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Use of Surveillance Imaging Following Treatment of Small Renal Masses
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Use of Surveillance Imaging Following Treatment of Small Renal Masses Keith J. Kowalczyk,*,† Andrew C. Harbin,† Toni K. Choueiri, Nathanael D. Hevelone, Stuart R. Lipsitz, Quoc-Dien Trinh, Ya-Chen Tina Shih and Jim C. Hu‡ From the Department of Urology, Georgetown University Hospital, Washington, DC (KJK, ACH), Lank Center for Genitourinary Oncology, Dana Farber Cancer Institute (TKC), and Center for Surgery and Public Health, Brigham and Women’s Hospital (NDH, SRL), Harvard Medical School, Boston, Massachusetts, Vattikuti Urology Institute, Henry Ford Health System, Detroit, Michigan (QDT), Cancer Prognostics and Health Outcomes Unit, University of Montreal Health Center, Montreal, Canada (QDT), Department of Medicine Program in the Economics of Cancer, Cancer Prognostics and Health Outcomes Unit, University of Chicago, Chicago, Illinois (YCTS), and Department of Urology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California (JCH)
Purpose: With the increasing incidence of small renal masses, there is greater use of ablation, nephron sparing surgery and surveillance compared to radical nephrectomy. However, patterns of care in the use of posttreatment imaging remain uncharacterized. The purpose of this study is to determine the rate of posttreatment imaging after various treatments for small renal mass. Materials and Methods: Using SEER (Surveillance, Epidemiology and End Results)-Medicare data during 2005 to 2009, we identified 1,682 subjects diagnosed with small renal mass and treated with open partial nephrectomy (330), minimally invasive partial nephrectomy (160), open radical nephrectomy (404), minimally invasive radical nephrectomy (535), thermal ablation (212) and surveillance (42). Use of imaging was compared within 24 months of treatment and multivariate regression models were constructed to identify factors associated with increased imaging use. Results: On adjusted analyses thermal ablation was associated with almost eightfold greater odds of surveillance imaging compared with open radical nephrectomy (OR 7.7, 95% CI 1.01e59.4). Specifically, thermal ablation was associated with increased computerized tomography (OR 5.28) and magnetic resonance imaging (OR 2.19) use and decreased ultrasound use (OR 0.59). Minimally invasive partial nephrectomy (OR 3.28) and open partial nephrectomy (OR 3.19) were also associated with increased computerized tomography use to a lesser extent. Conclusions: Subjects undergoing nephron sparing surgery undergo more posttreatment imaging compared to open radical nephrectomy. Although possibly associated with lower morbidity, thermal ablation is associated with significantly greater use of imaging compared to other small renal mass treatments. This may increase costs and radiation exposure, although further study is needed for confirmation. Key Words: ablation techniques, magnetic resonance imaging, kidney neoplasms
THE incidence of small renal masses 4 cm or smaller has increased due to the increased use of cross-sectional
imaging.1 This has led to advances in minimally invasive nephron sparing surgery and thermal ablative
0022-5347/13/1905-0001/0 THE JOURNAL OF UROLOGY® © 2013 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION AND RESEARCH, INC.
Dochead: Adult Urology
http://dx.doi.org/10.1016/j.juro.2013.05.109 Vol. 190, 1-6, November 2013 Printed in U.S.A.
Abbreviations and Acronyms CT ¼ computerized tomography MIPN ¼ minimally invasive partial nephrectomy MIRN ¼ minimally invasive radical nephrectomy MRI ¼ magnetic resonance imaging NSS ¼ nephron sparing surgery OPN ¼ open partial nephrectomy ORN ¼ open radical nephrectomy PN ¼ partial nephrectomy RCC ¼ renal cell carcinoma RFA ¼ radio frequency ablation RN ¼ radical nephrectomy SRM ¼ small renal mass TA ¼ thermal ablation UISS ¼ UCLA Integrated Scoring System Accepted for publication May 29, 2013. The data were de-identified and, therefore, the research protocol was exempt from institutional review boards. * Correspondence: Department of Urology, Georgetown University Hospital, 3800 Reservoir Rd NW, Washington, DC 20007 (telephone: (202) 444-4922; e-mail: keith.kowalczyk@gunet. georgetown.edu). † Equal study contribution. ‡ Supported by the Department of Defense Physician Training Award W81XWH-08-1-0283.
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techniques.2 Concerns over long-term effects on renal function have driven the management of SRMs away from RN and toward NSS.3 As such, when feasible, PN has become the new surgical standard of care for management of SRM.4 Thermal ablation, including RFA and cryoablation, has the potential benefits of improved convalescence, ease of operation and fewer complications.5 However, questions remain regarding long-term cancer control, incomplete tumor ablation and risk of local recurrence.6 Prospective, randomized studies evaluating ablative therapies are lacking,7 and there is uncertainty regarding appropriate postoperative imaging and monitoring.5 This uncertainty regarding posttreatment imaging surveillance does not only apply to TA, but also extends to all nephron sparing approaches, leading to confusion and disagreement on what is the most appropriate posttreatment surveillance protocol.59 While there are no guidelines from the National Comprehensive Care Network on postoperative surveillance imaging following surgical excision,9 the UISS is frequently used to identify patients requiring greater frequency of surveillance imaging.8 For example, the UISS generally recommends yearly cross-sectional imaging for low grade T1a renal masses for the first 3 years following surgery, and biannual screening in those with higher grade tumors and lower patient performance status. However, these guidelines were established for RN and discrepancies remain with regard to the optimal surveillance following NSS. Most recently, guidelines published by the American Urological Association (AUA) were released to address posttreatment surveillance imaging for SRM. However, they remain vague and suffer from poor quality evidence.10 Population level trends of imaging use following treatment for SRM are currently unknown. We evaluate the use of postoperative imaging following treatment for SRMs using a large population based data set.
PATIENTS AND METHODS Data Source We used SEER-Medicare data, comprised of a linkage of population based cancer registries from 20 SEER areas covering approximately 28% of the U.S. population with Medicare administrative data Medicare provides healthcare benefits to most Americans age 65 years or older.11 SEER-Medicare captures approximately 97% of incident cancer cases, and collects data such as patient demographics, tumor characteristics and initial course of treatment.12 For confidentiality purposes the National Cancer Institute mandates suppression of any data cells with N <11. Dochead: Adult Urology
Study Cohort We identified 31,145 subjects age 66 years or older with the first and only cancer diagnosis of RCC (ICD-9 code 189.0) from 2005 to 2007 with followup until 2009. After excluding subjects with tumors greater than 4 cm, 18,377 subjects remained. Subjects were excluded if diagnosed at autopsy or death, had Medicare entitlement on the basis of end stage renal disease, or were not enrolled continuously in both Medicare A and B throughout the study period because outcomes may not be accurately captured, reducing the sample size to 10,675. After excluding patients with multiple/bilateral renal surgeries or undefined renal procedures, 5,841 remained. Finally, after excluding patients lacking a final histological diagnosis, the final cohort included 1,682 patients. Using CPT-4 codes we identified 404 ORN (CPT 50220 and 50230), 535 MIRN (CPT 50546), 330 OPN (CPT 50240), 160 MIPN (CPT 50543) and 211 ablative therapies (RFA and/or cryoablation, CPT 50250 and 50542). As there is no identifier for robotic assistance available during the study period, MIRN and MIPN encompass both laparoscopic and robotic surgical approaches. Additionally, 42 subjects diagnosed with RCC via renal biopsy (CPT 50200 and 50205) without subsequent definitive therapy were classified as surveillance.
Independent Variables Age (66 to 69, 70 to 75, greater than 75 years) was obtained from the Medicare denominator file while race (white, black, other), U.S. Census region, education level and household income, population density (urban vs rural) and marital status were obtained from SEER. Comorbidity was assessed using the Klabunde modification of the Charlson index based on inpatient, outpatient and physician services the year before RCC diagnosis.13 Baseline renal insufficiency was defined by CPT-4 codes identifying acute renal failure, hemodialysis use, diabetic nephropathy, hypertensive nephropathy, chronic renal insufficiency and miscellaneous other renal diseases as previously described.14
Dependent Variables Tumor grade, stage and histology were obtained from SEER. Stage was defined using the AJCC Cancer Staging Manual, 7th edition.15 Tumor grade is defined by SEER as well, moderately and poorly differentiated. Histology was defined as clear cell, papillary, chromophobe and other. Use of imaging (CT, MRI, ultrasound and positron emission tomography, all associated with ICD-9 189.0, was identified from the Medicare file at various times following surgery/diagnosis (less than 12 months, 12 to 18 months, 18 to 24 months and 24þ months after surgery/ diagnosis). A summary of imaging codes used are listed in the supplementary Appendix (http://jurology.com/).
Statistical Analysis Baseline demographic and clinical characteristics were compared using chi-square tests. Stepwise logistic regression models, with exclusion of covariates with univariate p values greater than 0.2, were constructed to determine factors influencing use of all imaging, ultrasound, CT and MRI. All statistical analyses were
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229 230 231 232 233 234 235 236 237 238 239 240 CT (A), MRI (B) and ultrasound (C ) use after treatment and surveillance for SRM 241 242 243 performed using SASÒ version 9.2. All p values were On multivariate analysis ablation was associated 244 2-sided and considered significant at 0.05. with greater use of any imaging compared to 245 ORN (OR 7.7, 95% CI 1e59.4) while other treat246 ment modalities did not differ in use compared 247 to ORN (table 1 ). TA was associated with less 248 RESULTS ultrasound use after treatment (OR 0.59, 95% CI 249 Unadjusted demographic and pathological data are 0.37e0.94), while MIRN was associated with 250 presented in the supplementary table (http:// increased ultrasound use (OR 1.41, 95% CI 251 jurology.com/). Subjects undergoing MIPN and 1.04e1.92, table 2 ). TA (OR 5.28, 95% CI 252 OPN were younger and had fewer comorbidities 2.69e10.36), MIPN (OR 3.28, 95% CI 1.73e6.23) 253 (both p <0.001) relative to their ablation and and OPN (OR 3.19, 95% CI 1.99e5.12) were also 254 surveillance counterparts. Additionally, subjects associated with increased CT use compared to ORN 255 undergoing OPN and surveillance were most likely (table 3 ). Finally, TA was also associated with 256 to have baseline renal insufficiency (p <0.001). increased MRI use (OR 2.19, 95% CI 1.48e3.24) 257 Subjects undergoing OPN, ORN and MIRN had compared to ORN (table 4). 258 higher stage tumors (p <0.001). Ablation, MIRN, 259 ORN and surveillance were more commonly used in 260 the West while MIPN and OPN were most common 261 in the Northeast (p <0.001). Table 1. Multivariate analysis identifying factors associated 262 Ablation, MIPN and OPN were associated with with all surveillance imaging 24 months after treatment 263 greater use of posttreatment imaging. Within OR (95% CI) p Value 264 12 months, use of CT was 83.5% for subjects 265 undergoing TA, 73.8% for MIPN, 73.9% for OPN, Procedure (referent ORN): Ablation 7.70 (1.01e59.4) 0.050 266 55.3% for MIRN, 51.0% for ORN and 59.5% for MIPN 2.73 (0.60e12.31) 0.192 267 ½F1 surveillance (p <0.001, part A of the figure). After OPN 1.85 (0.69e4.95) 0.220 268 24 months, use was 37.3% for TA, 56.3% for MIPN, MIRN 1.39 (0.63e3.05) 0.413 Female (vs male) 1.42 (0.69e2.90) 0.344 269 49.7% for OPN, 40.9% for MIRN, 41.1% for ORN Age (vs 75þ): 270 and 28.6% for surveillance (p <0.001). MRI use after 65-69 1.09 (0.45e2.65) 0.845 271 TA was 23.1% within the first 12 months, 15.6% for 70-74 0.64 (0.29e1.42) 0.267 Region (vs West): 272 12 to 18 months and 10.9% for 18 to 24 months, Northeast 1.78 (0.71e4.50) 0.223 273 which was higher than MRI use following MIPN South 2.38 (0.77e7.40) 0.134 274 (14.4% within the first 12 months, 3.8% within 12 to Midwest 0.94 (0.35e2.52) 0.908 Grade (vs well differentiated): 275 18 months and 1.9% within 18 to 24 months after Other 0.86 (0.29e2.57) 0.784 276 treatment, all p <0.001, part B of figure). Moderately differentiated 1.20 (0.48e2.98) 0.701 277 Ultrasound was less likely to be performed Poorly differentiated 1.76 (0.49e6.32) 0.383 Unmarried (vs married) 0.78 (0.38e1.60) 0.494 278 compared to CT across all time intervals (part C of Race (vs white): 279 figure). It was least likely in the ablation and surBlack 0.61 (0.17e2.20) 0.446 280 veillance groups within 12 months and this trend Other 0.87 (0.20e3.89) 0.857 Stage 1 (vs III/IV) 0.69 (0.16e2.97) 0.165 281 continued beyond 24 months. Less than 11% of Income (vs greater than $60,000): 282 subjects underwent positron emission tomography Less than $35,000 0.81 (0.25e2.59) 0.718 283 and bone scan in all periods and the differences $35,000e$44,999 0.36 (0.12e1.11) 0.075 $45,000e$60,000 0.85 (0.24e3.05) 0.781 284 between treatment groups were not statistically Urban (vs rural) 3.53 (0.46e26.91) 0.224 285 significant (data not shown). Dochead: Adult Urology
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Table 2. Multivariate analysis identifying factors associated with ultrasound use 24 months after treatment OR (95% CI) Procedure (referent ORN): Ablation MIPN OPN MIRN Female (vs male) Age (vs 75þ): 65-69 70-74 Region (vs West): Northeast South Midwest
0.59 0.97 1.17 1.41 1.20
p Value
(0.37e0.94) (0.62e1.52) (0.82e1.66) (1.04e1.92) (0.95e1.52)
0.027 0.896 0.384 0.029 0.124
1.20 (0.90e1.59) 1.47 (1.10e1.95)
0.213 0.009
1.10 (0.83e1.47) 0.68 (0.49e0.94) 0.72 (0.49e1.07)
0.514 0.019 0.100
DISCUSSION Treatment options for SRM have expanded significantly beyond RN. 3e5,7 Given that up to 20% of SRM may be benign,16 there is significant risk of overtreatment, leading to the rationale for surveillance. However, a small proportion of SRM are aggressive and may be lethal if treatment is delayed.17 While AUA guidelines caution about the lack of data on long-term outcomes of TA, it is recommend it as an option in well selected patients.4,10 This guideline alludes to a preference for TA in older patients with comorbidities, though some advocate expanding indications to the young and healthy.18 The advantages of TA include shorter operative times, quicker convalescence, less pain and the ability to perform the procedure with the patient under sedation, thus allowing patients with more comorbidities to be candidates. Disadvantages include inadequate tissue for histological analysis when compared with surgery, limited application in large tumors and concerns of recurrence due to incomplete longterm followup data.9 Given a concern for tumor recurrence following TA, posttreatment surveillance imaging remains an important component in the treatment of these patients. However, there Table 3. Multivariate analysis identifying factors associated with CT use 24 months after treatment OR (95% CI) Procedure (referent ORN): Ablation MIPN OPN MIRN Female (vs male) Grade (vs well differentiated): Other Moderately differentiated Poorly differentiated Race (vs white): Black Other Stage I (vs III/IV) Urban (vs rural)
Dochead: Adult Urology
p Value
(2.69e10.36) (1.73e6.23) (1.99e5.12) (0.82e1.58) (0.91e1.62)
<0.001 <0.001 <0.001 0.445 0.195
0.98 (0.61e1.57) 1.11 (0.75e1.63) 1.76 (1.03e3.00)
0.928 0.608 0.039
0.66 0.73 0.71 1.52
0.131 0.334 0.244 0.138
5.28 3.28 3.19 1.14 1.21
(0.39e1.13) (0.39e1.38) (0.39e1.27) (0.87e2.63)
Table 4. Multivariate analysis identifying factors associated with MRI use 24 months after treatment OR (95% CI) Procedure (referent ORN): Ablation MIPN OPN MIRN Region (vs West): Northeast South Midwest Unmarried (vs married) Income (vs greater than $60,000): Less than $35,000 $35,000e$44,999 $45,000e$60,000 Charlson comorbidity (vs 0): 1 2 3 or Greater
p Value
2.19 1.22 0.99 1.18
(1.48e3.24) (0.77e1.93) (0.68e1.46) (0.84e1.65)
<0.001 0.406 0.977 0.332
1.29 0.73 0.69 1.29
(0.96e1.74) (0.52e1.04) (0.45e1.05) (0.96e1.74)
0.093 0.081 0.082 0.093
0.73 (0.52e1.04) 0.69 (0.45e1.05) 1.29 (0.96e1.74)
0.081 0.082 0.093
1.32 (0.99e1.77) 1.25 (0.82e1.90) 1.84 (1.28e2.66)
0.059 0.297 0.001
remains a lack of consensus regarding the frequency of surveillance imaging following TA and other nephron sparing approaches.19 Our study has several important findings. There is greater use of overall imaging, specifically CT and MRI, following TA compared to other SRM treatments. Since TA induces long-term necrosis of the tissue bed and does not involve direct and complete visualization of tumor excision, the process of tumor involution must be monitored with repeated imaging over time.20,21 In addition, due to the absence of large prospective trials examining ablation of renal tumors, there are no guideline recommendations regarding frequency of posttreatment imaging.20,21 Thus, there may be tremendous variation in the posttreatment care. This is particularly relevant given that repeated CT imaging may be associated with an increased risk of secondary malignancies, according to data from subjects exposed to whole body radiation from nuclear weapons.2224 This concern extends to patients undergoing MIPN and OPN, who which was also associated with increased CT use compared to ORN, although to a lesser extent than TA. In addition to the increased risk of secondary malignancy, the cost of posttreatment imaging represents an important consideration, especially given the current state of healthcare and desire to avoid wasteful diagnostic exams.23 Specifically, Chang et al recently examined the cost-effectiveness of various treatments for SRMs.24 Using a decision analytic Markov model, they found that the most cost-effective treatment for a healthy patient age 65 to 74 years old is laparoscopic PN, with ablation preferred for the elderly in whom surveillance fails.24 However, in contrast to the present study, the frequency of surveillance imaging did not vary between treatment types. Conversely, Castle et al
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found median total costs for OPN, robotic partial nephrectomy, laparoscopic RFA and CT guided RFA to be $17,018, $20,314, $13,965 and $6,475, respectively.25 However, frequency and costs of postoperative imaging were not considered. Our findings suggest that an additional financial burden due to increased imaging may be incurred when patients undergo ablation rather than surgical treatment for SRM. However, this trend is only suggested by our findings and a specific cost analysis study would be necessary to fully evaluate the financial impact of imaging use following TA and NSS. Subjects undergoing TA received more frequent imaging within 12 months of treatment and less frequent imaging 1 year after treatment. In addition, ultrasound was less likely to be used in the TA cohort, which may reflect in an increased use or preference for more costly MRI and CT following TA. Conversely, those undergoing surgical excision received less imaging within 1 year of surgery and more frequent imaging 12 to 24 months following surgery. This may reflect current practices based on risk stratification tools such as the UISS8 or the recommendations of the Canadian Urological Association (CUA),26 both of which do not recommend cross-sectional abdominal imaging until 2 years following treatment for low grade SRM.26 As seen in our study, patients undergoing TA receive more frequent and earlier imaging, which does not reflect UISS recommendations.27 The variation in imaging frequency across treatment modalities reflects the lack of consensus in postoperative imaging for these patients. While there are no widely adopted guidelines for imaging following TA, several series have described various surveillance protocols. Guillotreau et al reported 11% local recurrence with cryoablation, with imaging performed at 0, 3, 6 and 12 months postoperatively.28 In the cryoablation series by Duffey et al (116 across 4 institutions), followup imaging was not standardized but generally consisted of frequent MRI or CT within the first year and decreasing frequency after 12 months.29 Similarly, there are no clear guidelines for surveillance imaging following PN. The lack of consensus can lead to overuse of imaging, and emphasizes the need for standardized and evidenced-based imaging protocols, especially in the era of cost savings and health care reform. While guidelines put forth by the AUA and CUA aid somewhat in guiding posttreatment surveillance for SRM, they can only be as strong as the evidence that supports them, which is rarely exceeds grade C.10 Therefore, further study is needed to characterize the most clinically and costeffective surveillance imaging protocols to make more specific evidence-based guidelines.
Dochead: Adult Urology
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Our study must be considered within the context of our study design. Using an observational study design may not always control for unmeasured confounders such as body mass index and prior abdominal surgeries, which may influence treatment choice. However, we sought to control for confounding variables through strict inclusion and exclusion criteria and multivariate analysis. Our study is limited to Medicare beneficiaries age 65 years or older and may not be applicable to younger patients. Some studies show a relative underuse of PN in the elderly population,30 which may have created a selection bias toward TA or RN in our study population. Administrative data are designed for billing purposes and may lack detailed clinical information. Without detailed information on the findings of each imaging study, it is not possible to determine if frequency of imaging affected clinical outcomes. However, our aim was to report the current trends in imaging following treatment for SRMs in an effort to understand current practice rather than determine clinical outcomes, and potentially lead to future adoption of more evidencebased protocols. Many subjects were censored from the analysis in an effort to make our findings as accurate as possible. The removal of 90% of the patients from the data pool may have created a selection bias. However, subjects were censored to provide the most accurate data when analyzing population based datasets. Our active surveillance cohort only included subjects with biopsy proven RCC. Given the current state of renal mass biopsy in this population, this may have underestimated the volume of subjects on active surveillance. However, it is important to note that up to 20%16 of pT1a renal masses are benign and, therefore, we did not believe it was appropriate to included subjects that may have had benign disease.
CONCLUSIONS While there are many options for treating SRM, patients undergoing TA are significantly more likely to receive postoperative CT, MRI and ultrasound compared to other options. Additionally, MIPN and OPN are associated with increased CT use compared to ORN, although to a lesser extent than TA. In addition to increased recurrence rates for TA, this increased imaging use may be of concern to younger patients given the potential risks of repeated CT exposure. Additionally, increased imaging use may lead to increased health care costs, although more thorough cost analyses are needed. Given these findings, consensus guidelines on posttreatment surveillance for patients undergoing nephron sparing approaches are needed.
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Use of Surveillance Imaging Following Treatment of Small Renal Masses Keith J. Kowalczyk,*,† Andrew C. Harbin,† Toni K. Choueiri, Nathanael D. Hevelone, Stuart R. Lipsitz, Quoc-Dien Trinh, Ya-Chen Tina Shih and Jim C. Hu‡ From the Department of Urology, Georgetown University Hospital, Washington, DC (KJK, ACH), Lank Center for Genitourinary Oncology, Dana Farber Cancer Institute (TKC), and Center for Surgery and Public Health, Brigham and Women’s Hospital (NDH, SRL), Harvard Medical School, Boston, Massachusetts, Vattikuti Urology Institute, Henry Ford Health System, Detroit, Michigan (QDT), Cancer Prognostics and Health Outcomes Unit, University of Montreal Health Center, Montreal, Canada (QDT), Department of Medicine Program in the Economics of Cancer, Cancer Prognostics and Health Outcomes Unit, University of Chicago, Chicago, Illinois (YCTS), and Department of Urology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California (JCH)
Purpose: With the increasing incidence of small renal masses, there is greater use of ablation, nephron sparing surgery and surveillance compared to radical nephrectomy. However, patterns of care in the use of posttreatment imaging remain uncharacterized. The purpose of this study is to determine the rate of posttreatment imaging after various treatments for small renal mass. Materials and Methods: Using SEER (Surveillance, Epidemiology and End Results)-Medicare data during 2005 to 2009, we identified 1,682 subjects diagnosed with small renal mass and treated with open partial nephrectomy (330), minimally invasive partial nephrectomy (160), open radical nephrectomy (404), minimally invasive radical nephrectomy (535), thermal ablation (212) and surveillance (42). Use of imaging was compared within 24 months of treatment and multivariate regression models were constructed to identify factors associated with increased imaging use. Results: On adjusted analyses thermal ablation was associated with almost eightfold greater odds of surveillance imaging compared with open radical nephrectomy (OR 7.7, 95% CI 1.01e59.4). Specifically, thermal ablation was associated with increased computerized tomography (OR 5.28) and magnetic resonance imaging (OR 2.19) use and decreased ultrasound use (OR 0.59). Minimally invasive partial nephrectomy (OR 3.28) and open partial nephrectomy (OR 3.19) were also associated with increased computerized tomography use to a lesser extent. Conclusions: Subjects undergoing nephron sparing surgery undergo more posttreatment imaging compared to open radical nephrectomy. Although possibly associated with lower morbidity, thermal ablation is associated with significantly greater use of imaging compared to other small renal mass treatments. This may increase costs and radiation exposure, although further study is needed for confirmation. Key Words: ablation techniques, magnetic resonance imaging, kidney neoplasms
THE incidence of small renal masses 4 cm or smaller has increased due to the increased use of cross-sectional
imaging.1 This has led to advances in minimally invasive nephron sparing surgery and thermal ablative
0022-5347/13/1905-0001/0 THE JOURNAL OF UROLOGY® © 2013 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION AND RESEARCH, INC.
Dochead: Adult Urology
http://dx.doi.org/10.1016/j.juro.2013.05.109 Vol. 190, 1-6, November 2013 Printed in U.S.A.
Abbreviations and Acronyms CT ¼ computerized tomography MIPN ¼ minimally invasive partial nephrectomy MIRN ¼ minimally invasive radical nephrectomy MRI ¼ magnetic resonance imaging NSS ¼ nephron sparing surgery OPN ¼ open partial nephrectomy ORN ¼ open radical nephrectomy PN ¼ partial nephrectomy RCC ¼ renal cell carcinoma RFA ¼ radio frequency ablation RN ¼ radical nephrectomy SRM ¼ small renal mass TA ¼ thermal ablation UISS ¼ UCLA Integrated Scoring System Accepted for publication May 29, 2013. The data were de-identified and, therefore, the research protocol was exempt from institutional review boards. * Correspondence: Department of Urology, Georgetown University Hospital, 3800 Reservoir Rd NW, Washington, DC 20007 (telephone: (202) 444-4922; e-mail: keith.kowalczyk@gunet. georgetown.edu). † Equal study contribution. ‡ Supported by the Department of Defense Physician Training Award W81XWH-08-1-0283.
See Editorial on page .
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techniques.2 Concerns over long-term effects on renal function have driven the management of SRMs away from RN and toward NSS.3 As such, when feasible, PN has become the new surgical standard of care for management of SRM.4 Thermal ablation, including RFA and cryoablation, has the potential benefits of improved convalescence, ease of operation and fewer complications.5 However, questions remain regarding long-term cancer control, incomplete tumor ablation and risk of local recurrence.6 Prospective, randomized studies evaluating ablative therapies are lacking,7 and there is uncertainty regarding appropriate postoperative imaging and monitoring.5 This uncertainty regarding posttreatment imaging surveillance does not only apply to TA, but also extends to all nephron sparing approaches, leading to confusion and disagreement on what is the most appropriate posttreatment surveillance protocol.59 While there are no guidelines from the National Comprehensive Care Network on postoperative surveillance imaging following surgical excision,9 the UISS is frequently used to identify patients requiring greater frequency of surveillance imaging.8 For example, the UISS generally recommends yearly cross-sectional imaging for low grade T1a renal masses for the first 3 years following surgery, and biannual screening in those with higher grade tumors and lower patient performance status. However, these guidelines were established for RN and discrepancies remain with regard to the optimal surveillance following NSS. Most recently, guidelines published by the American Urological Association (AUA) were released to address posttreatment surveillance imaging for SRM. However, they remain vague and suffer from poor quality evidence.10 Population level trends of imaging use following treatment for SRM are currently unknown. We evaluate the use of postoperative imaging following treatment for SRMs using a large population based data set.
PATIENTS AND METHODS Data Source We used SEER-Medicare data, comprised of a linkage of population based cancer registries from 20 SEER areas covering approximately 28% of the U.S. population with Medicare administrative data Medicare provides healthcare benefits to most Americans age 65 years or older.11 SEER-Medicare captures approximately 97% of incident cancer cases, and collects data such as patient demographics, tumor characteristics and initial course of treatment.12 For confidentiality purposes the National Cancer Institute mandates suppression of any data cells with N <11. Dochead: Adult Urology
Study Cohort We identified 31,145 subjects age 66 years or older with the first and only cancer diagnosis of RCC (ICD-9 code 189.0) from 2005 to 2007 with followup until 2009. After excluding subjects with tumors greater than 4 cm, 18,377 subjects remained. Subjects were excluded if diagnosed at autopsy or death, had Medicare entitlement on the basis of end stage renal disease, or were not enrolled continuously in both Medicare A and B throughout the study period because outcomes may not be accurately captured, reducing the sample size to 10,675. After excluding patients with multiple/bilateral renal surgeries or undefined renal procedures, 5,841 remained. Finally, after excluding patients lacking a final histological diagnosis, the final cohort included 1,682 patients. Using CPT-4 codes we identified 404 ORN (CPT 50220 and 50230), 535 MIRN (CPT 50546), 330 OPN (CPT 50240), 160 MIPN (CPT 50543) and 211 ablative therapies (RFA and/or cryoablation, CPT 50250 and 50542). As there is no identifier for robotic assistance available during the study period, MIRN and MIPN encompass both laparoscopic and robotic surgical approaches. Additionally, 42 subjects diagnosed with RCC via renal biopsy (CPT 50200 and 50205) without subsequent definitive therapy were classified as surveillance.
Independent Variables Age (66 to 69, 70 to 75, greater than 75 years) was obtained from the Medicare denominator file while race (white, black, other), U.S. Census region, education level and household income, population density (urban vs rural) and marital status were obtained from SEER. Comorbidity was assessed using the Klabunde modification of the Charlson index based on inpatient, outpatient and physician services the year before RCC diagnosis.13 Baseline renal insufficiency was defined by CPT-4 codes identifying acute renal failure, hemodialysis use, diabetic nephropathy, hypertensive nephropathy, chronic renal insufficiency and miscellaneous other renal diseases as previously described.14
Dependent Variables Tumor grade, stage and histology were obtained from SEER. Stage was defined using the AJCC Cancer Staging Manual, 7th edition.15 Tumor grade is defined by SEER as well, moderately and poorly differentiated. Histology was defined as clear cell, papillary, chromophobe and other. Use of imaging (CT, MRI, ultrasound and positron emission tomography, all associated with ICD-9 189.0, was identified from the Medicare file at various times following surgery/diagnosis (less than 12 months, 12 to 18 months, 18 to 24 months and 24þ months after surgery/ diagnosis). A summary of imaging codes used are listed in the supplementary Appendix (http://jurology.com/).
Statistical Analysis Baseline demographic and clinical characteristics were compared using chi-square tests. Stepwise logistic regression models, with exclusion of covariates with univariate p values greater than 0.2, were constructed to determine factors influencing use of all imaging, ultrasound, CT and MRI. All statistical analyses were
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229 230 231 232 233 234 235 236 237 238 239 240 CT (A), MRI (B) and ultrasound (C ) use after treatment and surveillance for SRM 241 242 243 performed using SASÒ version 9.2. All p values were On multivariate analysis ablation was associated 244 2-sided and considered significant at 0.05. with greater use of any imaging compared to 245 ORN (OR 7.7, 95% CI 1e59.4) while other treat246 ment modalities did not differ in use compared 247 to ORN (table 1 ). TA was associated with less 248 RESULTS ultrasound use after treatment (OR 0.59, 95% CI 249 Unadjusted demographic and pathological data are 0.37e0.94), while MIRN was associated with 250 presented in the supplementary table (http:// increased ultrasound use (OR 1.41, 95% CI 251 jurology.com/). Subjects undergoing MIPN and 1.04e1.92, table 2 ). TA (OR 5.28, 95% CI 252 OPN were younger and had fewer comorbidities 2.69e10.36), MIPN (OR 3.28, 95% CI 1.73e6.23) 253 (both p <0.001) relative to their ablation and and OPN (OR 3.19, 95% CI 1.99e5.12) were also 254 surveillance counterparts. Additionally, subjects associated with increased CT use compared to ORN 255 undergoing OPN and surveillance were most likely (table 3 ). Finally, TA was also associated with 256 to have baseline renal insufficiency (p <0.001). increased MRI use (OR 2.19, 95% CI 1.48e3.24) 257 Subjects undergoing OPN, ORN and MIRN had compared to ORN (table 4). 258 higher stage tumors (p <0.001). Ablation, MIRN, 259 ORN and surveillance were more commonly used in 260 the West while MIPN and OPN were most common 261 in the Northeast (p <0.001). Table 1. Multivariate analysis identifying factors associated 262 Ablation, MIPN and OPN were associated with with all surveillance imaging 24 months after treatment 263 greater use of posttreatment imaging. Within OR (95% CI) p Value 264 12 months, use of CT was 83.5% for subjects 265 undergoing TA, 73.8% for MIPN, 73.9% for OPN, Procedure (referent ORN): Ablation 7.70 (1.01e59.4) 0.050 266 55.3% for MIRN, 51.0% for ORN and 59.5% for MIPN 2.73 (0.60e12.31) 0.192 267 ½F1 surveillance (p <0.001, part A of the figure). After OPN 1.85 (0.69e4.95) 0.220 268 24 months, use was 37.3% for TA, 56.3% for MIPN, MIRN 1.39 (0.63e3.05) 0.413 Female (vs male) 1.42 (0.69e2.90) 0.344 269 49.7% for OPN, 40.9% for MIRN, 41.1% for ORN Age (vs 75þ): 270 and 28.6% for surveillance (p <0.001). MRI use after 65-69 1.09 (0.45e2.65) 0.845 271 TA was 23.1% within the first 12 months, 15.6% for 70-74 0.64 (0.29e1.42) 0.267 Region (vs West): 272 12 to 18 months and 10.9% for 18 to 24 months, Northeast 1.78 (0.71e4.50) 0.223 273 which was higher than MRI use following MIPN South 2.38 (0.77e7.40) 0.134 274 (14.4% within the first 12 months, 3.8% within 12 to Midwest 0.94 (0.35e2.52) 0.908 Grade (vs well differentiated): 275 18 months and 1.9% within 18 to 24 months after Other 0.86 (0.29e2.57) 0.784 276 treatment, all p <0.001, part B of figure). Moderately differentiated 1.20 (0.48e2.98) 0.701 277 Ultrasound was less likely to be performed Poorly differentiated 1.76 (0.49e6.32) 0.383 Unmarried (vs married) 0.78 (0.38e1.60) 0.494 278 compared to CT across all time intervals (part C of Race (vs white): 279 figure). It was least likely in the ablation and surBlack 0.61 (0.17e2.20) 0.446 280 veillance groups within 12 months and this trend Other 0.87 (0.20e3.89) 0.857 Stage 1 (vs III/IV) 0.69 (0.16e2.97) 0.165 281 continued beyond 24 months. Less than 11% of Income (vs greater than $60,000): 282 subjects underwent positron emission tomography Less than $35,000 0.81 (0.25e2.59) 0.718 283 and bone scan in all periods and the differences $35,000e$44,999 0.36 (0.12e1.11) 0.075 $45,000e$60,000 0.85 (0.24e3.05) 0.781 284 between treatment groups were not statistically Urban (vs rural) 3.53 (0.46e26.91) 0.224 285 significant (data not shown). Dochead: Adult Urology
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Table 2. Multivariate analysis identifying factors associated with ultrasound use 24 months after treatment OR (95% CI) Procedure (referent ORN): Ablation MIPN OPN MIRN Female (vs male) Age (vs 75þ): 65-69 70-74 Region (vs West): Northeast South Midwest
0.59 0.97 1.17 1.41 1.20
p Value
(0.37e0.94) (0.62e1.52) (0.82e1.66) (1.04e1.92) (0.95e1.52)
0.027 0.896 0.384 0.029 0.124
1.20 (0.90e1.59) 1.47 (1.10e1.95)
0.213 0.009
1.10 (0.83e1.47) 0.68 (0.49e0.94) 0.72 (0.49e1.07)
0.514 0.019 0.100
DISCUSSION Treatment options for SRM have expanded significantly beyond RN. 3e5,7 Given that up to 20% of SRM may be benign,16 there is significant risk of overtreatment, leading to the rationale for surveillance. However, a small proportion of SRM are aggressive and may be lethal if treatment is delayed.17 While AUA guidelines caution about the lack of data on long-term outcomes of TA, it is recommend it as an option in well selected patients.4,10 This guideline alludes to a preference for TA in older patients with comorbidities, though some advocate expanding indications to the young and healthy.18 The advantages of TA include shorter operative times, quicker convalescence, less pain and the ability to perform the procedure with the patient under sedation, thus allowing patients with more comorbidities to be candidates. Disadvantages include inadequate tissue for histological analysis when compared with surgery, limited application in large tumors and concerns of recurrence due to incomplete longterm followup data.9 Given a concern for tumor recurrence following TA, posttreatment surveillance imaging remains an important component in the treatment of these patients. However, there Table 3. Multivariate analysis identifying factors associated with CT use 24 months after treatment OR (95% CI) Procedure (referent ORN): Ablation MIPN OPN MIRN Female (vs male) Grade (vs well differentiated): Other Moderately differentiated Poorly differentiated Race (vs white): Black Other Stage I (vs III/IV) Urban (vs rural)
Dochead: Adult Urology
p Value
(2.69e10.36) (1.73e6.23) (1.99e5.12) (0.82e1.58) (0.91e1.62)
<0.001 <0.001 <0.001 0.445 0.195
0.98 (0.61e1.57) 1.11 (0.75e1.63) 1.76 (1.03e3.00)
0.928 0.608 0.039
0.66 0.73 0.71 1.52
0.131 0.334 0.244 0.138
5.28 3.28 3.19 1.14 1.21
(0.39e1.13) (0.39e1.38) (0.39e1.27) (0.87e2.63)
Table 4. Multivariate analysis identifying factors associated with MRI use 24 months after treatment OR (95% CI) Procedure (referent ORN): Ablation MIPN OPN MIRN Region (vs West): Northeast South Midwest Unmarried (vs married) Income (vs greater than $60,000): Less than $35,000 $35,000e$44,999 $45,000e$60,000 Charlson comorbidity (vs 0): 1 2 3 or Greater
p Value
2.19 1.22 0.99 1.18
(1.48e3.24) (0.77e1.93) (0.68e1.46) (0.84e1.65)
<0.001 0.406 0.977 0.332
1.29 0.73 0.69 1.29
(0.96e1.74) (0.52e1.04) (0.45e1.05) (0.96e1.74)
0.093 0.081 0.082 0.093
0.73 (0.52e1.04) 0.69 (0.45e1.05) 1.29 (0.96e1.74)
0.081 0.082 0.093
1.32 (0.99e1.77) 1.25 (0.82e1.90) 1.84 (1.28e2.66)
0.059 0.297 0.001
remains a lack of consensus regarding the frequency of surveillance imaging following TA and other nephron sparing approaches.19 Our study has several important findings. There is greater use of overall imaging, specifically CT and MRI, following TA compared to other SRM treatments. Since TA induces long-term necrosis of the tissue bed and does not involve direct and complete visualization of tumor excision, the process of tumor involution must be monitored with repeated imaging over time.20,21 In addition, due to the absence of large prospective trials examining ablation of renal tumors, there are no guideline recommendations regarding frequency of posttreatment imaging.20,21 Thus, there may be tremendous variation in the posttreatment care. This is particularly relevant given that repeated CT imaging may be associated with an increased risk of secondary malignancies, according to data from subjects exposed to whole body radiation from nuclear weapons.2224 This concern extends to patients undergoing MIPN and OPN, who which was also associated with increased CT use compared to ORN, although to a lesser extent than TA. In addition to the increased risk of secondary malignancy, the cost of posttreatment imaging represents an important consideration, especially given the current state of healthcare and desire to avoid wasteful diagnostic exams.23 Specifically, Chang et al recently examined the cost-effectiveness of various treatments for SRMs.24 Using a decision analytic Markov model, they found that the most cost-effective treatment for a healthy patient age 65 to 74 years old is laparoscopic PN, with ablation preferred for the elderly in whom surveillance fails.24 However, in contrast to the present study, the frequency of surveillance imaging did not vary between treatment types. Conversely, Castle et al
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found median total costs for OPN, robotic partial nephrectomy, laparoscopic RFA and CT guided RFA to be $17,018, $20,314, $13,965 and $6,475, respectively.25 However, frequency and costs of postoperative imaging were not considered. Our findings suggest that an additional financial burden due to increased imaging may be incurred when patients undergo ablation rather than surgical treatment for SRM. However, this trend is only suggested by our findings and a specific cost analysis study would be necessary to fully evaluate the financial impact of imaging use following TA and NSS. Subjects undergoing TA received more frequent imaging within 12 months of treatment and less frequent imaging 1 year after treatment. In addition, ultrasound was less likely to be used in the TA cohort, which may reflect in an increased use or preference for more costly MRI and CT following TA. Conversely, those undergoing surgical excision received less imaging within 1 year of surgery and more frequent imaging 12 to 24 months following surgery. This may reflect current practices based on risk stratification tools such as the UISS8 or the recommendations of the Canadian Urological Association (CUA),26 both of which do not recommend cross-sectional abdominal imaging until 2 years following treatment for low grade SRM.26 As seen in our study, patients undergoing TA receive more frequent and earlier imaging, which does not reflect UISS recommendations.27 The variation in imaging frequency across treatment modalities reflects the lack of consensus in postoperative imaging for these patients. While there are no widely adopted guidelines for imaging following TA, several series have described various surveillance protocols. Guillotreau et al reported 11% local recurrence with cryoablation, with imaging performed at 0, 3, 6 and 12 months postoperatively.28 In the cryoablation series by Duffey et al (116 across 4 institutions), followup imaging was not standardized but generally consisted of frequent MRI or CT within the first year and decreasing frequency after 12 months.29 Similarly, there are no clear guidelines for surveillance imaging following PN. The lack of consensus can lead to overuse of imaging, and emphasizes the need for standardized and evidenced-based imaging protocols, especially in the era of cost savings and health care reform. While guidelines put forth by the AUA and CUA aid somewhat in guiding posttreatment surveillance for SRM, they can only be as strong as the evidence that supports them, which is rarely exceeds grade C.10 Therefore, further study is needed to characterize the most clinically and costeffective surveillance imaging protocols to make more specific evidence-based guidelines.
Dochead: Adult Urology
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Our study must be considered within the context of our study design. Using an observational study design may not always control for unmeasured confounders such as body mass index and prior abdominal surgeries, which may influence treatment choice. However, we sought to control for confounding variables through strict inclusion and exclusion criteria and multivariate analysis. Our study is limited to Medicare beneficiaries age 65 years or older and may not be applicable to younger patients. Some studies show a relative underuse of PN in the elderly population,30 which may have created a selection bias toward TA or RN in our study population. Administrative data are designed for billing purposes and may lack detailed clinical information. Without detailed information on the findings of each imaging study, it is not possible to determine if frequency of imaging affected clinical outcomes. However, our aim was to report the current trends in imaging following treatment for SRMs in an effort to understand current practice rather than determine clinical outcomes, and potentially lead to future adoption of more evidencebased protocols. Many subjects were censored from the analysis in an effort to make our findings as accurate as possible. The removal of 90% of the patients from the data pool may have created a selection bias. However, subjects were censored to provide the most accurate data when analyzing population based datasets. Our active surveillance cohort only included subjects with biopsy proven RCC. Given the current state of renal mass biopsy in this population, this may have underestimated the volume of subjects on active surveillance. However, it is important to note that up to 20%16 of pT1a renal masses are benign and, therefore, we did not believe it was appropriate to included subjects that may have had benign disease.
CONCLUSIONS While there are many options for treating SRM, patients undergoing TA are significantly more likely to receive postoperative CT, MRI and ultrasound compared to other options. Additionally, MIPN and OPN are associated with increased CT use compared to ORN, although to a lesser extent than TA. In addition to increased recurrence rates for TA, this increased imaging use may be of concern to younger patients given the potential risks of repeated CT exposure. Additionally, increased imaging use may lead to increased health care costs, although more thorough cost analyses are needed. Given these findings, consensus guidelines on posttreatment surveillance for patients undergoing nephron sparing approaches are needed.
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