Neoadjuvant Split-Dose Chemotherapy Represents Potential New Standard of Care for High-Risk UTUC

Neoadjuvant treatment with gemcitabine and split-dose cisplatin followed by surgical resection and lymph node dissection proved to be effective and well-tolerated for patients with high-risk upper tract urothelial carcinoma (UTUC), according to findings from a phase 2 trial (NCT01261728) published in the Journal of Clinical Oncology.

Patients (n = 57) achieved a pathologic response rate of 63% (95% CI, 49%-76%), with 19% achieving a pathologic complete response (pCR). At a median follow-up of 3.1 years (interquartile range [IQR], 2.0-6.1), the 2- and 5-year overall survival (OS) rates were 93% (95% CI, 86%-100%) and 79% (95% CI, 67%-94%), respectively (P < .001). Additionally, the 2- and 5-year progression-free survival (PFS) rates were 89% (95% CI, 81%-98%) and 72% (95% CI, 59%-87%), respectively (P < .001).

Patients who achieved a pCR (n = 11) or a pathologic partial response (n = 25) had 2-year PFS rates of 100% and 95%, respectively, vs 76% for nonresponders (n = 21). The 5-year PFS rates were 100% and 86% vs 47%, respectively.

Similar rates of superior responses from complete and partial responders compared with nonresponders were recorded for OS. Patients who achieved complete and partial responses had 2-year OS rates of 100% and 100%, respectively, vs 80% for nonresponders and 5-year OS rates were 100% and 90% vs 58%, respectively.

Management of UTUC, a rare form of urothelial cancer, is often based on treatments for urothelial carcinoma of the bladder (UCB), which include perioperative chemotherapy. Currently, only a few select groups of patients are eligible for adjuvant chemotherapy which has demonstrated improvement in survival outcomes for patients with high-risk UTUC, making prospective data in the neoadjuvant space key. Neoadjuvant chemotherapy is especially important for patients who become cisplatin-ineligible and who have poor renal function after radical nephroureterectomy (RNU).

Trial enrollment occurred from December 2010 to April 2019. Eligible patients received 4 cycles of split dose gemcitabine and cisplatin given at 1000 mg/m2 and 35 mg/m2, respectively, once dailyon days 1 and 8 of a 21-day cycle. The median duration from chemotherapy completion to surgery was 7 weeks (IQR, 5.0-8.1), 82% of patients had minimally invasive surgery, and no patients had demonstrated disease progression prior to surgery.

The primary end point of the multicenter, single arm trial was rate of pathologic response after treatment. Secondary end points included PFS, OS, tolerability, and safety. The primary end point was determined based on neoadjuvant chemotherapy trials in UCB because as the study was being designed there was no similar UTUC data. However, pathologic response has since been proven a viable endpoint in UTUC.

The median age of enrolled patients was 66 years (range, 58-71). Most patients (93%) had a high-grade tumor by endoscopic biopsy. A majority of patients were also White (95%), males (63%), and had hydronephrosis present (63%).

Additional findings from the study showed that when the first stage of treatment ended, 16 of 29 patients experienced a pathologic response, which met the threshold and allowed for continuation into the second stage. Originally, the trial was to include 54 evaluable patients to reject the null hypothesis if 28 of 54 patients achieved a pathologic response. The threshold was met in the first 54 patients when 33 experienced a pathologic response.

In terms of response by pathologic stage, patients who did not respond had stages ypT2 (24%), ypT3 (43%), and ypTanyN+ (33%). Patients who responded to treatment had stages ypTO (31%), ypTa (28%), ypTis (19%), and ypT1 (22%).

Level 1 evidence from the phase 3 POUT trial (NCT01993979) suggested that patients with locally advanced disease after RNU would benefit from adjuvant chemotherapy, however, up to 85% of patients have grade 3 or higher chronic kidney disease (CKD) after RNU making them ineligible for cisplatin-based chemotherapy.

During the chemotherapy administration period of the phase 2 trial, renal function was minimally affected, as the median eGFR value was 72 (IQR, 66-81) at baseline and 70 (IQR, 59-87) after chemotherapy. However, renal function was greatly affected during surgery. Within 90 days of surgery, stage 4 CKD occurred in 25% of patients and, although no patients required dialysis, the median 7-day, 12-month, and 24-month post-surgery eGFR values were 41 (IQR, 33-51), 42 (IQR, 35-59), and 40 (IQR, 34-52), respectively. Comparatively, the baseline eGFR for all patients was 67 (range, 62-77).

Regarding safety, toxicity-related dose reductions were observed in 21% of patients and early discontinuation occurred in 14%; 93% of patients experienced an adverse event and 74% experienced grade 3 or higher toxicity. Common grade 3 and higher adverse event included febrile neutropenia (7.0%), hyperglycemia (14.0%), thromboembolic event (7.0%), hypocalcemia (7.0%), and anemia (5.3%). Additionally, grade 3 or above decreased lymphocyte count (33.0%) and decreased neutrophil count (32.0%) were common. The 30-date rate of grade 3 or higher complications from surgery was 11%.

The results demonstrated in this trial are superior to historical data and support the use of neoadjuvant chemotherapy as standard-of-care treatment for patients with high-risk UTUC, study authors wrote in conclusion. Split-dose gemcitabine/cisplatin is a suitable option and, irrespective of the cycles received, all patients proceeded to surgery (TABLE).

Reference

Coleman JA, Yip W, Wong NC, et al. Multicenter phase II clinical trial of gemcitabine and cisplatin as neoadjuvant chemotherapy for patients with high-grade upper tract urothelial carcinoma. J Clin Oncol. Published online January 5, 2023. doi:10.1200/JCO.22.00763