Case Presentation: Treating Patients With Bladder/Urothelial Cancer Case Presentation

AB is a 63-year-old male with no underlying medical problems. He had a history of smoking (twenty pack years) and alcohol (five units per week on average). He had not been exposed to industrial chemicals. There was no familiar history of cancer. 

The patient presented to his general practitioner after having eight episodes in two months of macroscopic hematuria without any other symptoms. There was no history of trauma. Physical examination was unremarkable. A urine dipstick was positive for blood and no showed signs of infection. A urinary ultrasound scan showed a vesical tumor on the right side, kidneys were normal.

The patient was referred to an urologist for further evaluation. Cystoscopy indicated a single 4 cm papillary tumor. Cystoscopy and transuretheral resection of the bladder tumour were carried out soon after. The tumour was a unifocal 4 cm bladder lesion, which was resected down to muscle in its entirety. Additional random bladder biopsies were also sent for analysis. Histology revealed a grade 3 papillary transitional cell carcinoma of the bladder with invasion of muscularis propria and perivesical tissue (cT3a). A staging CT urogram showed no evidence of any upper tract abnormality, lymph nodes or metastases (cN0M0). Serum creatinine was 1.1 mg/dl.

The final decision made in the multidisciplinary committee was neoadjuvant chemotherapy and surgery. To note, the option of radiotherapy and chemotherapy concomitant was also discussed and could be an alternative for this patient. The patient received four cycles of dose dense MVAC (methotrexate 30 mg/m2 IV day 1, vinblastine 3 mg/m2 IV day 2, cisplatin 70 mg/m2 IV day 2 and doxorubicin 30 mg/m2 IV day 2) associated to pegfilgrastim 6 mg subcutaneous 24-48 hours after chemotherapy followed by  cystoprostatectomy with bilateral lymph node dissection. The patient presented grade 2 thrombocytopenia and grade 2 mucositis due to chemotherapy and no postoperative complications.

Currently, no biomarkers are used in the clinical setting to predict response to neoadjuvant chemotherapy in urothelial carcinoma. However, the evidence for the eventual individualization of treatment in muscle invasive bladder cancer based on genomics and molecular subtyping is growing. The most important and promising predictive biomarkers for cisplatin-based neoadjuvant chemotherapy are regulators of cell cycle and apoptosis, pathways involved in DNA repair (ATM, RB, FANCC), gene expression signatures, molecular subtypes (luminal-papillary, luminal infiltrated, luminal, basal-squamous, neuronal) and immunological parameters.

Histologically no evidence of cancer cells found in any of the removed tissue. The proposition was to follow up.

Our clinical case represents an ideal situation in which the patient benefits from neoadjuvant chemotherapy. There is level one evidence for cisplatin-based neoadjuvant chemotherapy in non-metastatic non muscle invasive bladder cancer patients, and achieving a pathological complete response or downstaging to non muscle invasive bladder cancer on the final surgical specimens is associated with high cure rate and increased survival.

This clinical case opens the discussion for future trials testing bladder preservation in those patients who obtain a complete pathological response after systemic treatment. The RETAIN (NCT02710734) trial is using a mutation profile (ATM, RB1, FANCC, ERCC2) with the goal of bladder preservation. The investigators hope that by identifying responders (cT0) patients with somatic mutations prospectively and monitoring them closely after neoadjuvant chemotherapy, cystectomy could be delay and patients will undergo active surveillance. The primary endpoint is metastasis free survival at 2 years. Currently, other clinical trials are exploring new bladder preservation strategies including definitive combination systemic therapy with chemotherapy and immunotherapy (NCT03558087; NCT04506554).

Common clinical practice is not reflected by this ideal patient situation and is confronted with several unmet needs. Approximately 40% to 60% of patients present pathological residual disease despite neoadjuvant chemotherapy, which is associated with a higher risk of recurrence and poor survival. Nearly half of the patients diagnosed with non-metastatic muscle invasive bladder cancer are unfit for cisplatin-based therapy and no alternative options of neoadjuvant treatment exist for these patients. Currently, many clinical trials are testing checkpoint inhibitors in the neoadjuvant setting with the objective to improve the activity on immunotherapy in terms of pathological complete response and reduce the risk of recurrence. First reports in this field show feasibility and great potential to significantly improve outcomes. We reported recently the preliminary results of the AURA (Oncodistinct-004) study evaluating avelumab as neoadjuvant strategy in cisplatin-eligible and cisplatin-ineligible patients with urothelial non-metastatic muscle invasive bladder cancer.

 At this time, we encourage participation in clinical trials for patients with non-metastatic muscle invasive bladder cancer in order to improve outcome and to identify molecular biomarkers for perioperative therapy patient selection.