BCG for Upper Tract Urothelial Fiction: Reasonable Option or Waste of Time??

Upper tract urothelial cancer (UTUC) refers to cancer of the lining of the kidney (renal pelvis) and ureter.  More information about UTUC can be found in our previous blogs about the Relationship between Upper and Lower Urinary Tract Urothelial Cancer, Causes of UTUC and Chemotherapy for Patients with UTUC. Like urothelial cancers of the bladder, some UTUC can be treated topically with medications like BCG.  This blog will review BCG treatment for patients with UTUC.

Who is a good candidate for BCG treatment?

Similar to urothelial cancers in the bladder, patients with carcinoma in situ (cis) or small, solitary tumors that are completely resected are the best candidates for BCG therapy. Patients with large, bulky, or unresectable tumors are unlikely to benefit from BCG treatment -- as BCG functions to stave off or prevent cancer progression, but is unlikely to have tumors regress.  In addition, patients with positive cytology and no visible tumors, in one or both ureters/kidneys, are eligible for BCG.  In these patients, care should be taken to ensure that the positive cytology did not originate in the bladder and contaminate the upper tract urine sample.  

What is the timing and duration of BCG treatment for UTUC?

In general, patients should wait 2 to 4 weeks following endoscopic resection and for hematuria to resolve prior to initiating BCG treatment.  This will minimize the risk of systemic absorption and side effects from BCG.

Just like bladder treatments, BCG induction is given once per week, every week for six weeks.  Four to six weeks following the last treatment, the patient should undergo cystoscopic evaluation with upper tract evaluations (washings for cytology and/or ureteroscopy with biopsy).  BCG maintenance is an option for UTUC but has not been well studied.

BCG from above or below?

With an ureteral stent in place, fluid can
"reflux" from the bladder up to the kidney.

One of the biggest questions asked by patients and practitioners is how to best get the BCG to the kidney and ureter.  For BCG to work, it must come in contact with the urothelium.  Therefore, BCG must be delivered to the renal pelvis and be allowed to drain down the ureter and into the bladder.  Early studies relied on the placement of ureteral catheters to "stent open" the ureteral orifices and allow BCG given in the bladder to "reflux" up the ureters and into the kidney.  However a number of studies have demonstrated unreliable results with this technique.  In fact, one study using cystograms (contrast dye) to observe reflux in these patients, found that retrograde flow was only observed in 56% of patients and only when a large volume of fluid was instilled into the bladder, a volume larger than usually given in most BCG treatments.[1]

Therefore for reliable delivery of BCG to the upper tract, two methods are employed.

1. ureteral catheters placed through the bladder
2. percutaneous nephrostomy tubes placed through the flank.  

Both of these methods have pros and cons:

Ureteral Catheters

Pros: Does not require anesthesia or sedation for placement.  Stents are removed at the end of each treatment and there is no indwelling hardware.

Cons: Must be placed each week in clinic through a cystoscope.  This is often done without anesthesia, and while safe and well-tolerated, is not the most comfortable procedure to undergo every week for six weeks.    Occasionally fluoroscopy is required to ensure proper placement of the ureteral catheter.  Can be challenging to administer BCG through narrow ureteral stents, limiting the amount of medication that can be given per minute and making treatments longer.

Percutaneous Nephrostomy Tubes

A percutaneous nephrostomy tube is placed through the back, into the kidney,
to reliably instill BCG to the upper tract.

Pros: Can be placed in one setting under anesthesia.  Most reliable method of delivering BCG to the entire upper tract.  Can deliver the medication in a timely fashion (typically instilled over 1 hour).
Cons: Must be  kept in place for the full six weeks of duration and require daily care (flushing with normal saline to keep patent).  Can be uncomfortable, particularly at night if a back or side sleeper.  There is a small risk of tumor seeding (<1%), or growth of cancer along the nephrostomy tube tract.[2]

What are the outcomes for upper tract BCG?

The data regarding BCG for UTUC is heterogeneous in nature, usually involving small patient series with varying tumor types (cis and T1 tumors) and management strategies (stents and percutaneous nephrostomy tubes).  There are no randomized trials comparing BCG to no BCG, comparing management strategies or types of BCG given (some studies give BCG-interferon).  In addition, some patients elect for BCG treatment and other patients are relegated to BCG treatment as they cannot undergo more extensive surgical treatment.

For patients with cis, results from approximately 122 patients are reported in the medical literature.  The overall response rates for BCG treatment in these studies is 86% (ranging from 60-100% in studies) over a mean time period of 15-55 months.  However, response rates refers to "normalization" of urine cytology and 25% of initial responders will recur and 10% will develop metastatic cancer.[3]

For patients with visible tumors who undergo endoscopic resection followed by BCG treatment, the recurrence rate is slightly higher than for those with cis.  In 141 patients, the recurrence rate is approximately 33% (ranging from 11-85%).  Recurrence rates vary with primary tumor grade and are approximately 25% for low-grade tumors and 35% for high-grade cancers.[3]  In the only non-randomized, comparative study evaluating patients who underwent endoscopic resection and received BCG in comparison to those who did not receive BCG, there was no benefit for patients who had high-grade cancer and received BCG.[4]

Summary

• BCG treatment is an option for patients with UTUC who have:
• carcinoma in situ
• a small and/or solitary tumor that is able to be completely resected
• persistent positive cytology with no discernable lesion
• BCG can reliably be given through ureteral catheters or percutaneous nephrostomy tubes
• "reflux" through existing catheters is not a reliable method to deliver BCG
• Response rates vary based on the tumor being treated
• Approximately 85% of patients with cis will have a response to BCG
• 25% may recur, 10% will develop metastases
• Approximately 30% of patients with a resected tumor will recur
• the recurrence rate is higher for patients with high-grade tumors

[1] O. Yossepowitch, D. A. Lifshitz, Y. Dekel, et al., “Assessment of vesicoureteral reflux in patients with self-retaining ureteral stents: implications for upper urinary tract instillation,” The Journal of Urology, vol. 173, no. 3, pp. 890–893, 2005.
[2] Rastinehad AR, Smith AD.  Bacillus Calmette-Guérin for upper tract urothelial cancer: is there a role?  J Endourol. 2009 Apr;23(4):563-8. doi: 10.1089/end.2008.0164. Review.
[3] Ardeshir R. Rastinehad and Arthur D. Smith. Journal of Endourology. April 2009, 23(4): 563-568. doi:10.1089/end.2008.0164.
[4]  Jabbour ME, Smith AD. Primary percutaneous approach to upper urinary tract transitional cell carcinoma. Urol Clin North Am 2000;27:739–750.