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Phase II trial of neoadjuvant systemic chemotherapy followed by extirpative surgery in patients with high grade upper tract urothelial carcinoma

  • Vitaly Margulis,
  • Maneka Puligandla,
  • Edouard J. Trabulsi,
  • Elizabeth R. Plimack,
  • Elizabeth R. Kessler,
  • Surena F. Matin,
  • Guilherme Godoy,
  • Ajjai Alva,
  • Noah M. Hahn,
  • Michael A. Carducci,
  • Jean Hoffman-Censits,
  • Collaborators

Publication: Journal of Urology, November 2020

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 armrom 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 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.

Commented by Dr. Xylinas

Through a prospective, multi-institutional, two-arms, non-randomized, phase II feasibility trial, Margulis et al. investigated the safety and efficacy of systemic neoadjuvant chemotherapy (NAC) for high-grade (HG) upper tract urothelial carcinoma (UTUC) [1]. Primary outcome measure was the rate of complete pathological response (pCR) after surgery (ypT0N0). Recruited patients underwent two different chemotherapy regimens depending on renal function: accelerated methotrexate, vinblastine, doxorubicin, cisplatin (aMVAC) or gemcitabine and carboplatin (GCa) for creatinine clearance (CrCl) values > 50 ml/min or included between 30-50 ml/min, respectively. Assuming an enrollment plan of 30 patients per treatment group from 2015 to 2017, data from 29 eligible patients in aMVAC arm and 6 in GCa arm were available for final analyzes. Indeed, enrollment in GCa group was closed due to poor accrual. As primary endpoint, aMVAC NAC achieved a 14% pCR rate (4/29 pts). A final pathological stage ≤ ypT1 in 62% of patients (18/29), a grade 3-4 toxicity rate of 23% (7/30 pts) with none grade 5 event, a median 1.4% renal function decrease following NAC and 40.8% after NAC plus surgery, were recorded as secondary outcomes in the aMVAC arm.

Margulis et al. must surely be complimented on their work and adding to the buddy of evidence supporting systemic chemotherapy administration in localized UTUC [1]. Responding to a need for knowledge, they structured a prospective trial and provided useful information. However, the research is limited by a small sample size. Authors chose pCR as primary outcome measure. Their approach is certainly interesting, although pCR may be questionable as surrogate endpoint of OS in the context of UTUC. Diagnosis of HG-UTUC was obtained indistinctly by biopsy or urine cytology with a mass on cross-sectional imaging or cytology with ureteroscopic mass visualization, as usually performed in daily practice. However, the limits of clinical staging for UTUC are well known, as are the difficulties of an accurate risk stratification. Considering the morbidity of chemotherapy, it may be legitimate to ask if a diagnostic approximation as close as possible to reality may be necessary to refer patients to NAC. Therefore, it can be discussed whether urine cytology added to imaging or endoscopic visualization could be adequate or whether a biopsy confirmation is needed. The reported results are noteworthy, even considering the sampling limits, but it remains to be clarified if 14% of ypT0N0 is enough. These and other considerations on the NAC feasibility for UTUC must necessarily find answers in the upcoming prospective trials.

Reference

[1] Margulis V, Puligandla M, Trabulsi EJ, Plimack ER, Kessler ER, Matin SF, et al. Phase II Trial of Neoadjuvant Systemic Chemotherapy Followed by Extirpative Surgery in Patients with High Grade Upper Tract Urothelial Carcinoma. J Urol 2019:101097JU0000000000000644. https://doi.org/10.1097/JU.0000000000000644.