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Surgical safety of radical cystectomy and pelvic lymph node dissection following neoadjuvant pembrolizumab in patients with bladder cancer: Prospective assessment of perioperative outcomes from the PURE-01 trial

  • Alberto Briganti,
  • Giorgio Gandaglia,
  • Simone Scuderi,
  • Andrea Gallina,
  • Renzo Colombo,
  • Nicola Fossati,
  • Francesco Barletta,
  • Antony Pellegrino,
  • Luigi Nocera,
  • Francesco Montorsi,
  • Andrea Necchi

Publication: European Uroloby, December 2019

No data are available on the surgical safety of radical cystectomy (RC) and pelvic lymph node dissection (PLND) after the administration of checkpoint inhibitors. We aimed at reporting the first prospective rigorous assessment of perioperative outcomes after RC and extended PLND following neoadjuvant pembrolizumab in a contemporary cohort of patients with muscle-invasive bladder cancer (MIBC) enrolled in the PURE-01 trial. From February 2017 to June 2019, a total of 68 consecutive patients who received three courses of 200 mg pembrolizumab intravenously every 3 wk and were subsequently treated with either open or robot-assisted RC and PLND at a single high-volume tertiary referral center were identified. All men had prospectively collected data about intra- and postoperative outcomes. Postoperative complications were graded according to the Clavien-Dindo system. Perioperative data were prospectively and systematically collected during patient interviews at 90 d after surgery according to the European Association of Urology (EAU) Guidelines Panel recommendations on reporting and grading complications. Overall, 52 (77%) versus 16 (23%) patients underwent robot-assisted versus open RC, and 31 patients (46%) received an orthotopic neobladder. Median blood loss and length of stay were 150 ml and 12 d, respectively. Overall, 52 (77%), 47 (69%), and 22 (32%) patients experienced any-grade complications, grade ≥2 complications, and readmission at 90 d, respectively. High-grade complications (defined as Clavien-Dindo ≥3a) were observed in 23 patients (34%). The most frequent complications were fever (n = 35, 52%) and ileus (n = 21, 31%). None of the patients experienced perioperative mortality at 90 d. Our data represent the first prospective evidence supporting the surgical safety of RC and PLND in patients with N0M0 MIBC who received neoadjuvant immunotherapy with pembrolizumab.

Dr Benjamin Pradere

Actually, barely 20% of eligible patients benefit from neoadjuvant chemotherapy in contemporary series despite the EAU guidelines. One of the reasons explaining this low rate is the associated morbidity of cisplatin-based chemotherapy regimens especially in frail patients. But during last years, many new trials have started the assessment of checkpoint inhibitors, which may have a better tolerance, in the neoadjuvant settings. PURE-01 is a prospective, single-arm, phase II trial evaluating Pembrolizumab (a PD-1 agent) administered for 3 cycles. This study has already shown promising results particularly in pathological downstaging.

Nevertheless, a neoadjuvant treatment before surgery has always raised questions about its impact on the surgical procedure and postoperative patients’ recovery. In the era of check point inhibitors, Briganti et al. presented here, the first study assessing prospectively the safety profile of radical cystectomy and pelvic lymph node dissection following neoadjuvant pembrolizumab in the PURE-01 trial.

In this paper, they reported the perioperative outcomes of 68 patients included in PURE-01 using the EAU guidelines on reporting and grading complications. All the patients benefit from the ERAS protocol during the perioperative period. Forty patients had a cT3 before surgery, the median time between the last administration of pembrolizumab and surgery was 24 days, to note 10% received a neoadjuvant chemotherapy after the checkpoint inhibitor. Most of the RC were performed by robotic approach (76.5%), and a high rate (46%) of ileal neobladder was performed.

Intraoperative results were similar to contemporary studies of radical cystectomy with a mean operating time of 366 min and 150ml of blood loss.

Overall, 77% experienced at least one complication and 34% had a Clavien-Dindo >=3a complication. One third need a readmission and no death was observed at 90th days. The most common complications were fever (52%) and ileus (31%).

Even if the rate of complications could seem quite high, only 10% of patients had Clavien-Dindo 3b or more complication. We have to congrats the authors to have rigorously assessed the posteroperative complications using a prospective collection system based on the EAU guidelines for reporting complications. This methodology of reporting complications is highly needed in future studies and will help to compare more objectively the outcomes of our surgical series.

Last, the authors compared these results to a cohort of patients who received in the same period neoadjuvant chemotherapy and who were not included in the PURE-01 protocol. They found a similar rate of postoperative complication but a lower blood loss rate in the pembrolizumab group (150 vs.300 p=0,046) but open cystectomy was more realized in the NAC group (but not significative p=0.05). Nevertheless, a multivariate analysis assessing the impact of the type of neoadjuvant treatment on perioperative outcomes found that Blood transfusion was lower in the pembrolizumab group (HR=0.75, 95%CI 0.09–0.61; p=0.01)

In conclusion, despite the small sample size of the cohort, the authors confirmed in this first prospective study the surgical safety of radical cystectomy with PLND after neoadjuvant pembrolizumab in patients with muscle invasive bladder cancer and point out the importance of a standardized assessment of complications using the EAU guidelines tool dedicated for adverse perioperative outcomes.