Dataset Information

Phase II Trial of Neoadjuvant Systemic Chemotherapy Followed by Extirpative Surgery in Patients with High Grade Upper Tract Urothelial Carcinoma.

ABSTRACT:

Purpose

Data supporting neoadjuvant chemotherapy of high grade upper tract urothelial carcinoma are scant. In this multi-institution, prospective, phase II trial we investigated pathological complete responses after neoadjuvant chemotherapy of high grade upper tract urothelial carcinoma.

Materials and methods

Patients with high grade upper tract urothelial carcinoma in whom nephroureterectomy was planned were assigned to 4 neoadjuvant chemotherapy cycles of accelerated methotrexate, vinblastine, doxorubicin and cisplatin in those with baseline creatinine clearance greater than 50 ml per minute or gemcitabine and carboplatin in those with creatinine clearance 30 to 50 ml per minute or less. The study primary end point was a pathological complete response (ypT0N0). The accrual goal was 30 patients per arm. An 18% pathological complete response was considered worth further study while a 4% pathological complete response would not have justified pursuing this regimen. With 28 eligible patients per arm success was defined as 3 or more pathological complete responses (10.7%) in a given arm. Secondary end points included safety, renal function and oncologic outcomes.

Results

A total of 30 patients enrolled in the accelerated methotrexate, vinblastine, doxorubicin and cisplatin arm from 2015 to 2017. Six patients enrolled in the gemcitabine and carboplatin arm, which closed due to poor accrual. Of the 29 patients eligible for accelerated methotrexate, vinblastine, doxorubicin and cisplatin, including 23 men and 6 women with a median age of 65 years (range 40 to 84), 80% completed all planned treatments, 3 (10.3%) achieved ypT0N0 and 1 achieved ypT0Nx for a pathological complete response in 13.8% (90% CI 4.9-28.8). In 1 patient receiving accelerated methotrexate, vinblastine, doxorubicin and cisplatin nephroureterectomy was deferred due to grade 4 sepsis. The grade 3-4 toxicity rate was 23% in the accelerated methotrexate, vinblastine, doxorubicin and cisplatin arm with no grade 5 event.

Conclusions

Accelerated methotrexate, vinblastine, doxorubicin and cisplatin neoadjuvant chemotherapy in patients with high grade upper tract urothelial carcinoma and creatinine clearance greater than 50 ml per minute was safe and demonstrated predefined activity with a 14% pathological complete response rate. Final pathological stage ypT1 or less in more than 60% of patients is encouraging. Together the results of this prospective trial support the use of neoadjuvant chemotherapy in eligible patients with high grade upper tract urothelial carcinoma.

SUBMITTER: Margulis V

PROVIDER: S-EPMC7735436 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Upper tract urothelial carcinoma comprises 5-10% of all urothelial carcinoma cases. This disease tends to have a more aggressive course than its lower urinary tract counterpart, with 60% of patients presenting with invasive disease and 30% of patients presenting with metastatic disease at diagnosis. The diagnostic workup of UTUC involves imaging with CT urogram, urine cytology, and direct visualization and biopsy of suspected lesions via ureteroscopy. Standard treatment of high-grade UTUC involves radical nephroureterectomy (RNU) and excision of the ipsilateral bladder cuff. Both the NCCN and EAU Guidelines include neoadjuvant chemotherapy as a treatment option for select patients with UTUC; however, there are no strict guidelines. Much of the rationale for neoadjuvant chemotherapy is based on extrapolation from data from muscle-invasive bladder cancer, which has demonstrated a 5-year OS benefit of 5-8%. Retrospective studies evaluating the use of NACT in urothelial carcinoma have yielded pathologic objective response rates of 48% in UTUC cohorts. The randomized Phase III POUT study noted a DFS advantage with adjuvant platinum-based chemotherapy, compared with surveillance in UTUC, of 70% vs. 51% at 2 years. Though not the standard of care, multiple studies have explored the use of perioperative immunotherapy or chemoimmunotherapy in the management of invasive urothelial carcinoma. The PURE-02 study explored the use of neoadjuvant pembrolizumab in patients with high-risk UTUC. A small study of 10 patients, it showed no significant signals of activity with neoadjuvant pembrolizumab. Another Phase II study of neoadjuvant ipilimumab and nivolumab in cisplatin-ineligible UTUC yielded more promising findings, with 3/9 patients attaining a pathologic CR and the remaining six pathologically downstaged. The ABACUS trial found a 31% pathologic complete response rate amongst cisplatin-ineligible MIBC patients treated with neoadjuvant atezolizumab. The use of adjuvant immunotherapy has been explored over three phase III trials. The CheckMate-274 trial found a DFS benefit with the addition of one year of adjuvant nivolumab in patients with high-risk urothelial carcinoma. The IMvigor-010 study of adjuvant atezolizumab was a negative study. The AMBASSADOR trial of adjuvant pembrolizumab is pending results. With the FDA approval of erdafitinib in metastatic urothelial carcinoma, similar targets have been explored for use in perioperative use in invasive urothelial carcinoma, as with adjuvant infigratinib in the PROOF-302 trial. As the treatment paradigm for urothelial carcinoma evolves, further prospective studies are needed to expand the perioperative treatment landscape of UTUC.