Upper Tract Urothelial Cancer Chemotherapy: When? For Whom?

Urothelial cancer refers to cancer of the lining of the urinary tract and was previously known as transitional cell carcinoma.  Urothelial cancers can occur in the bladder or the upper tract of the urinary system which includes the lining of the kidney (otherwise known as the renal pelvis) and the ureter.  Biologically, upper tract urothelial cancers (UTUC) are similar to urothelial cancers of bladder.  However, they have several important distinctions:

• UTUC is rare, accounting for only 5% of all urothelial cancers. [1]
• UTUC are more difficult to visualize and treat endoscopically.
• UTUC are morphologically similar to bladder cancers but have different embryologic origins and genetic characteristics.  
• Like urothelial cancer of the bladder, stage (i.e. depth of invasion) is the most important predictor of prognosis.  However, unlike the bladder, grade is highly correlated to stage:
• 91% of high-grade tumors in the renal pelvis are invasive
• 64% of high-grade tumors in the ureter are invasive [2] 
• Prognosis is different for UTUC compared to urothelial cancer of the bladder.
• Upwards of 19% of patients with UTUC present with metastases.[3]
• However, in matched cohorts with less aggressive disease, progression and death occurred with equal frequency among patients with UTUC and bladder cancers.[4] 
• The role of neoadjuvant and adjuvant chemotherapy is not well-established in UTUC (see below).

The last important distinction is that chemotherapy is almost considered "standard-of-care" either before or after removal of the bladder in certain circumstances.  Adjuvant chemotherapy (AC or chemotherapy immediately after surgery without any evidence of metastases) has an established niche for patients with adverse pathological features at the time of radical cystectomy for urothelial cancer of the bladder.
Similarly, neoadjuvant chemotherapy (NAC or chemotherapy before surgery) has a growing role in the treatment of muscle-invasive urothelial cancer of the bladder (please see prior blog entry Neoadjuvant Chemotherapy for Bladder Cancer: What Does It All Mean?). 

The role of NAC prior to nephroureterectomy (NU or removal of the kidney and ureter) or AC following surgery is less well-understood.  The lack of data supporting the use of either NAC or AC is based mostly on the poor overall survival rate for patients with high-grade and high-stage UTUC regardless of treatment and the subsequent lack of overall response rate to chemotherapy.  

However, there are a number of reasons that chemotherapy surrounding surgery makes sense.  First, patients with locally advanced disease experience a 50% or greater risk of progression and less than a 2-year median survival duration.[5-8]  Therefore surgery alone is not curative and the addition of a systemic therapy may improve cancer outcomes.   

Here we review the limited data regarding AC and NAC in the treatment of UTUC.

Adjuvant Chemotherapy (AC) Following Nephroureterectomy (NU)

A recent, systematic review of AC following NU examined one prospective study and nine retrospective studies (no randomized trials were available) comparing 482 patients receiving AC after NU and 1300 patients undergoing NU alone.  This analysis demonstrated a 50% reduction in disease recurrence and 60% reduction in overall death in favor of those patients receiving AC.[9]  Importantly, this was a heterogeneous group of patients with pT2-4, node-negative and node-positive disease; and all patients receiving AC had adequate renal function.         

Neoadjuvant Chemotherapy (NAC) Prior to Nephroureterectomy (NU)

There are a number of specific reasons why NAC before NU makes sense:

• NAC works for the bladder.
• Survival is improved 5-10% with chemotherapy before surgical removal of the bladder.
• UTUC is biologically similar to urothelial cancer of the bladder.
• NAC effectively down-stages urothelial cancer (discussed below)
• Many patients who undergo NU are not eligible for chemotherapy after surgery because they are older and/or have baseline chronic kidney disease.
• The best chemotherapies for urothelial cancer are filtered by the kidneys.
• Reduced filtering ability of the kidneys can cause:
• decreased efficacy of chemotherapy
• increased toxicities including worsening renal function

In two retrospective series of patients receiving NAC compared to historical patients undergoing NU alone, there was a significant proportion of down staging in the NAC group with a 14% complete response rate.[10]  The follow-up study demonstrated a 90% cancer-specific survival rate at 5-years compared to 57% in the NU alone group.[11]  A meta-analysis of NAC data demonstrated a disease-specific survival improvement of nearly 60% for NAC in retrospective studies; and favorable pathologic downstaging rates and survival rates upwards of 90% in two, prospective phase 2 NAC trials.[9]

Summary

Chemotherapy should play a role in the treatment of UTUC, should be considered in the time period surrounding NU and should be discussed as an option with patients.

  

Adjuvant Chemotherapy (AC) can improve cancer-recurrence rates and overall survival.  AC should be considered following NU in patients with:

• adequate renal function
• high-risk pathological features (pT3 or pT4, N1 or positive surgical margins)

Neoadjuvant Chemotherapy (NAC) effectively downstages tumors and may improve survival in limited studies.  NAC should be considered prior to NU in patients:

• invasive high-grade UTUC
• high-volume, high-grade UTUC with clinical suspicion of invasive disease
• baseline renal dysfunction that may preclude chemotherapy following surgery

More data and well-designed prospective studies are needed to define the exact role and benefits of AC and NAC in UTUC.

This entry was written by Phillip M. Pierorazio, MD, Assistant Professor of Urology and Oncology at the Brady Urological Institute at Johns Hopkins.

[1] Melamed MR, Reuter VE: Pathology and staging of urothelial tumors of the kidney and ureter. Urol Clin North Am 1993; 20: 333

[2] McCarron JP Jr, Mills C, Vaughn ED Jr. Tumors of the renal pelvis and ureter: current concepts and management. Semin Urol 1983;1:75–81.

[3] Akaza H, Koiso K, Niijima T,et al: Clinical evaluation of urothelial tumors of the renal pelvis and ureter based on a new classification system. Cancer 1970; 26: 58

[4] Catto JW, Yates DR, Rehman AR,et al: Behavior of urothelial carcinoma with respect to anatomic location. J Urol 2007; 177: 1715-1720

[5] Brown GA, Busby JE, Wood CG, et al. Nephroureterectomy for treating upper urinary tract transitional cell carcinoma: time to change the treatment paradigm? BJU Int. 2006; 98: 1176-1180.

[6] Hall MC, Womack S, Sagalowsky AI, Carmody T, Erickstad MD, Roehrborn CG. Prognostic factors, recurrence, and survival in transitional cell carcinoma of the upper urinary tract: a 30-year experience in 252 patients. Urology. 1998; 52: 594-601.

[7] Lehmann J, Suttmann H, Kovac I, et al. Transitional cell carcinoma of the ureter: prognostic factors influencing progression and survival. Eur Urol. 2007; 51: 1281-1288.

[8] 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; 35: 738-743.

[9] Jeffrey J. Leow, William Martin-Doyle, André P. Fay, Toni K. Choueiri, Steven L. Chang, Joaquim Bellmunt, A Systematic Review and Meta-analysis of Adjuvant and Neoadjuvant Chemotherapy for Upper Tract Urothelial Carcinoma, European Urology, Available online 16 March 2014, ISSN 0302-2838, http://dx.doi.org/10.1016/j.eururo.2014.03.003.

[10] S.F. Matin, V. Margulis, A. Kamat et al.  Incidence of downstaging and complete remission after neoadjuvant chemotherapy for high-risk upper tract transitional cell carcinoma.  Cancer, 116 (2010), pp. 3127–3134

[11] S. Porten, A. Siefker-Radtke, A. Kamat, C. Dinney, S. Matin.  Survival outcomes in patients undergoing neoadjuvant chemotherapy for upper tract urothelial cell carcinoma [abstract].  J Clin Oncol (Suppl 6) (2013), p. 311