Abstract
Purpose:
Patients undergoing endoscopic management for upper tract urothelial carcinoma often progress to definitive therapy with radical nephroureterectomy. This study examined the rate of progression as well as risk factors for transitions in treatment over time.
Methods:
Retrospective review at 2 institutions identified patients undergoing endoscopic management for upper tract urothelial carcinoma. Patients were assessed for progression to radical nephroureterectomy. Baseline characteristics were compared using Chi-Square analysis. Kaplan Meier method analyzed the probability of patients not progressing to radical nephroureterectomy. Cox proportional hazards identified factors associated with progression to radical nephroureterectomy.
Results:
Eighty-one patients had endoscopic management alone, and 89 progressed to radical nephroureterectomy. The two groups had similar age, histories of bladder cancer, and Charlson Comorbidity Index. Positive urinary cytology, ureteroscopic visualization, and biopsy grade were higher in those progressing to RNU (p<0.001). Hazard modeling demonstrated higher rates of progression to radical nephroureterectomy with positive biopsy (HR 11.8, 95% CI 2.4–59.5, p=0.003) or visible lesion on ureteroscopy (HR 8.4, 95% CI 3.0–23.9, p<0.001). Patients with a higher Charlson Comorbidity Index were less likely to have radical nephroureterectomy. On Kaplan Meier modeling, the probability of not undergoing radical nephroureterectomy at 2 years and 5 years were 50% and 20%, respectively.
Conclusions:
Patients who progress to radical nephroureterectomy after endoscopic management have fewer comorbid conditions and changes in disease status including visible lesions on ureteroscopy and positive biopsies. The high rate of progression to radical nephroureterectomy reinforces the need for long-term follow up these patients.
Keywords: disease progression, endoscopy, ureteral neoplasms, urothelial carcinoma
Introduction
Upper tract urothelial carcinoma (UTUC) is a devastating disease with late-stage presentation, high recurrence rate, and high cancer-specific mortality rates. At the time of diagnosis, 60% of UTUC is invasive, which is more than twice that of urothelial carcinoma found in the lower tract [1,2]. Patients diagnosed with UTUC have an overall 5-year survival of only 57% [3]. Based on the European Association of Urology (EAU) guidelines, the gold standard for treatment of UTUC is radical nephroureterectomy (RNU), but in a recent update of these guidelines, the panel advocated for nephron-sparing surgery for appropriately selected low-risk cases of UTUC [4]. Prior studies discussed less invasive techniques, such as segmental ureterectomy or endoscopic management (EM) with ablative techniques, in patients with functional or anatomic indications, such as chronic renal insufficiency, bilateral disease, and solitary kidneys [4,2]. More recently, the use of these less invasive techniques has been expanded to patients without the above indications and performed on a more elective basis [5].
The advantages of preserving renal functional units in selected patients comes from the renal cell carcinoma literature showing implications of chronic kidney disease and the potential decrease in long-term cardiovascular events [6–9]. Elective endoscopic management has been performed successfully in patients with low-grade noninvasive UTUC with no reports of a significant difference in overall survival and cancer-specific survival when compared to those undergoing definitive therapy with RNU [10,11]. Recurrence rates with EM have been reported at 48% to 60%, and ultimate failure rates (defined as upstaging or progressive disease) as high as 24% [12]. The follow-up after EM for UTUC is crucial since disease progression or recurrence may necessitate more definitive gold-standard therapy.
With EM becoming a more accepted option for UTUC and now included in EAU guidelines, it is imperative to understand the rate of progression from EM to RNU and the risk factors that may contribute to this change in therapy. The objective of this study was to determine these rates of change in treatment and influencing factors for this change in treatment decision at 2 large tertiary referral centers.
Materials and Methods
Identification of Patient Cohort & Data Collection
After receiving Institutional Review Board approval, we retrospectively assessed data at two large tertiary referral centers (Memorial Sloan Kettering Cancer Center and Washington University Medical Center) to identify patients who underwent at least 2 instances of endoscopy for UTUC between 2000 and 2014. Patients were initially identified using CPT codes for antegrade and retrograde ureteroscopy and/or pyeloscopy and ICD-9 codes for hydronephrosis, abnormal urine findings, and neoplasm in the bladder, ureter, or kidney. This list was further pared down using chart review to include only those who underwent multiple instances of EM for pathologically confirmed UTUC. Patients were included to have had endoscopic nephron-sparing treatment if they had at least 2 endoscopies at least 3 months apart. The electronic medical records were assessed for demographics, endoscopic and surgical interventions for UTUC, biopsy and cytology results, and other medical problems for calculation of Charlson Comorbidity Index (CCI) and history of bladder cancer.
Statistical analysis
Patients were stratified by those who only underwent EM (EM group) and those who were managed initially with EM and then subsequently underwent RNU (RNU group). Characteristics between the EM group and the RNU group were compared using Chi-Square. The Kaplan-Meier method was used to analyze the probability of UTUC patients who underwent EM to progress to RNU. Cox proportional hazards identified risk factors associated with progression to RNU.
Results
One hundred seventy patients were identified from the 2 institutions: 81 in the EM group and 89 in the RNU group. Mean and median follow-up times were 32.7 and 24.8 months for the EM group, compared with 57.3 and 41.5 months for the RNU group, respectively. The two groups were similar for age, BMI, CCI, and history of bladder cancer. The groups differed on biopsy grade, rates of positive urine cytology, and rates of endoscopic visualization of tumor (p < 0.001). Complete demographics are included in Table 1. Cox proportional hazard modeling is shown in Table 2: positive endoscopic biopsy (HR 11.8 for high grade vs. negative, p = 0.003) and visible lesion on endoscopy (HR 8.4, 95% CI 3.0–23.9, p < 0.001) were predictors for progression to RNU, and CCI was a negative predictor for progression (HR 0.2 for CCI of 3 or greater vs. 0, p = 0.001). Kaplan-Meier analysis, depicted in Figure 1, predicts that patients on EM have progressively higher rates of RNU over time. The extrapolated rates of progression to RNU at 2 years and 5 years were 50% and 80%, respectively.
Table 1.
Patient Characteristics
| Variable | EM Group (81) | RNU Group (89) | p-value |
|---|---|---|---|
| Follow-Up (months) | |||
| Median | 24.8 | 41.5 | |
| Mean | 32.7 | 57.3 | <0.001 |
| St. Dev | 33.4 | 43.5 | |
| Age (years) | |||
| Mean | 72 | 69.3 | 0.078 |
| St. Dev | 11.4 | 9.1 | |
| BMI | |||
| Mean | 28.5 | 28.2 | 0.892 |
| St. Dev | 5.9 | 4.5 | |
| History of Bladder Cancer | |||
| No | 38.3% | 32.6% | 0.438 |
| Yes | 61.7% | 67.4% | |
| Biopsy Grade | |||
| Negative | 12.3% | 2.2% | <0.001 |
| Low Grade | 8.6% | 12.4% | |
| High Grade | 9.9% | 34.8% | |
| Not Done/Unknown | 69.1% | 50.6% | |
| Cytology | |||
| Negative | 46.9% | 13.5% | <0.001 |
| Positive | 27.2% | 52.8% | |
| Not Done/Unknown | 25.9% | 33.7% | |
| CCI | |||
| CCI=0 | 11.1% | 9.0% | 0.141 |
| CCI=1 | 2.5% | 7.9% | |
| CCI=2 | 29.6% | 18.0% | |
| CCI>=3 | 56.8% | 65.2% | |
| URS Visualization | |||
| No | 42.3% | 7.1% | <0.001 |
| Yes | 57.7% | 93.9% |
Table 2.
Cox proportional hazard modeling for risk of progression to RNU
| 95% Confidence Interval | ||||
|---|---|---|---|---|
| Variable | Hazard Ratio | Lower | Upper | p-value |
| URS Positive vs. Negative | 8.4 | 3.0 | 23.9 | <0.001 |
| BX: High Grade vs. Negative | 11.8 | 2.4 | 59.5 | 0.003 |
| BX: Low Grade vs. Negative | 10.2 | 1.9 | 54.7 | 0.007 |
| BX: Not Done/Unknown vs. Negative | 8.2 | 1.6 | 42.8 | 0.013 |
| Cytology: Not Done/Unknown vs. Negative | 1.2 | 0.5 | 2.9 | 0.627 |
| Cytology: Positive vs. Negative | 1.7 | 0.7 | 3.8 | 0.226 |
| Age | 1.0 | 1.0 | 1.0 | 0.211 |
| BMI | 1.0 | 0.9 | 1.0 | 0.137 |
| CCI=1 vs. CCI=0 | 0.3 | 0.1 | 0.9 | 0.036 |
| CCI=2 vs. CCI=0 | 0.2 | 0.1 | 0.7 | 0.006 |
| CCI>=3 vs. CCI=0 | 0.2 | 0.1 | 0.5 | 0.001 |
| Bladder Cancer | 0.7 | 0.4 | 1.3 | 0.261 |
Fig. 1.
Kaplan Meier probability of not progressing to RNU after EM for UTUC. The dashed lines correspond to 95% confidence intervals
Discussion
This study evaluated a large comprehensive cohort of UTUC patients who underwent EM to determine rates of progression to RNU and risk factors that may contribute to progression. We found positive endoscopic biopsy and visible lesion on endoscopy to be positive predictors of progression and higher CCI to be a negative predictor of progression. The Kaplan-Meier curve predicted increasing rates of progression over time with 80% of patients progressing to RNU at 5 years. This data suggests that few patients on EM were cured of UTUC. Rather, patients had recurrence and progression of their disease similar to those undergoing transurethral resection for bladder tumors.
About 20 prior retrospective series assessing EM for UTUC report delayed RNU rates of 0–30%. These series have varying lengths of follow-up, and many selected for favorable tumor characteristics [13]. For instance, Elliott et al. evaluated 44 cases of UTUC over 5 years. Of the 44, the authors selected 20 patients for EM based on tumor size less than 2 cm and perceived ability to completely resect tumor burden by urography and endoscopic appearance. Of the 20 EM patients, 3 (15%) underwent RNU: at 0 months for high-grade disease, at 6 months for high-grade recurrence, and at 24 months for visualized local recurrence [14]. Another large series, Suh et al., attempted EM on all patients in their cohort. EM was successful in 35/61; of these, 8 elected for RNU, and 1 died of unrelated illness. The remaining 26 patients were surveilled with ureteroscopy every 3 months with a mean follow-up of 15.8 months. Seven patients (27%) eventually required RNU for multifocal or high-grade disease [15].
Compared to prior studies, our data had longer follow-up time and included all patients who underwent EM, rather than only those with smaller or lower-grade tumors. These factors may explain our higher rates of progression to RNU. With only 20% of patients sustaining EM at 5 years, follow-up for endoscopically managed UTUC is extremely important. Given the rarity of UTUC and relatively new adoption of EM, there is a paucity of guidelines on surveillance after EM. The EAU has published grade C recommendations including: 1) urine cytology and CT urography at 3 and 6 months and then annually, and 2) endoscopy and selective cytology at 3 months, 6 months, every 6 months over the following 2 years, and then annually [4]. As follow-up for EM requires a high level of compliance, one could argue that initial RNU should be considered in all patients with unilateral disease and normal kidney function.
There are a few important limitations to this study. The small sample size prevented us from assessing which diagnostic and therapeutic interventions may have decreased progression to RNU. In addition, the retrospective nature of our work prevented us from controlling for factors, such as indication for progression to RNU. Despite its shortcomings, this study evaluates endoscopically managed UTUC patients from 2 high-volume tertiary referral centers over a mean of 5 years.
Conclusions
Those patients that progress to RNU after EM have fewer comorbid conditions at baseline and changes in disease status including visible lesions on ureteroscopy and positive biopsies. Kaplan-Meier analysis predicted that 80% of patients would progress to RNU by 5 years after initial EM. This reinforces the underlying need for long-term follow-up of disease status in those having EM for UTUC.
Acknowledgements
Funding was provided in part by the Sidney Kimmel Center for Prostate and Urologic Disease
Financial support: K08DK097302-01A1, UL1 TR000448, R24 HS19455, KM1CA156708, P30 CA008748, Sidney Kimmel Center for Prostate and Urologic Disease
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