Marker-based follow-up of patients with non-muscle-invasive low/intermediate risk bladder cancer (UroFollow)

Status:

completed 01/2020

Aims:

Non-muscle-invasive bladder cancer (NMIBC) rarely progresses after resection, but 30% to 60% of these patients develop a recurrent non-muscle-invasive tumour within three years after resection. The follow-up of bladder cancer patients aiming at the early detection of recurrence is currently conducted by cystoscopy, which patients often experience as painful. Urine-based tumour markers could be a non-invasive alternative, but their performance has not yet been proven. The prospective randomized UroFollow aimed to trial examines the performance of markers in comparison with cystoscopy for the detection of recurrent tumours in patients with NMIBC.

Activities/Methods:

Conducting a multicentre controlled phase III-clinical trial to compare the detection of recurrence in patients with NMIBC using FDA-approved (food and drug administration), commercially available, urine-based tumour tests (UroVysion, ImmunoCyt/uCyt+, NMP22) in the "marker arm" vs. cystoscopy in the "usual-care arm".

Results:

The project was not completed by the end of 2019, as originally planned. The intended sample size of 248 eligible bladder cancer patients was not achieved. During the period 04/2016 to 12/2019, 210 patients were enrolled (study period of three to 3.75 years, depending on center initiation). One-hundred and seventy-five patients were considered eligible. Of these, 12 participants had not yet undergone the 3-month urethrocystocopy (UC) before randomization into the marker or usual care study arm.

The original sample-size calculation was based on assumptions regarding a tumour recurrence rate of 30 % during the 3-year follow-up and an expected sensitivity of the UroVysion-cytology marker panel of 80 %. The recurrence rate in the usual care arm, which reflects the 'true' recurrence rate for this study arm, was 13 % after a median follow-up of 18 months. It is not likely that the expected recurrence rate of at least 30 % assumed for sample-size calculation will be met after 36 months of follow-up. The majority (90 %) of recurrent tumours detected so far occurred within 1.5 years after transuretral resection of the bladder (TURB). The observed imbalance of recurrent tumours between marker arm (n=5) and usual care arm (n=11) – although not statistically significant due to the small number of cases – suggests that some recurrences were not detected by the marker panel during follow-up. All tumours detected so far were small. However, a final assessment of marker sensitivity in the marker arm is only possible by a final UC. These have been performed to a limited extent so far.

Additional marker testing parallel to the 3-month UC after the initial TURB resulted in a combined marker sensitivity (UroVysion and cytology) of 11 %. The tumors detected during this period were smaller than 3 cm (as were the tumors observed during follow-up). Of five recurrent tumours diagnosed in the marker arm during follow-up, four were detected by positive cytology findings. UroVysion was only positive in one case (a patient with carcinoma in situ, i.e., a progressive tumor according to the study protocol). The fifth recurrence was not detected by study markers, but diagnosed during cystoscopy triggered by the patient’s clinical symptoms for bladder cancer. It should be noted that all results do not include the proposed “experimental markers", but only the marker algorithm of UroVysion and cytology that was used for the randomized patient follow-up.

The label-free biophotonic methods, IR and Raman imaging, were successfully verified in parallel with the primary study objectives. In IR imaging, cystitis, low-grade tumours, and high-grade tumours were differentiated in a few minutes using bladder tissue. For the analysis of urine cell sediment, Raman imaging showed promise as a future technology. However, a final assessment of these results need to be performed in further studies.

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