Does perioperative systemic therapy represent the optimal therapeutic paradigm in organ-confined, muscle-invasive urothelial carcinoma?

Luca Scafuri1,2, Antonella Sciarra3, Felice Crocetto4, Matteo Ferro5, Carlo Buonerba*,1,2, Francesco Ugliano6, Germano Guerra6, Roberto Sanseverino7 & Giuseppe Di Lorenzo1,2,6 1Oncology Unit, Hospital ‘Andrea Tortora,’ ASL Salerno, Pagani, 84016, Italy 2Associazione O.R.A., Somma Vesuviana, Naples, Italy 3Department of Experimental Medicine, University of Campania ‘Luigi Vanvitelli,’ Naples, NA, 80131, Italy 4Department of Neurosciences, Reproductive Sciences & Odontostomatology, Federico II University, Naples, 80131, Italy 5Division of Urology, European Institute of Oncology (IEO), IRCCS, Milan, 20099, Italy 6Department of Medicine & Health Science, University of Molise, Campobasso, 86100, Italy 7Department of Urology, Umberto I Hospital, ASL Salerno, Nocera Inferiore, 84014, Italy *Author for correspondence: carbuone@hotmail.com

Sequential use of neoadjuvant and adjuvant therapy in urothelial carcinoma patients may represent a diseasespecific paradigm that may be appliable with success both to chemotherapy and immunotherapy. In this regard, we read with interest the results obtained in one recently published meta-analysis that assessed survival differences in patients with pT3-T4 and/or pN+ muscle-invasive BCa who underwent neoadjuvant chemotherapy + surgery with versus without adjuvant chemotherapy [13]. In the overall sample of 3096 participants, of whom 2355 (76.1%) and 741 (23.9%) did not and did receive adjuvant chemotherapy, respectively, adjuvant chemotherapy was associated with a significant advantage in overall survival (HR: 0.84; 95%CI: 0.75-0.94; p = 0.002) and disease-specific survival (HR: 0.56: 95% CI: 0.32-0.99; p = 0.05). Interestingly, the magnitude of the overall versus disease-specific survival advantage may be more limited, possibly due to the medium-to-long term effects of chemotherapy on noncancerspecific survival, which is consistent with findings obtained by our research group, suggesting a higher noncancer mortality in BCa patients undergoing four versus three cycles of neoadjuvant platinum-based chemotherapy [14]. In this regard, perioperative immunotherapy may be more advantageous compared with chemotherapy in terms of noncancer-specific survival. Results from Phase III Checkmate 274 trial conducted in patients with urothelial cancer who were randomized to 1 year anti-PD-1 agent nivolumab or placebo administered after radical cystectomy or (nephro)-ureterectomy have been published recently [15]. Adjuvant nivolumab compared with placebo for a year was associated with a significant HR for recurrence or death of 0.70 (98% CI: 0.55-0.90; p < 0.001), with median disease-free survival (DFS) of 20.8 versus 10.8 months, respectively. Of note, there was a signal of a potential greater effectiveness of nivolumab in patients who had undergone prior neoadjuvant cisplatin-based chemotherapy (HR for progression = 0.51). This finding is consistent with differences in median DFS reported in the Phase III IMvigor010 trial assessing adjuvant atezolizumab versus observation in urothelial carcinoma patients after radical surgery [16], with a median DFS of 16.8 versus 19.4 months in those who had not received neoadjuvant chemotherapy compared with 19.8 versus 16.5 months in those who had received neoadjuvant chemotherapy. We also note that neoadjuvant immunotherapy based on anti-PD-1 agents prior to cystectomy has yielded exciting results. The updated results obtained in the PURE-01 in 114 BCa patients receiving pembrolizumab prior to cystectomy shoed a pT0 rate of 37% (95% CI: 28-46) and a pT ≤ 1 rate of 55% (95% CI: 46-65) [17].
Given the results reviewed here, we hypothesize that the best possibilities of cure in patients with muscle-invasive urothelial cancer are provided by perioperative cisplatin-based chemotherapy + immunotherapy combination. Given medium-to-long term toxicity associated chemotherapy, novel trials may be designed to explore the approach based on delivering a minimum number of cisplatin-based chemotherapy cycles (e.g., three) prior to surgery in combination with immunotherapy and administer immunotherapy only as adjuvant therapy in those who have achieved a complete pathologic response. The perioperative use of pembrolizumab in combination with chemotherapy in cisplatin-eligible muscle-invasive BCa and of pembrolizumab with or without enfortumab vedotin in cisplatin-ineligible muscle-invasive BCa is currently being explored in ongoing Phase III trials [18]. The results of these trials are eagerly awaited and may confirm that the 'perioperative paradigm' represents the best therapeutic approach in patients with muscle-invasive urothelial carcinoma undergoing radical surgery.
Financial & competing interests disclosure C Buonerba (in the last 3 years) has provided consulting to Ipsen. His Institution has received research funding from Sanofi, Astellas and AstraZeneca. C Buonerba serves as an editorial board member of Future Science OA. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
No writing assistance was utilized in the production of this manuscript.

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