Neoadjuvant chemotherapy (NAC) with gemcitabine and split-dose cisplatin appears to be well tolerated and does not lead to significant delays in surgery for patients with high-risk upper tract urothelial carcinoma (UTUC), according to the findings of a prospective multicenter phase 2 trial.
Progression-free survival (PFS) and overall survival (OS) with this combination therapy are superior to historical series without it.
The trial is the first fully accrued and completed study of its kind to evaluate the role of NAC followed by effective surgery for high-risk UTUC. To date, no randomized controlled phase 3 neoadjuvant trials have been completed, so these new data are the strongest evidence available. The investigators concluded that their findings support the use of NAC as a standard of care for high-risk UTUC, with gemcitabine and split-dose cisplatin as a viable option.
The study, published in the Journal of Clinical Oncology, provides an alternative dose schedule of gemcitabine and split-dose cisplatin in the neoadjuvant setting for high-risk UTUC. The findings suggest favorable outcomes, and potentially increasing the number of patients eligible for perioperative chemotherapy.
“The chemotherapy regimen was well tolerated, and all patients were able to proceed to surgery,” said lead study author Jonathan A. Coleman, MD, of Memorial Sloan Kettering Cancer Center in New York, New York. “It was nice to see that no particular difficulties were experienced, while doing these procedures nor anything unusual for patients during recovery.”
Despite effective surgery by radical nephroureterectomy and lymph node dissection, high-grade UTUC is associated with a poor prognosis. The authors noted that NAC has been shown to improve survival in patients with invasive urothelial carcinoma of the bladder, but its role for treating UTUC remains undefined. Dr Coleman’s team enrolled 57 patients (21 female, 36 male) with high-risk UTUC before extirpative surgery. Patients had a mean age of 66 years (range: 58 to 71 years).
All patients had radiographic cT2-4 disease on baseline imaging, 53 (93%) had high-grade histology on biopsy, and 4 (7%) had high-grade cytology without a biopsy.
All participants were scheduled to receive 4 cycles of gemcitabine and split-dose cisplatin before surgical resection and lymph node dissection. The primary study endpoint was rate of pathologic response (defined as ypT2N0). Secondary endpoints included PFS, OS, safety, and tolerability.
Of the 57 patients, 36 (63%) had a pathologic response and 11 (19%) had a complete pathologic response (ypT0N0), Dr Coleman and colleagues reported in the Journal of Clinical Oncology. After a median follow-up of 3.1 years, the 2- and 5-year PFS rates were 89% and 72%, respectively. The 2- and 5-year OS rates were 93% and 79%, respectively. The investigators observed treatment-related toxicities in 53 patients (93%). Grade 3 toxicities occurred in 42 patients (74%). Four patients (7%) had febrile neutropenia. There were no treatment-related deaths.
Toxicities resulting in early discontinuation included 3 patients suffering a thromboembolic event (5%), 2 patients developing renal dysfunction (4%), and 1 patient experiencing a cardiovascular event (2%).
“The use of neoadjuvant platinum-based chemotherapy is the standard of care in treating patients with advanced, high-risk urothelial cancer of the lower urinary tract and it is gratifying and no surprise that similar response rates and related clinical benefits can be seen for patients with UTUC,” Dr Coleman said.
When treated with surgery alone, high-grade UTUC is associated with poor 5-year survival rates, but that could be changed through combination approaches.
“Improving outcomes can only come through multi-disciplinary care, utilizing additional therapies,” Dr Coleman said. “Similar to the experience in lower tract urothelial cancer, neoadjuvant treatment in UTUC allows patients the best opportunity to receive effective forms of systemic therapy, takes advantage of optimal renal function, and also allows for standard surgical interventions.”
Minhaj Siddiqui, MD, Associate Professor of Surgery and Director of Urologic Oncology at the University of Maryland School of Medicine in Baltimore, said the current study will likely be highly considered in future guidelines on how to best treat UTUC and provide guidance for development of future studies. “I was impressed by how well the drugs were tolerated in the group,” Dr Siddiqui said. “These drugs are toxic to the kidneys and not well tolerated in patients with lower kidney function. Inherently, patients with cancer of the kidney often have worse kidney function, so there is concern how well these patients would tolerate this combination.”
Amy Nicole Luckenbaugh, MD, Assistant Professor of Urology at Vanderbilt University in Nashville, Tennessee, said these data should change the landscape for perioperative care for high-risk UTUC. “Although it may not be feasible, it would be interesting to randomize patients to neoadjuvant versus adjuvant therapy to determine if there is a difference on OS and PFS,” Dr Luckenbaugh stated. “That being said, that is a challenging trial to conduct and we may just need to extrapolate outcomes from each respective study.”
“What surprised me most about the study was the time it took — 10 years to complete this single arm study of patients with high-grade UTUC,” said Karim Chamie, MD, Associate Professor of Urology at the University of California, Los Angeles. “This suggests to me the reluctance of surgeons to recommend neoadjuvant chemotherapy over an upfront nephroureterectomy. The authors need to be commended for bringing this study to the forefront as we develop more comprehensive guidelines for patients with UTUC.”
The perceived suboptimal complete response rate seen in patients with UTUC compared with muscle-invasive bladder cancer should not discourage physicians from using NAC in a cohort of patients with an unmet need, Dr Chamie said.
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