Prognostic Factors for Long-Term Survival in Patients with Renal-Cell Carcinoma After Radiofrequency Ablation

Abstract

Purpose:

To assess the long-term survival and prognostic factors in patients with renal-cell carcinoma (RCC) who were treated with radiofrequency ablation (RFA).

Patients and Methods:

A retrospective review of the records of all patients who underwent RFA of biopsy-proven RCC from February 2006 to December 2010 was performed in our institution. Univariate and multivariate analyses were used to evaluate the prognostic factors for long-term survival after RFA.

Results:

RFA was performed in 122 patients (102 men, 20 women) with preoperative imaging available. Mean patient age was 58.5 years (standard deviation [SD]: 14.5), and mean tumor size was 3.4 cm (SD: 1.1). Tumor stage was T_1a 93 (76.2%) or T_1b 29 (23.8%). The mean follow-up period for RFA was 64.9 months (±11.6) (range 9–83 mos). In total, 5-year cancer-specific survival, 5-year disease-free survival (DFS), 5-year recurrence-free survival (RFS), 5-year metastasis-free survival, and 5-year overall survival (OS) of this cohort was 98.3%, 90.8%, 94.2%, 99.2%, and 98.4%, respectively. In comparison with patients in >3 cm group, patients in ≤3 cm group had better 5-year DFS (P = 0.009), 5-year OS (P = 0.036) and 5-year RFS (P = 0.011). Age and tumor size affected survival rates significantly at univariate analysis (P = 0.031, P = 0.033). Only tumor size was shown to have independent prognostic value in multivariate analysis (P = 0.034).

Conclusion:

In appropriately selected patients, RFA is an effective treatment option that provides comparable long-term survival. With use of RFA, there is a high probability of long-term survival of patients with small tumor size.

Introduction

The increasing use of cross-sectional imaging has contributed to a rise in the incident detection of small renal masses (SRMs). Surgical resection in the form of radical nephrectomy (RN) used to be the gold standard treatment for patients with clinically small localized tumors. Recently, nephron-sparing surgery (NSS) has replaced the ‘‘gold standard’’ of RN in patients whose renal tumors can be completely removed. More and more researchers have reported their results that partial nephrectomy (PN) can achieve comparable oncologic outcomes and preserve renal function better compared with RN in patients with stage T₁ renal cell carcinoma (RCC).^1,2

Open PN as well as laparoscopic PN, however, is associated with significant morbidity.³ Because of the potential morbidity caused by extirpative surgery, ablative therapy such as cryoablation and radiofrequency ablation (RFA) has been widely advocated as a treatment option of minimally invasive and renal function-preserving therapy in selective candidates. The current American Urological Association guidelines have recommended RFA as an option for patients with T₁ disease.⁴

Over the past decade, RFA has been increasingly accepted as an alternative method for the nephron-sparing treatment of stage T_1a RCC, and RFA can provide durable oncologic and functional outcomes for selected T_1a renal tumors.⁵ Recently, more and more researchers have extended the indications of RFA from tumors no larger than 4 cm to tumors larger than 4 cm. Takaki and associates⁶ reported their monocentric results that RFA could provide comparable RCC-related and disease-free survival (DFS) and preserving renal function to RN in stage T_1b RCC. Although many studies have shown that RFA is a safe, feasible, nephron-sparing, and effective treatment modality for RCC, long-term oncologic and functional outcomes are limited in most of the available studies.

To our knowledge, several reports on prognostic factors influencing long-term survival rates with RFA of RCC have been published to date; however, consensus concerning the prognostic factors is controversial.^7,8 The purpose of our study was to assess the long-term survival afforded by RFA of biopsy-proven RCC and determine prognostic factors in patients with RCC who were treated with RFA.

Patients and Methods

Institutional Review Board approval was obtained to review retrospectively the consecutive records of patients who underwent RFA laparoscopically or percutaneously for a single renal tumor between February 2006 and December 2010 at our hospital. Only those patients with histologically confirmed RCC and a minimum radiographic follow-up of 5 years after treatment were included in our present study. Those patients who had synchronous bilateral, multiple ipsilateral tumors, or distant metastases were excluded. Patients with a history of hereditary RCC syndromes or a familial history of RCC were also excluded from our study cohort.

R.E.N.A.L. (radius; exophytic/endophytic; nearness; anterior/posterior; location) score was calculated according to the described protocol for the system by two independent urology residents with rich experience in nephrometry scoring.⁹ The accuracy was confirmed by a senior urologist. Each observer was blinded to the results of the other observers' assessments. The low-, moderate-, and high-complexity groups were scored 4∼6, 7∼9, and 10∼12 for R.E.N.A.L. system, respectively.

Techniques for laparoscopic RFA¹⁰ and percutaneous RFA¹¹ have been described in our former studies. All patients underwent a tumor biopsy (TruCore, 22G; Medical Device Technologies, Gainesville, FL) before RFA, and the cool-tip system (Radionics, Burlington, MA) was used. The surgical approach was determined by the surgeon based on tumor location. Posterior tumors were selectively managed percutaneously or laparoscopically, while those anterior tumors located near adjacent organs or bowel were typically treated laparoscopically.

Based on the manufacturer's recommendations, RFA was performed for a cycle of 12 minutes for tumors <4 cm and two-cycle ablation for tumors ≥4 cm. Extra cycles were given if incomplete ablation was judged by the surgeon on visual inspection or with the help of contrast-enhanced ultrasonography (Fig.1). In our institution, all patients were followed up with contrast-enhanced imaging to evaluate the ablated tumors. Contrast-enhanced CT was performed at 7 days, 1 month, 3 months, 6 months, every 6 months until 3 years after the RFA procedure and every year thereafter. Patients who had renal insufficiency or contrast agent allergy received MRI with gadolinium enhancement.

FIG. 1.

Laparoscopic radiofrequency ablation (RFA) was applied in a 36-year-old man with a 3.3 cm tumor in the upper pole of the right kidney. (A) Enhancement was found in the tumor's location by contrast-enhanced ultrasonography after initial RFA; (B) no enhancement was shown in the suspicious area after a second round of RFA was administered.

Successful ablation was defined as the lesion showing less than 10 Hounsfield units (HU) of contrast medium enhancement on CT or no qualitative evidence of enhancement on enhanced MRI.¹² Persistent evidence of enhancement (10–15 HU) in the ablation lesion on the first-month postoperative imaging study was defined as incomplete ablation.⁸ Any new enhancement (>10 HU) within the ablation lesion after a previously confirmed complete response was defined as tumor recurrence.¹³ Estimated glomerular filtration rate (eGFR) was calculated using the modified Modification of Diet in Renal Disease equation (MDRD).¹⁴ Preoperative eGFR was compared with early eGFR (lowest measured eGFR 7–100 days postoperatively) and late eGFR (latest eGFR of last follow-up period).

Univariate analyses were conducted using independent samples t tests for continuous variables and chi-square tests for categorical variables. The preoperative GFR, early GFR after treatment, and late GFR at the last follow-up were compared within the patient group by using the paired and Student t tests. The overall survival (OS), cancer-specific survival (CSS), recurrence-free survival (RFS), metastasis-free survival (MFS), and DFS were respectively defined as the proportion of patients who did not die from any cause, the proportion of patients who did not die from any cancer including RCC, the proportion of patients free from local recurrence, the proportion of patients free from metastatic recurrence, and the proportion of patients free from local recurrence or metastatic recurrence. Mortality data were captured from the national mortality registry.

Univariate and multivariate regression analyses were performed to determine predictors of survival. All statistical analyses were conducted by using IBM SPSS vol. 19.0 (Chicago, IL) with a P value < 0.05 considered statistically significant.

Results

A total of 122 patients were included in our study cohort. Table 1 reports the baseline demographics and tumor characteristics.

Table 1.

Patient Demographics and Tumor Characteristics

Variables
Patients (n)	122
<65 y	73 (59.8%)
≥65 y	49 (40.2%)
Mean age (y) (SD)	58.5 (±14.5)
Mean kg/m² body mass index (SD)	25.6 (±1.8)
<25	44 (36.1%)
≥25, <30	76 (62.3%)
≥30	2 (1.6%)
Sex (n, %)
Male	102 (83.6%)
Female	20 (16.4%)
Performance score (ECOG)
0	107 (87.7%)
1	11 (9.0%)
2	4 (3.3%)
ASA score
Mean (SD)	2.0 (±0.8)
range	1–3
Side (n, %)
Left	52 (42.6%)
Right	70 (57.4%)
Tumor location (n, %)
Anterior	44 (36.1%)
Posterior	78 (63.9%)
Tumor stage (n, %)
T_1a	93 (76.2%)
T_1b	29 (23.8%)
R.E.N.A.L. score (SD)	8.0 (±1.0)
Low complexity (n, %)	14 (11.5%)
Intermediate complexity (n, %)	93 (76.2%)
High complexity (n, %)	15 (12.3%)
Biopsy data (n, %)
Clear renal-cell carcinoma	113 (92.6%)
Chromophobe carcinoma	7 (5.7%)
Papillary carcinoma	2 (1.7%)
Preoperative tumor size, cm (SD)	3.4 (±1.1)
≤3cm	56 (45.9%)
>3cm	66 (54.1%)
Surgical approach (n, %)
Percutaneous	20 (16.4%)
Laparoscopic	102 (83.6%)
Estimated blood loss (mL) (SD)	84.9 (±59.3)
Operative time (min) (SD)	140.0 (±26.1)
Mean hospital stay (d) (SD)	7.8 (±1.5)
GFR-MDRD(mL/min/1.73 m²) (SD)
Pretreatment GFR	92.7 (±28.4)
Early GFR	81.7 (±28.3)
Late GFR	81.6 (±34.2)
Follow-up (mos) (SD)	64.9 (±11.6)

SD = standard deviation; ECOG = Eastern Cooperative Oncology Group; ASA = American Society of Anesthesiologists; R.E.N.A.L. = radius; exophytic/endophytic; nearness; anterior/posterior; location; GFR = glomerular filtration rate; MDRD = Modification of Diet in Renal Disease.

Table 2A shows the detail information of oncologic outcomes after RFA, and Table 2B details the oncologic outcomes stratified by tumor size with a cutoff of 3 cm. Overall, six (4.9%) patients had incomplete ablation on the first-month postoperative imaging study (four tumors were larger than 3 cm), resulting in the rate of primary ablation success at 97.5% (119/122). Four of them underwent percutaneous RFA for the initial treatment and were subsequently successfully re-ablated for one cycle with laparoscopic technique to remain disease-free until now. The other two patients refused to receive a second RFA with a routine imaging follow-up.

Table 2A.

Oncologic Outcomes

Variable
Incomplete ablation (n, %)	6 (4.9%)
Local recurrence (n, %)	7 (5.7%)
Time to local recurrence (mos) (median, range)	18 (12–30)
Metachronous renal tumors (n, %)	3 (2.5%)
Time to diagnosis of new tumors (mos) (median, range)	21 (12–24)
Extrarenal metastases (n, %)	1 (0.8%)
Time to diagnosis of new metastases (mos)	42

Table 2B.

Oncologic Outcomes Stratified by Tumor Size (3 cm Cutoff)

	All patients (n, %)	≤3 cm (n, %)	>3 cm (n, %)	P value
Total (n)	122 (100%)	56 (45.9%)	66 (54.1%)	-
Incomplete ablation	6 (4.9%)	2 (3.6%)	4 (6.1%)	0.831
Local recurrence	7 (5.7%)	0	7 (10.6%)	0.017
Metachronous renal tumors	3 (2.5%)	1 (1.8%)	2 (3.0%)	1.000
Extrarenal metastases	1 (0.8%)	0	1 (1.5%)	1.000
Disease-free survival	111 (91.0%)	55 (98.2%)	56 (84.8%)	0.008
Cancer specific mortality	2 (1.6%)	0	2 (3.0%)	0.495
All-cause mortality	5 (4.1%)	0	5 (7.6%)	0.064
5-y recurrence-free survival	94.2%	100%	89.0%	0.011
5-y metastasis-free survival	99.2%	100%	98.4%	0.346
5-y cancer-specific survival	98.3%	100%	96.8%	0.181
5-y disease-free survival	90.8%	98.2%	84.3%	0.009
5-y overall survival	98.4%	100%	92.4%	0.036

Bold text indicates statistically significant values.

Seven (5.7%) patients had local recurrence with a median time to recurrence of 18 months (range 12–30 mos), all of whom had tumors larger than 3 cm. Of patients in whom local recurrence developed, six patients underwent salvage RFA with a complete response and remain without evidence of recurrence after the salvage surgery. The remaining patient chose to watch and wait without further disease progression for 48 months.

Metachronous renal tumors occurred in lesions remote from the previous ablation area in one (1.8%) patient with ≤3 cm RCC and two (3.0%) patients with >3 cm RCC; median time to diagnosis of new tumors was 21 months (range 12–24 mos). Patients with two contralateral new renal tumors that were confirmed to be RCC underwent RFA and remain disease free until now. One patient with ipsilateral new RCC received radical nephrectomy for the tumor's nearness to the sinus and remains disease free at 64 months until now.

In the >3 cm group, there was one (1.5%) patient with a diagnosis of extrarenal metastases with a time to diagnosis of 42 months. The patient with a solitary confirmed liver metastasis lesion underwent salvage RFA, and he is alive for 22 months after the procedure. In total, 5-year CSS, 5-year DFS, 5-year RFS, 5-year MFS, and 5-year OS of this cohort was 98.3%, 90.8%, 94.2%, 99.2%, and 98.4%, respectively. In comparison with patients in the >3 cm group, patients in the ≤3 cm group had better 5-year DFS (98.2% vs 84.3%, P = 0.009), 5-year OS (100% vs 92.4%, P = 0.036), and 5-year RFS (100% vs 89.0%, P = 0.011). There was no significant difference, however, of 5-year MFS (100% vs 98.4%, P = 0.346) and CSS (100% vs 96.8%, P = 0.181) between ≤3 cm group and >3 cm group.

Univariate and multivariate regression analyses demonstrated that sex, American Society of Anesthesiologists (ASA) score, Eastern Cooperative Oncology Group, body mass index, tumor stage, tumor side, tumor location, R.E.N.A.L. score, tumor complexity, surgical approach and pathology could not predict DFS significantly (Table 3). Age and tumor size predicted DFS significantly in univariate regression analysis (P = 0.031, P = 0.033). Only tumor size (≤3 cm/>3 cm) was a significant prognostic predictor for DFS at multivariate regression analysis (P = 034).

Table 3.

Univariate and Multivariate Analyses of Prognostic Factors for Disease–Free Survival

	Univariate analyses			Multivariate analyses
Variables	HR	95% CI	P value	HR	95% CI	P value
Sex (male/female)	1.111	0.222–5.555	NS	0.695	0.085–5.682	NS
Age (<65 y, ≥65 y)	4.571	1.150–18.178	0.031	0.994	0.075–13.243	NS
ASA	0.412	0.114–1.686	NS	0.546	0.142–1.872	NS
ECOG	1.521	0.518–4.666	NS	0.535	0.123–2.334	NS
BMI	0.653	0.196–2.172	NS	0.937	0.201–4.377	NS
Tumor size (≤3 cm, >3 cm)	9.655	1.196–77.918	0.033	10.397	1.287–125.178	0.034
Tumor stage (T_1a/T_1b)	3.125	0.878–11.121	NS	1.099	0.141–8.568	NS
Tumor side	0.873	0.252–3.027	NS	0.871	0.154–4.933	NS
Tumor location	1.542	0.443–5.368	NS	1.019	0.340–3.051	NS
R.E.N.A.L. score	1.123	0.649–1.943	NS	1.331	0.184–9.640	NS
Tumor complexity	1.478	0.411–5.321	NS	0.724	0.049–10.755	NS
Surgical approach	0.831	0.156–4.641	NS	1.112	0.131–9.413	NS
Pathology	1.910	0.493–7.410	NS	1.423	0.307–6.602	NS

HR = hazard ratio; CI = confidence interval; NS = not significant; BMI = body mass index.

Bold text indicates statistically significant values.

Discussion

Surgical excision is the gold standard for clinical T₁ RCC, and PN is an accepted standard for localized T₁ RCC for the sake of nephron sparing. Ablative therapy has been widely used in patients who are poor surgical candidates, and local oncologic control is considerable. RFA is becoming increasingly applied in the management of SRM in selected patients. Recent data suggest that RFA has excellent oncologic outcomes, with a 95% 5-year DFS for patients with tumors of <3 cm.⁷ Although many researchers believe that treatment success of RFA in the SRM is strongly correlated with tumor size, increasing studies apply RFA in treating patients with large renal tumors (T_1b or larger) and achieve similar oncologic outcome.⁶

To date, studies with sufficient long-term follow-up to assess the efficacy of RFA in managing RCC are limited. Our current study detailed our experience of 122 patients with biopsy-proven RCC undergoing RFA to evaluate survival-related issues. Our focus was to analyze the prognostic factors of various clinicopathologic parameters regarding long-term survival, with the aim of clarifying which group of patients is most likely to benefit from RFA.

In the previous selective series, Psutka and colleagues⁸ reported a 5-year RFS of 95.2%, 5-year DFS of 88.6%, and 5-year CSS of 99.4% for cT₁ RCC after RFA. The 5-year CSS, 5-year DFS, 5-year RFS, 5-year MFS, and 5-year OS of this cohort was 98.3%, 90.8%, 94.2%, 99.2%, and 98.4%, respectively. Our long-term outcomes are favorable and comparable to the outcomes of existing studies.

Larger tumors have an increased likelihood of incomplete ablation. Tumor enhancement disappeared in only 45.0% of tumors after a single RFA,¹⁵ and local recurrence developed in 50% of tumors treated with RFA¹⁶ when RFA was performed in tumors larger than 4 cm. There were four patients with tumors larger than 3 cm who had incomplete ablation in our present study; however, the number was obviously smaller than that reported in the literature.

No significant difference of incomplete ablation rates was found between ≤3 cm RCC and >3 cm RCC in our cohort (P = 0.831). In our series, intraoperative contrast-enhanced ultrasonography (CEUS) was used to monitor the damage; the incomplete ablation rate was relatively low after the initial RF session. Thus, we can extend the indications of RFA from ≤3 cm RCC to >3 cm RCC even larger tumors with the help of effective monitoring techniques (CEUS is not available in some areas; it can be replaced by real-time thermometry¹⁷).

In the present study, two variables (age and tumor size) were found to be important risk factors that affected survival rates at univariate analysis. Only tumor size was shown to have independent prognostic value at multivariable analysis. Tumor size is a significant predictor of oncologic outcomes in patients who underwent RFA.⁷ Oncologic outcomes stratified by tumor size with a cutoff of 3 cm from our study showed that patients with ≤3 cm RCC had better 5-year DFS, 5-year OS, and 5-year RFS (P = 0.009, P = 0.036, P = 0.011, respectively) compared with those with >3 cm RCC.

Tumor stage with a cutoff of 4 cm used to be a common tool in evaluating the efficacy of RFA, and studies indicated that higher stage correlated with a decreased disease-free survival⁸; however, numbers of patients with T_1b RCC in such studies were rather smaller than those of T_1a RCC, which would influence the reliability of results. When adopting a cutoff of 3 cm, the patient numbers had a much better balance between each group in our cohort, and we believe that the results from our study are more reliable. More and more studies reported that size cutoff of 3 cm could provide good efficacy in predicting the prognosis of patients undergoing RFA.^7,18,19 It is very safe to conclude that RFA in the ≤3 cm RCC group can obtain good local oncologic control and achieve a considerable survival rate. Further larger sample studies are needed to validate our results in the future.

When compared with that of PN, the ages were much older and the ASA score was significantly higher in patients who underwent RFA. Univariate regression analysis from our data revealed that ages predicted DFS significantly. Poor preoperative ASA score has been reported to increase mortality not related to RCC after surgery.²⁰ In our present cohort, three relatively older patients died of cerebrovascular accident or cardiovascular accident, and only two patients died of RCC. Thus, a safe conclusion can be drawn that the long-term oncologic efficacy of RFA will be evaluated more accurately by excluding the above-mentioned risk factors. The excellent 5-year survival outcomes suggest that indications of RFA should be extended to younger and healthier patients who desire minimally invasive therapy selectively.

There is no doubt that several limitations were involved in our present study. First, a retrospective design and obvious selection bias existed in our study. A randomized controlled trial could be ideal and may be realized in the future. Second, the sample size of our study was relatively small. A larger number of patients might yield more power to observe smaller effect sizes. In addition, all the operations were performed by a well-trained urologist (Dr. Hongqian Guo) in our center, so the results may not be widely applicable.

Conclusion

Results of this study confirmed the long-term effectiveness of RFA for patients with RCC. Tumor size was identified as a significant independent prognostic factor in patients with RCC who were treated with RFA. There is a significantly higher probability of long-term survival for patients with smaller tumor size.

Footnotes

Author Disclosure Statement

This work was supported by Jiangsu Graduate Student Innovation Grant (No.KYZZ15_0066).

Abbreviations Used

References

Crepel

, Jeldres

, Perrotte

, et al. Nephron-sparing surgery is equally effective to radical nephrectomy for T1BN0M0 renal cell carcinoma: A population-based assessment. Urology, 2010; 75:271–275.

Badalato

, Kates

, Wisnivesky

, et al. Survival after partial and radical nephrectomy for the treatment of stage T1bN0M0 renal cell carcinoma (RCC) in the USA: A propensity scoring approach. BJU Int, 2012; 109:1457–1462.

Tracy

, Raman

, Donnally

, et al. Durable oncologic outcomes after radiofrequency ablation: Experience from treating 243 small renal masses over 7.5 years. Cancer, 2010; 116:3135–3142.

Campbell

, Novick

, Belldegrun

, et al. Guideline for management of the clinical T1 renal mass. J Urol, 2009; 182:1271–1279.

, Bedir

, Cadeddu

, Gahan

. Long-term outcomes in healthy adults after radiofrequency ablation of T1a renal tumours. BJU Int, 2014; 113: 51–55.

Takaki

, Soga

, Kanda

, et al. Radiofrequency ablation versus radical nephrectomy: Clinical outcomes for stage T1b renal cell carcinoma. Radiology, 2014; 270:292–299.

Best

, Park

, Youssef

, et al. Long-term outcomes of renal tumor radio frequency ablation stratified by tumor diameter: Size matters. J Urol, 2012; 187:1183–1189.

Psutka

, Feldman

, McDougal

, et al. Long-term oncologic outcomes after radiofrequency ablation for T1 renal cell carcinoma. Eur Urol, 2013; 63:486–492.

Kutikov

, Uzzo

. The R.E.N.A.L. nephrometry score: A comprehensive standardized system for quantitating renal tumor size, location and depth. J Urol, 2009; 182:844–853.

10.

Chang

, Ji

, Zhao

, et al. The application of R.E.N.A.L. nephrometry scoring system in predicting the complications after laparoscopic renal radiofrequency ablation. J Endourol, 2014; 28:424–429.

11.

Zhao

, Wang

, Zhang

, et al. Improved outcome of percutaneous radiofrequency ablation in renal cell carcinoma: A retrospective study of intraoperative contrast-enhanced ultrasonography in 73 patients. Abdom Imaging, 2012; 37:885–891.

12.

Farrell

, Charboneau

, DiMarco

, et al. Imaging-guided radiofrequency ablation of solid renal tumors. AJR Am J Roentgenol, 2003; 180:1509–1513.

13.

Park

, Anderson

, Matsumoto

, et al. Radiofrequency ablation of renal tumors: Intermediate-term results. J Endourol, 2006; 20:569–573.

14.

Lucas

, Stern

, Adibi

, et al. Renal function outcomes in patients treated for renal masses smaller than 4 cm by ablative and extirpative techniques. J Urol, 2008; 179:75–80.

15.

Zagoria

, Traver

, Werle

, et al. Oncologic efficacy of CT-guided percutaneous radiofrequency ablation of renal cell carcinomas. AJR Am J Roentgenol, 2007; 189:429–436.

16.

Ferakis

, Bouropoulos

, Granitsas

, et al. Long-term results after computed-tomography-guided percutaneous radiofrequency ablation for small renal tumors. J Endourol, 2010; 24:1909–1913.

17.

Lorber

, Glamore

, Doshi

, et al. Long-term oncologic outcomes following radiofrequency ablation with real-time temperature monitoring for T1a renal cell cancer. Urol Oncol, 2014; 32:1017–1023.

18.

Hiraoka

, Kawauchi

, Nakamura

, et al. Radiofrequency ablation for renal tumors: Our experience. Int J Urol, 2009; 16:869–873.

19.

Zagoria

, Hawkins

, Clark

, et al. Percutaneous CT-guided radiofrequency ablation of renal neoplasms: Factors influencing success. AJR Am J Roentgenol, 2004; 183:201–207.

20.

Zini

, Patard

, Capitanio

, et al. Cancer-specific and non-cancer-related mortality rates in European patients with T1a and T1b renal cell carcinoma. BJU Int, 2009; 103:894–898.