experimental combination of VG shows a higher response rate but does not prolong survival. In patients with MIBC, a more cisplatin-dose-intense 3-week schedule achieves significantly more complete responses compared to a 4-week schedule of GC as neoadjuvant chemotherapy prior to cystectomy

Stereotactic body radiation therapy is beneficial for a subgroup of patients with urothelial cancer and solitary metastatic disease: a single institution real-world experience

Abstract Background Standard treatment options for patients with metastatic urothelial cancer (mUC) include systemic platinum-based chemotherapy, immunotherapy, antibody-drug-conjugates, and targeted therapy. Oligometastatic disease (OMD) may be an intermediate state between localized and generalized cancer. The best treatment strategy for OMD and oligoprogressive (OPD) disease is poorly studied in mUC but local stereotactic body radiation therapy (SBRT) could be an option to avoid or delay systemic treatment. The aim of this study was to assess the efficacy and feasibility of SBRT given in a real-world patient population. Methods All patients with mUC treated with SBRT at Karolinska University Hospital, Stockholm, Sweden between 2009 and 2022 were included in this study. Baseline clinical characteristics, treatment data, SBRT dosimetry data and treatment outcome were collected retrospectively. The study endpoints were local control rate (LCR), progression-free-survival (PFS), overall survival (OS) and feasibility of SBRT. Results In total 39 patients were treated with SBRT. The median follow-up was 25.6 months. The LCR was 82%. PFS and OS were 4.1 and 26.2 months, respectively. Treatment was well tolerated; all patients but one (treatment related pain) completed the planned SBRT. Number of metastases irradiated with SBRT was significantly associated with outcome; patients with only one irradiated lesion had more favourable PFS compared to individuals with 2 or more metastases (HR 4.12, 95% CI: 1.81–9.38, p = 0.001). A subgroup of patients (15%) achieved a sustained long-term survival benefit and never required systemic treatments after SBRT. Conclusions SBRT was well tolerated and associated with high LCR. A subpopulation of patients with single metastatic lesion achieved long-term OS and never required subsequent systemic treatment after SBRT. Prospective randomized studies are warranted to discover treatment predictive biomarkers and to investigate the role of SBRT in oligometastatic UC

Different Responses to Neoadjuvant Chemotherapy in Urothelial Carcinoma Molecular Subtypes

Background: For muscle-invasive bladder cancer (MIBC), no tissue biomarkers are available for clinical use to predict response to neoadjuvant chemotherapy.Objective: To investigate how molecular subtypes impact pathological response and survival in patients receiving preoperative cisplatin-based chemotherapy.Design, setting, and participants: Classification of a retrospective cohort of 149 patients was performed by tumor transcriptomic profiling and immunostaining. A cohort treated with radical cystectomy alone and public data sets were used for comparison and external validation.Outcome measurements and statistical analysis: Complete pathological response in the cystectomy specimen (ypT0N0) and survival were compared in predefined molecular subtypes. Differential gene expression and chemotherapy response were explored beyond molecular subtypes.Results and limitations: Patients with genomically unstable (GU) and urothelial-like (Uro) tumors had higher proportions of complete pathological response (16/31 [52%] and 17/54 [31%]), versus five out of 24 (21%) with the basal/squamous (Ba/Sq) subtype following neoadjuvant chemotherapy and radical cystectomy. Molecular subtype was independently associated with improved survival for patients with GU tumors (hazard ratio [HR] 0.29, 95% confidence interval [CI]: 0.11-0.79) and UroC tumors (HR 0.37, 95% CI: 0.14-0.94) compared with Ba/Sq tumors, adjusting for clinical stage. In addition, expression of the gene coding for osteopontin (SPP1) showed a subtype-dependent effect on chemotherapy response.Conclusions: Urothelial cancer of the luminal-like (GU and Uro) subtypes is more responsive to cisplatin-based neoadjuvant chemotherapy. A second-generation of subtype-specific biomarkers, for example, SPP1, may be a way forward to develop a more precision-based treatment approach for neoadjuvant chemotherapy in MIBC