Longitudinal GFR Trends after Neoadjuvant Chemotherapy Prior to Nephroureterectomy for Upper Tract Urothelial Carcinoma - Beyond the Abstract

In our recently published article in Urologic Oncology: Seminars and Original Investigations,1 we investigated longitudinal renal function outcomes in patients managed with neoadjuvant chemotherapy followed by radical nephroureterectomy (RNU) for upper tract urothelial carcinoma (UTUC). Neoadjuvant chemotherapy in this cohort was defined as receipt of ≥3 cycles of pre-operative systemic chemotherapy, and we stratified outcomes based on cisplatin- or non-cisplatin-based regimens.

In 152 patients managed with neoadjuvant chemotherapy prior to RNU, the mean GFR decline one-year post surgery was 22.3 ml/min/1.73 m2 (mean decline of 26.2 ml/min/1.73 m2 in patients who received cisplatin vs. 8.8 ml/min/1.73 m2 without cisplatin, P < 0.01). Notably, post-operative GFR nadired 3- months after surgery and remained stable in longitudinal follow-up for both the cisplatin and non-cisplatin cohorts. Thirty-four patients (22% of cohort) exhibited GFR improvement after neoadjuvant chemotherapy (prior to RNU) compared to pre-treatment baseline. We performed exploratory analysis on this cohort and identified an association between GFR improvement after chemotherapy with invasive final pathologic stage (P = 0.018) and worse overall survival (P = 0.049). We concluded that GFR changes in response to neoadjuvant chemotherapy and RNU are (1) chemotherapy regimen-dependent, (2) may be inversely associated with oncologic outcomes.

Current tools to select patients for neoadjuvant vs. adjuvant chemotherapy are quite rudimentary, with most relying simply on biopsy grade. To take this one step further, clinicians might make an estimation of post-nephroureterectomy performance status and renal function to predict whether a patient would be a candidate for risk-stratified adjuvant cisplatin-based therapy after RNU, an approach supported by Level 1 trial data.2 While there has been an abundance of recent clinical tools to predict renal function after extirpative surgery for renal cell carcinoma,3-5 few studies have evaluated post-nephroureterectomy GFR trends, and ours is the first to describe such trends in patients managed with neoadjuvant chemotherapy. Indeed, current efforts are underway to develop a nomogram to predict post-nephroureterectomy GFR which could guide decision making regarding the timing of systemic therapy.

In a second step, clinical risk stratification can be used to inform the use of a neoadjuvant approach in invasive or occult metastatic disease for the management of micrometastasis and primary tumor downstaging.6-8 It is estimated that clinical understaging occurs in up to 60% of UTUC patients,9 highlighting the importance of utilizing risk stratification to improve clinical staging accuracy. Our finding that GFR improvements after neoadjuvant chemotherapy are associated with more invasive disease on final pathology may potentially guide clinical decision-making such as intensification of systemic therapy in these patients. This association requires further investigation but could serve as a promising additional tool to dynamically adapt a treatment strategy after the initial clinical risk stratification.

Written by: Patrick J. Hensley, MD, Craig V. Labbate, MD, & Surena F. Matin, MD, Department of Urology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

References: 

  1. Labbate CV, Hensley PJ, Miest TS, Qiao W, Adibi M, Shah AY, et al. Longitudinal GFR trends after neoadjuvant chemotherapy prior to nephroureterectomy for upper tract urothelial carcinoma. Urol Oncol 2022:S1078-1439(22)00235-6. https://doi.org/10.1016/j.urolonc.2022.06.014.
  2. Birtle A, Johnson M, Chester J, Jones R, Dolling D, Bryan RT, et al. Adjuvant chemotherapy in upper tract urothelial carcinoma (the POUT trial): a phase 3, open-label, randomised controlled trial. Lancet 2020;395:1268–77. https://doi.org/10.1016/S0140-6736(20)30415-3.
  3. Aguilar Palacios D, Wilson B, Ascha M, Campbell RA, Song S, DeWitt-Foy ME, et al. New Baseline Renal Function after Radical or Partial Nephrectomy: A Simple and Accurate Predictive Model. J Urol 2021;205:1310–20. https://doi.org/10.1097/JU.0000000000001549.
  4. Rathi N, Yasuda Y, Palacios DA, Attawettayanon W, Li J, Bhindi B, et al. Split Renal Function Is Fundamentally Important for Predicting Functional Recovery After Radical Nephrectomy. Eur Urol Open Sci 2022;40:112–6. https://doi.org/10.1016/j.euros.2022.04.008.
  5. Ferraris F, Raman JD, Musso CG, Rozanec J. Measuring renal function before kidney surgery - evolving towards precision in medicine. Nat Rev Urol 2022;19:450–1. https://doi.org/10.1038/s41585-022-00613-1.
  6. Freifeld Y, Ghandour R, Singla N, Woldu S, Clinton T, Kulangara R, et al. Preoperative predictive model and nomogram for disease recurrence following radical nephroureterectomy for high grade upper tract urothelial carcinoma. Urol Oncol 2019;37:758–64. https://doi.org/10.1016/j.urolonc.2019.06.009.
  7. Foerster B, Abufaraj M, Matin SF, Azizi M, Gupta M, Li W-M, et al. Pretreatment Risk Stratification for Endoscopic Kidney-sparing Surgery in Upper Tract Urothelial Carcinoma: An International Collaborative Study. Eur Urol 2021;80:507–15. https://doi.org/10.1016/j.eururo.2021.05.004.
  8. Petros FG, Qiao W, Singla N, Clinton TN, Robyak H, Raman JD, et al. Preoperative multiplex nomogram for prediction of high-risk nonorgan-confined upper-tract urothelial carcinoma. Urol Oncol 2019;37:292.e1-292.e9. https://doi.org/10.1016/j.urolonc.2018.12.002.
  9. Mori K, Katayama S, Laukhtina E, Schuettfort VM, Pradere B, Quhal F, et al. Discordance Between Clinical and Pathological Staging and Grading in Upper Tract Urothelial Carcinoma. Clin Genitourin Cancer 2022;20:95.e1-95.e6. https://doi.org/10.1016/j.clgc.2021.10.002.

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