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.

List of scientific papers

I. Karin Holmsten, Line Hammer Dohn, Niels Viggo Jensen, Carl-Henrik Shah, Fredrik Jäderling, Helle Pappot and Anders Ullén. Vinflunine treatment in patients with metastatic urothelial cancer: A Nordic retrospective multicenter analysis. Oncol Lett. 2016; 12: 1293-1300.
https://doi.org/10.3892/ol.2016.4775

II. Carl-Henrik Shah, Helle Pappot, Mads Agerbæk, Karin Holmsten, Fredrik Jäderling, Jeffrey Yachnin, Per Grybäck, Hans von der Maase and Anders Ullén. Safety and activity of sorafenib in addition to vinflunine in post-platinum metastatic urothelial carcinoma (VINSOR): Phase I trial. Oncologist. 2019; 24: 745-e213.
https://doi.org/10.1634/theoncologist.2018-0795

III. Karin Holmsten, Niels Viggo Jensen, Lene Sonne Mouritsen, Erika Jonsson, Camilla Mellnert, Mads Agerbæk, Cecilia Nilsson, Mette Moe, Andreas Carus, Elisabeth Öfverholm, Outi Lahdenperä, Yvonne Brandberg, Hemming Johansson, Mats Hellström, Hans von der Maase, Helle Pappot and Anders Ullén. Vinflunine/gemcitabine versus carboplatin/gemcitabine as first-line treatment in cisplatin-ineligible patients with advanced urothelial carcinoma: A randomised phase II trial (VINGEM). Eur J Cancer. 2020; 127: 173-182.
https://doi.org/10.1016/j.ejca.2019.08.033

IV. Karin Holmsten, Lise Høj Omland, Anne Birgitte Als, Mads Agerbæk, Line Hammer Dohn, Henriette Lindberg, Niels Viggo Jensen, Andreas Carus, Mette Moe, Abolfazl Hosseini, Cecilia Radkiewicz, Helle Pappot and Anders Ullén. Three-week versus four-week schedule of neoadjuvant gemcitabine and cisplatin in muscle-invasive bladder cancer: Implications for efficacy and safety. [Submitted]