BERKELEY, CA (UroToday.com) - Upper tract urothelial cancer (UTUC) accounts for roughly 5% of all urothelial cancers and at presentation, 30% of patients will demonstrate invasive and/or locally advanced disease, 30-40% have regional lymph node involvement, and 20% harbor metastatic disease.[1, 2] Following surgery, 45-60% of patients with advanced disease will experience systemic recurrence and disease progression. Five-year cancer specific survival (CSS) rates for patients with advanced UTUC range from 12.2%-74.7%. Due to poor oncologic outcomes associated with advanced disease, the treatment of UTUC requires a multi-modality approach, consisting of neoadjuvant and/or adjuvant chemotherapy and extirpative therapy. However, the use of chemotherapy has not been widely adopted or standardized. Not surprisingly, despite available advancements in the treatment of urothelial carcinoma, the rates of systemic recurrence and progression in patients with advanced UTUC have not improved over the past 3 decades.
Improved oncological outcomes in patients with UTUC should be leveraged through better risk stratification accuracy. Diagnosis and staging of UTUC is usually achieved through a combination of cross-sectional tomographic imaging, upper tract endoscopy, urine cytology, and tumor biopsy. Several limitations exist that hamper accurate risk assessment. Notable limitations include poor sensitivity of urine cytology, technical difficulties of obtaining accurate biopsy specimens, and limited accuracy of clinical stage assessment.[5, 6] However, recent technical advancements such as new generation endoscopic tools, enhanced cross-sectional imaging protocols, biomarkers, and multi-variable predictive models may allow for enhanced risk-assessment and, ultimately, personalized treatment strategies.[7, 8, 9]
Urothelial tumors are chemosensitive to platinum-based regimens as evidenced by studies demonstrating tangible complete and partial tumor response rates and improved survival in patients with urothelial malignancy.[10, 11] Yet, due to the paucity of randomized trials in UTUC, the efficacy of different chemotherapeutic regimens in UTUC is extrapolated from bladder cancer and retrospective UTUC series.[12, 13] Additionally, one must also consider timing of chemotherapy. A minimum eGFR of 50-60 mL/minute/1.73m2 is required to safely tolerate cisplatin-based chemotherapy. Several studies have shown a 25-52% and 65-78% incidence of CKD before and after RNU, respectively, which contributes to a decreased eligibility to receive cisplatinbased chemotherapy in the adjuvant setting.[14, 15]
Administration of neoadjuvant and adjuvant chemotherapy both carry their own theoretical advantages. As opposed to neoadjuvant chemotherapy, administration of adjuvant therapy allows for chemotherapeutic regimens and administration based on risk features of the final tissue specimen. The theoretical advantages of neoadjuvant chemotherapy include the eradication of subclinical metastatic disease prior to surgical extirpation, improved patient tolerability prior to surgical extirpation, and the ability to deliver higher chemotherapy doses.
However, the role and efficacy of adjuvant chemotherapy in the treatment of UTUC is still largely based on small, single-center studies and retrospective multi-institutional cohorts. Several authors have shown a lack of significant survival benefit in patients receiving adjuvant therapy.[16, 17] However, in the only prospective study to date, Bamias, et al. evaluated the efficacy of adjuvant systemic chemotherapy in UTUC. The authors showed 5-year DFS and OS were 40.2% and 52%, respectively, but was limited by a lack of comparison cohort.
Evidence for the use of neoadjuvant chemotherapy in UTUC is derived from studies in bladder cancer patients. Patients who received neoadjuvant therapy had a 5 % absolute improvement in CSS compared to patients treated with cystectomy alone. In patients with UTUC, retrospective studies have shown that the use of neoadjuvant therapy has been associated with pathological downstaging. Matin, et al.’s retrospective review of 150 patients who underwent treatment of biopsy-proven high-grade UTUC disease, the overall incidence of pT2 or higher disease was significantly lower in the neoadjuvant group compared to the control patients (46.5% vs. 65%; p=.043). Other authors have reported improved oncologic outcomes in patients with advanced disease treated with pre-surgical systemic chemotherapy. In a multicenter UTUC collaboration, Youssef, et al. described the effects of neoadjuvant chemotherapy in patients with node-positive disease. Significant improvement in 5-year CSS of 44% versus 36% was seen in patients treated with neoadjuvant chemotherapy and RNU, versus patients treated with RNU only, respectively.
Challenges associated with thoughtful implementation of the neoadjuvant paradigm center around difficulties with patient selection and delay of definitive local therapy. Although there are no established and validated patient selection criteria, typically, neoadjuvant therapy is reserved for patients with high-grade invasive urothelial cancer, with or without additional adverse pathologic features, such as sessile architecture, lympho-vascular invasion, and infiltrative component on cross-sectional imaging.[19, 21]
As we enhance our understanding of the biology of UTUC, the ultimate strategy should be centered on improvement of oncological outcomes and decrease of treatment morbidity. These goals can be achieved through enhanced patient risk stratification, utilization of nephron-sparing approaches in appropriately selected patients, and thoughtful integration of multi-modal therapies in patients deemed to be at high risk of disease relapse.
- Raman JD, Messer J, Sielatycki JA, Hollenbeak CS. Incidence and survival of patients with carcinoma of the ureter and renal pelvis in the USA, 1973-2005. BJU Int. 2011 Apr;107(7):1059-64.
- Margulis V, Shariat SF, Matin SF, et al. Outcomes of radical nephroureterectomy: a series from the Upper Tract Urothelial Carcinoma Collaboration. Cancer. 2009 Mar 15;115(6):1224-33.
- Ozsahin M, Zouhair A, Villa S, et al. Prognostic factors in urothelial renal pelvis and ureter tumours: a multicentre Rare Cancer Network study. Eur J Cancer. 1999 May;35(5):738-43.
- Adibi M, Youssef R, Shariat SF, et al. Oncological outcomes after radical nephroureterectomy for upper tract urothelial carcinoma: comparison over the three decades. International Journal of Urology: Official journal of the Japanese Urological Association. 2012 Dec;19(12):1060-6.
- Chen GL, El-Gabry EA, Bagley DH. Surveillance of upper urinary tract transitional cell carcinoma: the role of ureteroscopy, retrograde pyelography, cytology and urinalysis. J Urol. 2000 Dec;164(6):1901-4.
- Smith AK, Stephenson AJ, Lane BR, et al. Inadequacy of biopsy for diagnosis of upper tract urothelial carcinoma: implications for conservative management. Urology. 2011 Jul;78(1):82-6.
- Matin SF, Kamat AM, Grossman HB. High-frequency endoluminal ultrasonography as an aid to the staging of upper tract urothelial carcinoma: imaging findings and pathologic correlation. J Ultrasound Med. 2010 Sep;29(9):1277-84.
- Brien JC, Shariat SF, Herman MP, et al. Preoperative hydronephrosis, ureteroscopic biopsy grade and urinary cytology can improve prediction of advanced upper tract urothelial carcinoma. J Urol. 2010 Jul;184(1):69-73.
- Margulis V, Youssef RF, Karakiewicz PI, et al. Preoperative multivariable prognostic model for prediction of nonorgan confined urothelial carcinoma of the upper urinary tract. J Urol. 2010 Aug;184(2):453-8.
- Grossman HB, Natale RB, Tangen CM, et al. Neoadjuvant chemotherapy plus cystectomy compared with cystectomy alone for locally advanced bladder cancer. N Engl J Med. 2003 Aug 28;349(9):859-66.
- Neoadjuvant chemotherapy in invasive bladder cancer: update of a systematic review and meta-analysis of individual patient data advanced bladder cancer (ABC) meta-analysis collaboration. Eur Urol. 2005 Aug;48(2):202-5; discussion 5-6.
- Roupret M, Zigeuner R, Palou J, et al. European guidelines for the diagnosis and management of upper urinary tract urothelial cell carcinomas: 2011 update. Eur Urol. (Consensus Development Conference). 2011 Apr;59(4):584-94.
- Audenet F, Yates DR, Cussenot O, Roupret M. The role of chemotherapy in the treatment of urothelial cell carcinoma of the upper urinary tract (UUT-UCC). Urologic Oncology. 2010 Sep 28.
- Lane BR, Smith AK, Larson BT, et al. Chronic kidney disease after nephroureterectomy for upper tract urothelial carcinoma and implications for the administration of perioperative chemotherapy. Cancer. 2010 Jun 15;116(12):2967-73.
- Huang WC, Levey AS, Serio AM, et al. Chronic kidney disease after nephrectomy in patients with renal cortical tumours: a retrospective cohort study. Lancet Oncol. 2006 Sep;7(9):735-40.
- Hellenthal NJ, Shariat SF, Margulis V, et al. Adjuvant chemotherapy for high risk upper tract urothelial carcinoma: results from the Upper Tract Urothelial Carcinoma Collaboration. J Urol. 2009 Sep;182(3):900-6.
- Vassilakopoulou M, de la Motte Rouge T, Colin P, et al. Outcomes after adjuvant chemotherapy in the treatment of high-risk urothelial carcinoma of the upper urinary tract (UUT-UC): results from a large multicenter collaborative study. Cancer. 2011 Dec 15;117(24):5500-8.
- Bamias A, Deliveliotis C, Fountzilas G, et al. Adjuvant chemotherapy with paclitaxel and carboplatin in patients with advanced carcinoma of the upper urinary tract: a study by the Hellenic Cooperative Oncology Group. J Clin Oncol. 2004 Jun 1;22(11):2150-4.
- Matin SF, Margulis V, Kamat A, et al. Incidence of downstaging and complete remission after neoadjuvant chemotherapy for high-risk upper tract transitional cell carcinoma. Cancer. 2010 Jul 1;116(13):3127-34.
- Youssef RF, Shariat SF, Lotan Y, et al. Upper urinary tract urothelial carcinoma with loco-regional nodal metastases: insights from the Upper Tract Urothelial Carcinoma Collaboration. BJU Int. 2011 Oct;108(8):1286-91.
- Sternberg CN, Donat SM, Bellmunt J, et al. Chemotherapy for bladder cancer: treatment guidelines for neoadjuvant chemotherapy, bladder preservation, adjuvant chemotherapy, and metastatic cancer. Urology. 2007 Jan;69(1 Suppl):62-79.
Bishoy A. Gayed, MD, Gregory Thoreson, MD, and Vitaly Margulis, MD as part of Beyond the Abstract on UroToday.com. This initiative offers a method of publishing for the professional urology community. Authors are given an opportunity to expand on the circumstances, limitations etc... of their research by referencing the published abstract.
University of Texas Southwestern Medical Center, Dallas, TX, USA