# Review of Topical Treatment of Upper Tract Urothelial Carcinoma

Authors: Kenneth G. Nepple; Fadi N. Joudi; Michael A. O'Donnell
Journal: Advances in Urology
 (2009)

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## Abstract

A select group of patients with upper tract urothelial carcinoma may be appropriate candidates for minimally invasive management. Organ-preserving endoscopic procedures may be appropriate for patients with an inability to tolerate major surgery, solitary kidney, bilateral disease, poor renal function, small tumor burden, low-grade disease, or carcinoma in situ.  We review the published literature on the use of topical treatment for upper tract urothelial carcinoma and provide our approach to treatment in the office setting.


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## Body

## 1. Introduction

Nephroureterectomy
with open excision of bladder cuff remains the standard of care for
organ-confined upper tract urothelial cancer in patients with a normal
contralateral kidney. Laparoscopic surgery has broadened the population of
patients who are able to tolerate this surgery; however, due to concerns for
preservation of renal function or inability to tolerate surgery, a selected
group of patients may be suitable candidates for less-invasive management with
endoscopic approach. Organ-preserving
endoscopic procedures may be appropriate for patients with a solitary kidney,
bilateral disease, poor renal function, or inability to tolerate major surgery [1, 2]. In addition, the indications
for minimally invasive therapy have evolved to include small tumor burden,
low-grade disease, or carcinoma in situ in patients with normal contralateral renal
function [3]. Patients with high-grade disease, multifocal
tumors, or history of recurrent tumor are not ideal candidates for topical
therapy because of risk of recurrent or progressive disease. Patients
managed with less invasive treatment must be made aware of the concern for
progressive or recurrent disease. In addition, patients must be compliant with
both the treatment regimen and the required subsequent follow-up.The role of
intravesical immunotherapy in non-muscle-invasive urothelial cancer of the
bladder has been firmly established [4, 5]. A variety of agents have been utilized (Table 1), with BCG showing
the greatest efficacy [4]. In the treatment of upper tract urothelial
carcinoma, instillation of topical immunotherapy has been used as primary or
adjuvant treatment, but upper tract treatment can be problematic because agents
must be delivered to the renal pelvis and ureter to be effective. A challenge
to the practicing urologist is finding a way to implement this treatment in the
busy office setting. We review the published literature on topical treatment of
upper tract urothelial cancer, and provide our approach to treatment in the
office setting.Table 1
Mechanism of immunotherapy agents.
BCGInflammatory host responseRelease of cytokinesInterferonLymphocyte activationCytokine releasePhagocyte stimulationAntiproliferative actionsAntiangiogenicThiotepaAlkylating agentCrosslinks nucleic acidsMitomycin CInhibits DNA synthesisGemcitabineDeoxyctidine analogInhibits DNA synthesis


## 2. Upper Tract Evaluation

Patients must be properly selected for topical upper tract treatment. Upper tract
abnormalities are often identified as a filling defect on delayed images of a
CT urogram or IVP done for hematuria work-up or during selective upper tract
washings for a positive bladder cytology in the absence of any bladder
pathology. Our operative evaluation for positive cytology includes evaluation
of both the bladder and upper tract for source of positive cytology. Initially,
a rigid cystoscope is introduced and the bladder is inspected. The bladder is
drained and a bladder wash with normal saline is obtained for cytology by
rinsing the bladder several times. Cytology from the first kidney is obtained
using normal saline washes through a 5 french open-ended ureteral catheter. To
reduce the chance of bladder contamination, positive pressure saline is infused
through the catheter up until the point in which it is introduced into the
ureter The catheter is advanced up into the renal pelvis (~25 cm) and two 5–7 cc
saline washes are obtained followed by additional washes at 20, 15, and 10 cm.
The catheter is then readvanced up into the renal pelvis where the remaining
fluid is aspirated and pooled together with the other washes. A retrograde
pyelogram is then performed from the renal pelvis downwards as the catheter is
removed. The same procedure is then performed on the contralateral upper tract.
It should be noted that special care must be taken to avoid contamination of
specimens by using different ureteral catheters for each side. If any
abnormality is seen on retrograde pyelogram, then the upper tract should be
evaluated with ureteroscopy with subsequent upper tract wash, brush biopsy, or
tissue biopsy as deemed appropriate. The bladder should be inspected and five
random bladder biopsies taken in a stellate manner (trigone, base, dome, and
both lateral side walls). An essential
component of a complete evaluation is to obtain a separately labeled biopsy
from the prostatic urethra, which can serve as a sanctuary site for urothelial
carcinoma.Patients treated with topical infusion therapy typically have either carcinoma in situ
or lesions that have been resected endoscopically. A mass in the collecting
system or ureter identified on retrograde pyelogram or CT urogram prompts a
focused operative evaluation. Small lesions may be amenable to endoscopic
treatment (ureteroscopic or percutaneous) as discussed elsewhere in this
special issue. It is highly unlikely that topical treatment by itself would
eradicate radiographically visible disease. After primary treatment or the
presence of hematuria, BCG treatment should be delayed 2 to 4 weeks to allow
the urothelium to heal and decrease the likelihood of systemic side effects. Of
note, in patients with positive cytology from both the bladder and upper tract
with no mass lesion, the status of the upper tract should be considered
inconclusive. In these cases, we generally start with intravesical treatment as
the positive upper tract cytology could be due to contamination from the
bladder. Restaging after intravesical therapy is prudent to reevaluate the
upper tracts. If the bladder is disease-free and the upper tract cytology
continues to be positive, then this rules out the possibility of contamination
and should be treated accordingly.


## 3. Office-based Approach for Upper Tract Treatment

We use an office-based approach for placement of ureteral catheter(s) for upper tract
therapy. Flexible cystoscopy is performed, sometimes with oral
narcotic/benzodiazapine premedication or intravenous sedation (morphine,
versed) based on patient preference. The ureteral orifice is visualized and
cannulated with a 0.018 inch angled glidewire that is passed to the renal
pelvis. A 4 F whistle-tip catheter is then passed over the glidewire (Figure1). Under direct vision, the catheter is slid over the wire into the ureter and
a second ureteral catheter with the tip cut off is used as a pusher to further
advance the catheter. Using the catheter markings as a guide, the catheter is
typically advanced to 25 cm to place it in the renal pelvis. The flexible scope is then carefully backed
out leaving the catheter in the mid renal pelvis. The guidewire is subsequently
removed once proper positioning is established. It is very helpful to use
fluoroscopy, at least for the first session, to establish proper catheter
position and rule out unexpected anatomical difficulties. Free flow of urine
from the catheter or retrograde injection of contrast verifies proper position
in the collecting system. Ureteral catheters are secured via silk ties to a
foley catheter placed to drain the bladder and brought to rest at the bladder
neck (Figure 2). The Foley catheter is either left to straight drainage or
elevated over the bedrail to allow some collection into the bladder depending
on whether simultaneous bladder exposure is desired. It may also be capped
during treatment if formal intravesical instillation is performed at the same
time. This particular technique of using a small caliber ureteral catheter over
a small slippery wire is usually very atraumatic and allows free fluid flow
around and out the splinted ureter. If trauma or bleeding is encountered, then
treatment may need to be deferred in the case of BCG. In patients who have
previously undergone cystectomy with urinary diversion, treatment is usually
performed with percutaneous nephrostomy tube as retrograde access to the ureter
is difficult.Figure 1Figure 2We use a treatment regimen of low-dose BCG (one-third to one-tenth standard dose) plus
interferon-alpha-2b (50–100 million units) in 50 cc normal saline based on the
effectiveness of this combination in non-muscle-invasive bladder cancer [5]. The viscosity of the full-dose
BCG suspension is such that it will not spontaneously drip under gravity
instillation through such a small 4 french catheter. The patient is positioned
supine. The medication is suspended in an IV bag no more than 30 cm above the
kidney level. Medication is instilled via microdrip tubing at the rate of 1
drop per 2 seconds, corresponding to a rate of approximately 30 cc/h.
Medication is only instilled via gravity and should never be placed on a pump
due to concern for increased intrarenal pressure. At the conclusion of
treatment, the foley catheter is drained and then removed, bringing the
attached ureteral catheters out with it. If treatments are not able to be
administered via ureteral catheters, then a percutaneous nephrostomy tube can
be placed at the beginning of treatment and medicine can be instilled via
nephrostomy tube, with the tube capped between weekly treatments.Patients receive weekly treatment for 6 sessions over 6 weeks. Then, 6 weeks following the last treatment, patients are restaged with
bilateral upper tract washings and retrograde pyelograms, bladder washing, and
random bladder biopsies along with prostatic urethral biopsy. If the results
are negative, consideration is given to 3 future maintenance treatments
starting 6 weeks later. While there have been no published results on the
efficacy of maintenance treatment, the addition of 3 weekly maintenance treatments is well established
for bladder CIS [6].


## 4. Literature Review

The true benefit of topical therapy, either as a primary
treatment for carcinoma in situ or as an adjuvant for endoscopically treated
tumors, is difficult to assess based on the variance in the reported
literature. In contrast to bladder cancer, which is relatively common, upper
tract urothelial cancer is uncommon and, therefore, a single center is not able
to accrue significant numbers of patients for a prospective study.
Additionally, heterogeneous groups of patients receive such therapy (solitary
versus multifocal disease, primary versus recurrent, low- versus high-grade).
Retrospective case reviews can also have methodological flaws. The goal is to
maximize the effectiveness of treatment while minimizing side effects and
complications. Multiple different treatment regimens have been utilized with
BCG being used most commonly (Table2). No randomized studies have been
performed to evaluate such therapy, and most studies have set the number of
instillations empirically based on expert opinion or extrapolating from
intravesical treatment regimens.Table 2
Topical therapy of upper tract urothelial cancer.
StudyIndicationNo. patients/no. renal unitsTherapyMean follow-up, monthsCommentsJarret et al. 199519Adjuvant to percutaneous treatment17 patients/19 renal unitsBCG55No significant improvement in survival with BCGElliott et al. 199618Adjuvant to endoscopy18 patientsBCG, thiotepa, MMCNANo difference in outcome between treated and untreatedYokogi et al. 19967CIS5 patients/8 renal unitsBCG10–46NED in 5/8 renal unitsMartinez-Pineiro et al. 199617Adjuvant to endoscopy26 patientsBCG, MMC, thiotepa3112.5% recurrence with BCG, 14% with MMC, 60% with thiotepaKeeley and Bagley, 19971Adjuvant to ureteroscopy19 patients/21 renal unitsMMC3035% complete response, 27% partial response, 38% no responsePatel and Fuchs, 199812Adjuvant to ureteroscopy13 patients/17 renal unitsBCG15NED in 15/17 renal unitsNishino et al. 20008CIS6 patients/8 renal unitsBCG22NED in 8/8 renal unitsNonomura et al. 20009CIS11 patientsBCGNANED in 7/11 patientsBurns et al. 200114CIS, adjuvant to endoscopy15 patients/23 renal unitsBCG-IFN1570% response rateThalmann et al. 200213Not eligible for open surgery37 patients/41 renal unitsBCG4287% recurred or progressed; 32% CIS were disease-freeMiyake et al. 200211CIS15 patients/16 renal unitsBCG30NED in 14/16 renal unitsPalou et al. 200420Adjuvant to percutaneous treatment19 patientsBCG in 14, MMC in 55160% recurrence in treated patients vs 27% in untreated patientsKatz et al. 200716CIS, adjuvant to endoscopy10 patients/11 renal unitsBCG-IFN2480% complete response, 20% partial response*BCG - bacillus Calmette-Guerin; MMC - mitomycin C; CIS - carcinoma in situ; IFN - interferon; NED - no evidence of disease; NA - not applicable.


## 5. BCG

In 1996, Yokogi et al. analyzed therapeutic outcomes of BCG perfusion therapy for upper
urinary tract CIS in 8 renal units—5 through a
percutaneous nephrostomy tube and 3 through a retrograde ureteral catheter [7]. Follow-up cystoscopy,
retrograde pyelography, and selective urinary cytology were obtained 4 weeks
after the last treatment and every 3 months thereafter. In 5 of 8 renal units,
the cytology remained negative for 10 to 46 months after treatment, while the
other 3 renal units had persistently positive cytology. Of 2 patients treated
through a ureteral catheter, 1 developed a ureteral stricture and the other
developed renal tuberculosis, which emphasizes that urologists must be mindful
of the development of complications.In contrast, Nishino et al. used BCG perfusion treatment (instilled weekly for 4
or 8 weeks) to treat upper tract CIS via retrograde catheterization with either
a 6 French ureteral catheter or an 8 French indwelling double J ureteral stent [8]. At a mean follow-up of 22
months (range 9–38 months), all 8
renal units had negative cytology, and cytology became negative after 1 or 2
instillations of BCG. However, 1 patient had recurrent CIS in the prostatic
urethra treated with intravesical BCG instillation. Complications included
ureteral stenosis in 2 patients and self-limited irritative symptoms occurred
in all patients.An indwelling ureteral stent was used to treat 11 patients with upper tract CIS as reported
by Nonomura et al. in 2000 [9]. Reflux up the ureteral stent
was confirmed using contrast at the time of initial ureteral stent placement.
BCG was instilled into the bladder weekly, 6 times in total as 1 course. At the
end of 1 course, 9 cases showed negative urinary cytology; however, 2 patients
had recurrence in the upper urinary tract after 4 and 8 months, and repeat BCG
therapy was not effective. Two patients never normalized their cytology. The
mean recurrence-free time was 19.6 months. As side effects, 8 cases (72.7%)
developed bladder symptoms, and 4 presented with fever higher than 38°C, but
the authors reported that no patient needed antitubercular treatment.The efficacy of retrograde flow to the upper tract via an indwelling double J
ureteral stent has been questioned. Yossepowitch et al. used performed
cystograms with an indwelling stent in place and reported that retrograde flow
occurred in only 56% of patients. Additionally, the mean minimal intravesical
volume to obtain reflux was 170 mL, which is higher than the typically
instilled treatment volume [10].Miyake et al. evaluated the efficacy of intrarenal BCG instillation for the treatment of
CIS of the upper urinary tract [11]. Sixteen patients (17 renal
units) were treated with BCG administered once weekly, 6 times in total using
percutaneous nephrostomy tube in 5 patients, and a retrograde ureteral catheter
in 11. During the median follow-up period of 30 months (range 9–90 months), 13
patients (14 renal units) remained cytologically negative. However, 1 of these
13 patients had CIS in the bladder and prostatic urethra 34 months after the
BCG therapy and underwent radical cystectomy. Bladder irritability and fever
higher than 38°C was observed in 12 and 9 patients, respectively; however, no
patient received antitubercular treatment.In the adjuvant setting after ureteroscopic tumor ablation, Patel and Fuchs in 1998
reported on the use of topical BCG therapy (indwelling stent and intravesical
BCG in 3 renal units, and ureteral catheter instillation passed through a
suprapubic stab incision in 14 which allowed the avoidance of weekly
cystoscopy) [12]. At a mean follow-up of 15
months, 15 of 17 renal units were preserved and remained tumor-free. Patients
in this series were followed with regular flexible ureteroscopy along with
cytology washings in the clinic using topical anesthesia. The authors
attributed the favorable outcome in preserving renal units to improved
resections made possible by the development of small caliber ureteroscopes,
improved optics, and new ablative energy sources such as the holmium:YAG laser.In one of the largest series of topical upper tract treatment, Thalmann et al. (2002)
retrospectively evaluated the results of BCG therapy for upper urinary tract
disease in patients not eligible for nephroureterectomy [13]. Thirty-seven patients (22
with CIS, 15 with Ta or higher after endoscopic resection) were treated with 6
weekly perfusions of BCG via a 10 French nephrostomy tube. At a median
follow-up of 42 months (range 8–137 months), 14
patients (38%) died of urothelial cancer, 11 (29%) of other causes, and 12
(33%) were alive. Other adverse outcomes included severe septicemia in 2
patients. There was no seeding of the nephrostomy tube tract and dialysis was
avoided. Overall median survival was 42
months (range 1–137 months) with median recurrence-free survival of 21 months (range 1–137 months). The authors noted that this was a patient
population with a poor prognosis and while BCG extended survival for some patients, it did not
provide cure except for some patients with CIS. Of the patients treated in the
adjuvant setting for papillary disease, only 13% remained without recurrent or
progressive disease with a median time of recurrence of 10 months. In contrast,
treatment of CIS resulted in 32% of renal units remaining disease-free for a
median follow-up of 51 months.


## 6. BCG Plus Interferon

The data regarding supplemental interferon is not firmly established, validated, or
widely used for bladder cancer and certainly not for upper tract transitional
cell carcinoma. However, there have been two reports of its use in treating
upper tract urothelial carcinoma. We have reported on 15 patients (23 renal
units) with upper tract urothelial cancer after endoscopic resection who
received 6 weekly adjuvant low-dose BCG (one-tenth standard dose) and
interferon-α (100 million units) [14, 15]. Nineteen of the renal units had CIS, 2 had Ta
grade 1, one had Ta grade 3, and one had T1 grade 3. Sixteen were treated with
ureteral catheters while seven were treated with percutaneous nephrostomy
tubes. At a mean follow-up of 15.3 months (range 3–44 months), the
response rate was 70% (16 of 23 renal units). The highest response rate was in
patients with CIS (14 of 19; 74%). One patient had BCG sepsis that required 6
months of antitubercular therapy.In 2007, Katz et al. published their initial experience with upper tract BCG-IFN [16]. A series of 10 patients (11
renal units) received 6 weekly courses of BCG (half strength) plus IFN-α2b (50 million units) via ureteral catheter.
With a median follow-up of 24 months, 80% demonstrated a complete response,
while 20% had a partial response (decrease in tumor size, number, or both). The
authors reported that
the treatment was well tolerated in the office setting and did not note any
complications.


## 7. Other Agents

Less information is available on the use of mitomycin C topical treatment. In 1997,
Keeley and Bagley reported on adjuvant mitomycin C (40 mg in 3 divided doses
via ureteral catheter) in 19 patients (21 renal units) for high volume,
recurrent, or multifocal urothelial carcinoma [1]. No systemic side effects
occurred during or after treatment with mitomycin C which was attributed to the
high molecular weight of mitomycin and limited systemic absorption. Thirty-five
percent had a complete response, 27% had a partial response (reduction in tumor
size > 50%), and 38% had no response. Tumors with a complete response were of
similar size and grade as those that did not respond as well. With a mean
follow-up of 30 months, none of the patients suffered local disease progression
or died of disease; however, nearly all of the patients required repeat
ureteroscopic treatment for residual or recurrent disease.Due to confounding variables and heterogeneous treatment groups, direct comparisons
between treatment groups in a study can be difficult. One study in 1996 from
Martínez-Piñeiro et al. reported on a series of upper tract carcinoma in which
26 patients received adjuvant supplemental topical therapy, and attempted to
make comparisons between different treatments [17]. BCG and mitomycin C seemed
to be most effective at preventing recurrences, with recurrence rates of 12.5%
and 14.2%, respectively, compared to 60% for thiotepa. Fatal aplastic anemia
from systemic absorption of MMC was reported in 1 patient. In 1996, Elliott et
al. reported the Mayo Clinic experience with endoscopic treatment of upper
tract urothelial carcinoma in which 18 of 44 patients received some form of
topical therapy (BCG in 9, MMC in 5, thiotepa in 4) [18]. Their methods did not report
mode of delivery. In their sample, a difference was not found in recurrence
between those who did and did not receive adjuvant topical therapy. Similarly,
Jarrett et al. reported that BCG therapy showed no significant improvement in
survival in 19 of 30 renal units [19].Similarly, comparisons between treatment and nontreatment groups may be complicated by
selection bias. In 2004, Palou et al. presented results of the percutaneous
approach to resection of upper urinary tract urothelial carcinoma in which 14
and 5 patients received BCG and MMC instillations, respectively [20]. Median time to recurrence
was 24 months and the rate of kidney preservation was 74%. The authors reported
a recurrence rate of 58% in those who received topical therapy compared to 27%
in those who did not; however, the topical therapy group was higher risk with
higher grade disease and comprised more patients with multiple tumors. There
was a trend of recurrence in patients with multifocal tumors, history of
bladder carcinoma in situ, and tumor in renal pelvis. The authors concluded
that the percutaneous approach to renal urothelial tumor should be considered a
valid option with a good long-term outcome; however, there was an obligation to
a long-lasting, strict surveillance.An alternative experimental treatment regimen in refractory patients is sequential
gemcitabine and mitomycin C. Medication dosage is 1 gm gemcitabine in 50 cc phosphate-buffered
normal saline, then 40 mg mitomycin C in 40 cc sterile water. The gemcitabine
is instilled followed by the mitomycin immediately afterward. We reported in
2006 on a group of patients with treatment refractory non-muscle-invasive
bladder cancer (8 of 37 had upper tract involvement [21]. Gemcitabine alone was
effective in only 1 of 14 patients (7%) while sequential treatment with
gemcitabine followed by mitomycin was successful in 13 of 23 patients (57%).
The rationale for sequential treatment is that gemcitabine is too acidic and
affects mitomycin activity if given together. Additionally, gemcitabine
primarily kills cells undergoing DNA synthesis (S-phase) while mitomycin is non-cell
phase-specific and leads to cell cycle arrest. Gemcitabine is given first
followed by mitomycin to maximize therapeutic efficacy.


## 8. Conclusions

Without large
prospective or randomized data, the topical treatment of upper tract urothelial
cancer is to some extent anecdotal. Topical treatment of upper tract urothelial
cancer has a role in selected patients, who must be committed to close
follow-up because of the risk of recurrence and more concerning progression.
The goal of treatment is to provide noninvasive, nephron-sparing treatment
without compromising oncologic outcomes. Treatment can be successfully
performed in the setting of a busy urologist's office. Further study is needed
to identify the best candidates for this treatment approach and to determine which
agents and schedule are most optimal. Our office-based approach to upper tract
urothelial carcinoma provides the clinician with the framework to implement
this treatment in practice.



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