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Natural History of Renal Cortical Neoplasms During Active Surveillance With Follow-up Longer Than 5 Years
Renal Cancer Natural History of Renal Cortical Neoplasms During Active Surveillance With Follow-up Longer Than 5 Years Georgios Haramis, Adam C. Mues, Juan Carlos Rosales, Zhamshid Okhunov, Alberto Perez Lanzac, Ketan Badani, Mantu Gupta, Mitchell C. Benson, James McKiernan, and Jaime Landman OBJECTIVES
METHODS
RESULTS
CONCLUSIONS
To present our experience with patients who elected active surveillance for renal cortical neoplasms (RCNs) with ⱖ5 years of follow-up. Few data are available regarding the long-term natural history of RCNs during surveillance. We retrospectively reviewed our urologic oncology database and identified 44 patients with 51 RCNs who had received active surveillance for ⬎5 years of follow-up. The patient and tumor characteristics and tumor growth rate and overall survival data were evaluated. The median patient age was 71.7 years (range 55-92), with 32 patients (72.7%) having a Charlson comorbidity index of ⱖ2. The median tumor size was 2.67 cm (range 0.9-8.6) at diagnosis. Biopsy was performed in 17 patients (38.6%). Of these 17 patients, clear cell renal cell carcinoma was diagnosed in 15 and papillary renal cell carcinoma in 2 patients. The median follow-up was 77.1 months (range 60-137), and the median growth rate was 0.15 cm/y. Of these patients, 2 (4.5%) required delayed intervention. One underwent laparoscopic radical nephrectomy because of a high tumor growth rate, and one elected to withdraw from active surveillance because of personal anxiety, despite having a stable tumor size for 72 months. The latter patient underwent laparoscopic renal cryoablation. Histopathologic examination revealed clear cell renal cell carcinoma in both cases. No metastases or cancer-related deaths occurred in our cohort; 1 patient died of cardiovascular disease. Most RCNs undergoing surveillance for ⬎5 years grew slowly. The metastatic potential appeared minimal in patients who demonstrated low or absent tumor growth for a long period. UROLOGY 77: 787–791, 2011. © 2011 Elsevier Inc.
T
he incidence of renal cell carcinoma (RCC) has increased steadily by an average of 2-3% annually during the past 3 decades.1 The increased incidence of RCC can mainly be attributed to the widespread use of cross-sectional abdominal imaging during evaluation of nonrelated abdominal symptoms, leading to the incidental detection of asymptomatic small renal masses. The increase has been more notable in patients ⬎70 years, an age group that typically presents with significant medical comorbidities.2 The accepted standard of treatment of RCC has traditionally been radical nephrectomy. The evolution of nephron-sparing surgery, along with the emergence of minimally invasive techniques such as cryotherapy and radiofrequency ablation, has dramatically changed the From the Department of Urology, Columbia University Medical Center, New York, New York Reprint requests: Georgios Haramis, M.D., Department of Urology, Columbia University Medical Center, 161 Fort Washington Avenue, Room 1154, New York, NY 10032. E-mail: [email protected] Submitted: June 7, 2010, accepted (with revisions): September 18, 2010
© 2011 Elsevier Inc. All Rights Reserved
available treatment options in the past few years. However, despite the earlier diagnosis and treatment, the cancer-specific death rates have failed to decrease, suggesting a probable overtreatment of a slow-growing disease with low metastatic potential.3 Furthermore, approximately 20% of clinical Stage 1 renal masses will be benign, and only 20-30% of malignant tumors in this size range will demonstrate potentially aggressive features, providing the rationale for noninterventional management for selected patients.4,5 Although not recommended for young, relatively healthy patients, active surveillance (AS) is considered a reasonable treatment option for selected patients. AS has generally been recommended for patients with a limited life expectancy or those who are unfit for a surgical procedure.6 In the present data, a number of series have provided important information regarding the natural history of renal cortical neoplasms (RCNs) during surveillance. However, most AS series have been small retrospective studies with limited follow-up. To date, no series has presented longer term AS data.7,8 As such, we report on 0090-4295/11/$36.00 doi:10.1016/j.urology.2010.09.031
787
what is, to our knowledge, the largest, single-center series of patients with RCN who continued in surveillance for ⬎5 years.
MATERIAL AND METHODS We retrospectively reviewed our institutional review boardapproved renal cell neoplasm database and identified 223 patients undergoing AS. Among this population, 44 patients with 51 RCNs remained under AS for a minimal period of 5 years. For each patient, a complete record was maintained, including an initial contrast-enhanced axial imaging study (computed tomography [CT] or magnetic resonance imaging). The initial images were reviewed by the treating urologist to evaluate the solid mass features, enhancement, tumor size, and maximal cross-sectional dimension. All patients with strong suspicion of metastatic disease, as indicated by the clinical symptoms or laboratory findings, underwent metastatic evaluation with additional diagnostic procedures (chest CT, bone scan) before enrollment to AS. The exclusion criteria included patients with suspected transitional cell carcinoma, a history of hereditary RCC syndrome, metastatic disease at diagnosis, or cystic renal masses (except for Bosniak IV cysts). The decision to proceed with AS was not determined by prospectively established selective criteria. Instead, the patients underwent an extensive discussion of all available treatment options. The decision to proceed with AS was a consensus between the treating surgeon and the patient according to the patient factors, including age, comorbidities, overall surgical risk, tumor metrics, and the patient’s willingness to undergo surgery. The Charlson comorbidity index was determined for all patients. No standardized imaging protocol was used. However, after the first 3 years of AS, all patients underwent an annual follow-up evaluation consisting of axial abdominal imaging (CT or magnetic resonance imaging), chest radiography, and blood chemistry. The tumor size at the initial and follow-up evaluations was measured as the maximal cross-sectional diameter. All radiologic evaluations that were not performed at our medical center were obtained and evaluated by the treating urologist. The measurements were performed at consistent anatomic levels within the kidney by direct comparison with existing studies. The patient and tumor characteristics, including age, sex, comorbidities, tumor growth rates, and survival data, were recorded. Failure of AS was defined as either progression to metastatic disease or a change in management from AS to delayed intervention.
RESULTS A total of 44 patients with 51 RCNs receiving AS with ⱖ60 months of follow-up were identified. The median patient age was 71.7 years (range 55-92). Of the 44 patients, 21 (47.7%) were men and 23 (52.3%) were women. The Charlson comorbidity index was evaluated for the entire cohort, with 32 patients (72.7%) having an index of ⱖ2 and 12 (27.3%) a Charlson index of 1. The median duration of AS was 77.1 months (range 60-137), and the median number of overall imaging studies performed per patient was 9 (range 6-14; Table 1). All 51 tumors were incidentally diagnosed; no patient had presented with clinical symptoms. Of the 44 patients, 788
Table 1. Patient and tumor characteristics Characteristic
Value
Age (y) Median Range Sex (n) Male Female Charlson index (n) ⱖ2 1 Multifocal disease (n) Bilateral disease (n) Initial tumor size (cm) Median Range Ending tumor size (cm) Median Range Lesion type (n) Solid Cystic Patients with biopsy (n) Overall mean growth rate (cm/y) Follow-up (mo) Median Range Imaging studies/person (n) Median Range Patients withdrawn from AS (n) Progression/metastasis Cancer-related deaths Noncancer-related deaths (n)
71.7 55-92 21 (47.7) 23 (52.3) 32 (72.7) 12 (27.3) 7 (15.9) 4 (9) 2.67 0.9-8.6 4 1-10.7 36 (70.6) 15 (29.4) 17 (38.6) 0.15 77.1 60-137 9 6-14 2 (4.5) 0 0 1 (2.2)
Data in parentheses are percentages.
7 (15.9%) had been diagnosed with multiple lesions and 4 (9%) had bilateral tumors. Most RCNs were solidenhancing masses (n ⫽ 36, 70.6%), and the remaining lesions were Bosniak IV cysts (n ⫽ 15, 29.4%). The median tumor size on axial imaging at diagnosis was 2.67 cm (range 0.9-8.6), with 41 tumors (80.3%) measuring ⬍4 cm (Stage cT1a). The median tumor size at the end of the observation period was 4 cm (range 1-10.7). The overall mean tumor growth rate was 0.15 cm/y (range 0-1.73), with larger tumors (⬎4 cm) exhibiting a faster growth rate at 0.31 cm/y (range 0-1.73). Of the 51 tumors under AS, 15 (29.4%) did not demonstrate any interval growth. Of the 44 patients, 17 (38.6%) underwent biopsy of their renal mass. The histopathology report confirmed malignant pathologic features in all the cases. More specifically, 15 biopsy specimens (88.2%) demonstrated clear cell RCC and 2 (11.8%) revealed papillary RCC. The mean growth rate of the pathologically confirmed tumors was 0.25 cm/y. Finally, the median initial and terminal serum creatinine levels were comparable at 1.1 mg/mL (range 0.8-1.4) and 1.2 mg/mL (range 0.9-1.6), respectively. Two patients (4.5%) failed AS. The first patient had an initial tumor size of 8.6 cm that exhibited an average growth rate of 0.44 cm/y. He underwent laparoscopic radical nephrectomy, after spending 60 months on AS. UROLOGY 77 (4), 2011
Histopathologic examination revealed Stage pT2 clear cell RCC. At 24 months postoperatively, no recurrence had been reported. The second patient elected to withdraw from AS because of personal anxiety and despite having stable disease for 72 months. The tumor size was 2.5 cm, and he eventually underwent laparoscopic renal cryotherapy. The intraoperative biopsy demonstrated clear cell RCC, and the patient had had no recurrence at 12 months postoperatively. Only 1 patient died during the course of the present evaluation. That patient (2.2%) died of another medical condition (heart failure) after undergoing AS for 96 months. His tumor demonstrated zero interval growth. No metastases or cancer-related deaths were reported in the entire cohort.
COMMENT The natural history of localized RCN is not well-known because of their early removal after diagnosis in most cases. Although the reference standard has remained surgical excision or ablation, AS has been increasingly implemented in selected patients, with growing published data supporting this management strategy.9-11 Recent guidelines published by the American Urological Association for the management of small renal tumors recommends AS as a reasonable treatment for patients with Stage T1 RCN and decreased life expectancy, or those with increased surgical risk. Despite the growing body of evidence trying to better assess the biology of RCN, very little is known about the natural history of tumors that have remained on AS for a long period. As such, we evaluated patients who continued with AS for a minimal period of 5 years in an effort to optimize patient management decisions. The median patient age in the present study was 71.7 years, similar to that described in other major studies.9,10,12 Of the 44 patients, 32 (75.7%) had a Charlson comorbidity index of ⱖ2. A recently published report by Berger et al13 reported that advanced patient age and medical comorbidities can independently reduce the overall survival benefit of patients who undergo nephrectomy for renal tumors. Despite the lack of strict selective criteria, we believe that elderly patients with severe comorbidities are ideal candidates for AS, because they have a significantly greater surgical risk and can be treated with a noninterventional approach. The tumor size has traditionally been used in selecting patients for AS, with many urologists recommending AS for RCNs of ⬍4 cm. The mean tumor size in our population was 2.67 cm (range 0.9-8.6), with 80.3% of the lesions Stage cT1a. Most solid, enhancing renal masses are RCC. Remzi et al14 retrospectively analyzed 287 RCNs ⬍4 cm that underwent surgery. They reported that 81.9% of all small renal masses were RCC.14 However, recent data have suggested that smaller lesions might have a greater chance of being benign. Frank et al15 retrospectively examined 2935 solid renal tumors that were surgically treated during a 30-year period and reUROLOGY 77 (4), 2011
ported that 46.3%, 22.4%, 22%, and 19.9% of renal lesions ⬍1, ⬍2, ⬍3, and ⬍4 cm to be benign, respectively. Gill et al16 treated 100 tumors with a mean size of 2.8 cm with laparoscopic partial nephrectomy and reported that 30% of the lesions were benign. These results have provided a pathologic basis for the use of AS management of RCN. However, the tumor size alone at presentation cannot predict malignancy and progression.17 The individual growth kinetics of suspicious RCNs have been used to determine a possible delayed intervention and eventual withdrawal of patients from AS. Most RCNs grow slowly, with average growth rates ranging from 0.09 to 0.86 cm/y.9,10 In a recently published study, Rosales et al18 examined 223 RCNs in 212 patients on AS and reported a median growth rate of 0.34 cm/y (range 0.29-2.3). In a meta-analysis of several AS studies, Chawla et al17 analyzed 234 lesions and found an overall growth rate of 0.28 cm/y. The observed growth rate in the present study was 0.15 cm/y (range 0-1.73). Although the initial tumor size cannot predict tumor growth, we found interesting that the growth rate of larger tumors (⬎4 cm) was double that of the entire cohort (0.31 cm/y). Mues et al19 recently reported a mean growth rate of 0.57 cm/y for large renal masses (cT1bN0M0 and cT2N0M0) undergoing AS. A total of 15 patients (29.4%) in our cohort exhibited a zero tumor growth rate on follow-up imaging. In the present data, the number of RCNs that remained stable has been 26%-33%.20 However, these findings should be interpreted with caution, because tumors with zero growth rates might also have malignant potential.21 It is likely that the key factor contributing to the slow growth rate in our cohort was that we excluded patients with follow-up of ⬍5 years. It is likely that most faster growing tumors in our overall AS series underwent intervention before the 5-year follow-up period. In our entire AS cohort, we had 212 patients, of whom 11 patients (5.1%) underwent intervention and 4 (1.9%) had progression to metastatic disease. As such, the patients reported in the present series were somewhat selected for the particularly indolent nature of their disease. Taking this into consideration, the results of the present study should not be used to prospectively make treatment decisions regarding patients presenting with RCNs. However, it is of value that once patients have been followed up for 5 years, the probability remains high that they will not require intervention. To date, controversy still exists regarding the value of biopsy for RCNs, with many urologists expressing concerns regarding the overall accuracy and complication rates. However, fine needle aspiration and core biopsy techniques have improved, and they can be applied in an outpatient setting with low morbidity.22,23 Schmidbauer et al24 published a prospective study of 78 patients who had undergone 18-gauge core biopsy under CT guidance. They also used the same sheath for fine needle aspiration and cytologic analysis. The masses were surgically re789
moved, and the histology reports were compared with the preoperative biopsy results. The investigators reported a sensitivity of 93.5% and 90.6% for core biopsy and fine needle aspiration, respectively. In our study, 17 patients (38.6%) underwent biopsy, with all lesions RCC. With improved techniques and the emergence of novel molecular and gene markers, biopsy will not only differentiate between malignant and benign renal masses, but it will also significantly effect clinical management, providing useful information about the aggressiveness and prognosis of RCNs. Also, none of the patients undergoing biopsy in our series experienced a complication or documented tumor seeding. Two patients (4.5%) from our entire cohort elected to stop AS. The first patient underwent ablation of a 2.5-cm tumor despite AS and stable disease for 72 months. This patient was encouraged to continue with AS but refused. This case underscores the fear and anxiety that patients do experience with AS protocols. This factor has yet to be quantified in any RCN AS evaluation. The other patient had an 8.6-cm lesion at presentation, making it highly suspicious for RCC. That patient was observed because of severe comorbidities; however, the tumor demonstrated a growth rate (0.44 cm/y) almost 3 times greater than the rest of the cohort. After 60 months of AS, he underwent laparoscopic radical nephrectomy. The pathology report revealed clear cell RCC in both cases. Although no pre-established cutoff growth rate has been determined for delayed intervention, we believe that rapid growth of RCNs under AS should always be a point of concern and should be treated with surgery or ablation, independent of the tumor’s size. Several studies, including data recently published from our institution, have supported that RCNs under AS can be managed expectantly without compromising the oncologic outcome.6,18,25,26 In the meta-analysis performed by Chawla et al,17 only 3 (1%) of 287 patients had developed metastatic disease during AS. Similar low rates have also been published in other studies.6,8,18,27 A common finding in all series was that no metastasis was reported in the absence of tumor growth. With the longest median follow-up of AS ever reported at 77.1 months (range 60-137) and with a median tumor growth rate of 0.15 cm/y, it was notable that no patient developed metastasis and no cancerrelated deaths were recorded. Again, in our overall series of AS for RCNs, 4 patients (1.9%) progressed to metastatic disease, with 1 patient (0.5%) dying of RCC during AS. Despite the metastatic potential of RCN, tumors with a slow initial growth rate that have remained stable for a long time are less likely to manifest progression or metastasis. As such, we intuitively believe that initial close evaluations (every 3-6 months) should be followed by annual follow-up examinations if the tumor shows an initial slow growth rate, with CT remaining the most accurate imaging modality, despite the radiation dose and intravenous contrast requirement. 790
The present study had several limitations, mostly related to its retrospective nature. It was a single-institution data set in which no well-defined criteria were used for patient selection, surveillance, or intervention. The patients in the present cohort were of a particularly advanced age and represented a group with a heterogeneous population of lesions, with only a part of them having malignant confirmation by biopsy. Finally, it is imperative to note that, by definition, the patient population described in the present series was selected by not having undergone intervention or disease progression in the first 5 years of follow-up. Large, prospective, clinical trials are required to more precisely define the role and safety of AS in the management of RCN.
CONCLUSIONS The results of the present study have shown that RCNs that undergo AS for ⱖ5 years exhibit a minimal growth rate with low metastatic potential. The average growth rate of 0.15 cm/y was one half the average growth rate currently documented in the published data. Although surgical treatment remains the standard therapy, AS can be a viable treatment option for elderly patients with concomitant medical conditions. References 1. Pantuck AJ, Zisman A, Belldegrun AS. The changing natural history of renal cell carcinoma. J Urol. 2001;166:1611-1623. 2. Chow WH, Devesa SS, Warren JL, et al. Rising incidence of renal cell cancer in the United States. JAMA. 1999;281:1628-1631. 3. Parsons JK, Schoenberg MS, Carter HB. Incidental renal tumors: casting doubt on the efficacy of early intervention. Urology. 2001; 57:1013-1015. 4. Pahernik S, Ziegler S, Roos F, et al. Small renal tumors: correlation of clinical and pathological features with tumor size. J Urol. 2007; 178:414-417. 5. Remzi M, Ozsoy M, Klingler HC, et al. Are small renal tumors harmless? Analysis of histopathological features according to tumors 4 cm or less in diameter. J Urol. 2006;176:896-899. 6. Kouba E, Smith A, McRackan D, et al. Watchful waiting for solid renal masses: insight into the natural history and results of delayed intervention. J Urol. 2007;177:466-470. 7. Kato M, Suzuki T, Suzuki Y, et al. Natural history of small renal cell carcinoma: evaluation of growth rate, histological grade, cell proliferation and apoptosis. J Urol. 2004;172:863-866. 8. Lamb GW, Bromwich EJ, Vasey P, et al. Management of renal masses inpatients medically unsuitable for nephrectomy—natural history, complications, and outcome. Urology. 2004;64:909-913. 9. Abou Youssif T, Kassouf W, Steinberg J, et al. Active surveillance for selected patients with renal masses: updated results with longterm follow-up. Cancer. 2007;110:1010-1014. 10. Crispen PL, Viterbo R, Fox EB, et al. Delayed intervention of sporadic renal masses undergoing active surveillance. Cancer. 2008; 112:1051-1057. 11. Kunkle DA, Egleston BL, Uzzo RG. Excise, ablate or observe: the small renal mass dilemma—a meta-analysis and review. J Urol. 2008;179:1227-1233. 12. Abouassaly R, Lane BR, Novick AC. Active surveillance of renal masses in elderly patients. J Urol. 2008;180:505-508. 13. Berger DA, Megwalu VA II, et al. Impact of comorbidity on overall survival in patients surgically treated for renal cell carcinoma. Urology. 2008;72:359-363.
UROLOGY 77 (4), 2011
14. Remzi M, Katzenbeisser D, Waldert M, et al. Renal tumour size measured radiologically before surgery is an unreliable variable for predicting histopathological features: benign tumours are not necessarily small. BJU Int. 2007;99:1002-1006. 15. Frank I, Blute ML, Cheville JC, et al. Solid renal tumors: an analysis of pathological features related to tumor size. J Urol. 2003;170(6 Pt. 1):2217-2220. 16. Gill IS, Matin SF, Desai MM. Comparative analysis of laparoscopic versus open partial nephrectomy. J Urol. 2003;170:64-68. 17. Chawla SN, Crispen PL, Hanlon AL, et al. The natural history of observed enhancing renal masses: meta-analysis and review of the world literature. J Urol. 2006;175:425. 18. Rosales JC, Haramis G, Moreno J, et al. Active surveillance of renal cortical neoplasms. J Urol. 2010;183:1698-1702. 19. Mues AC, Haramis G, Badani K, et al. Active surveillance for larger (cT1bN0M0 and cT2N0M0) renal cortical neoplasms. Urology. 2010;76:620-623. 20. Klaver S, Joniau S, Van Poppel H. Surveillance as an option for the treatment of small renal masses. Adv Urol. 2008:705958: 1-6.
UROLOGY 77 (4), 2011
21. Kunkle DA, Crispen PL, Chen DY, et al. Enhancing renal masses with zero net growth during active surveillance. J Urol. 2007;177: 849-853. 22. Neuzillet Y, Lechevallier E, Andre M, et al. Accuracy and clinical role of fine needle percutaneous biopsy with computerized tomography guidance of small (less than 4.0cm) renal masses. J Urol. 2004;171:1802-1805. 23. Silverman SG, Gan YU, Mortele KJ. Renal masses in the adult patient: the role of percutaneous biopsy. Radiology. 2006;240:6-22. 24. Schmidbauer J, Remzi M, Memarsadeghi M, et al. Diagnostic accuracy of computed tomography-guided percutaneous biopsy of renal masses. Eur Urol. 2008;53:1003-1011. 25. Crispen PL, Viterbo R, Boorjian SA, et al. Natural history, growth kinetics, and outcomes of untreated clinically localized renal tumors under active surveillance. Cancer. 2009;115:2844-2852. 26. Crispen PL, Viterbo R, Fox EB, et al. Delayed intervention of sporadic renal masses undergoing active surveillance. Cancer. 2008; 112:1051-1057. 27. Volpe A, Panzarella T, Rendon RA, et al. The natural history of incidentally detected small renal masses. Cancer. 2004;100:738-745.
791
METHODS
RESULTS
CONCLUSIONS
To present our experience with patients who elected active surveillance for renal cortical neoplasms (RCNs) with ⱖ5 years of follow-up. Few data are available regarding the long-term natural history of RCNs during surveillance. We retrospectively reviewed our urologic oncology database and identified 44 patients with 51 RCNs who had received active surveillance for ⬎5 years of follow-up. The patient and tumor characteristics and tumor growth rate and overall survival data were evaluated. The median patient age was 71.7 years (range 55-92), with 32 patients (72.7%) having a Charlson comorbidity index of ⱖ2. The median tumor size was 2.67 cm (range 0.9-8.6) at diagnosis. Biopsy was performed in 17 patients (38.6%). Of these 17 patients, clear cell renal cell carcinoma was diagnosed in 15 and papillary renal cell carcinoma in 2 patients. The median follow-up was 77.1 months (range 60-137), and the median growth rate was 0.15 cm/y. Of these patients, 2 (4.5%) required delayed intervention. One underwent laparoscopic radical nephrectomy because of a high tumor growth rate, and one elected to withdraw from active surveillance because of personal anxiety, despite having a stable tumor size for 72 months. The latter patient underwent laparoscopic renal cryoablation. Histopathologic examination revealed clear cell renal cell carcinoma in both cases. No metastases or cancer-related deaths occurred in our cohort; 1 patient died of cardiovascular disease. Most RCNs undergoing surveillance for ⬎5 years grew slowly. The metastatic potential appeared minimal in patients who demonstrated low or absent tumor growth for a long period. UROLOGY 77: 787–791, 2011. © 2011 Elsevier Inc.
T
he incidence of renal cell carcinoma (RCC) has increased steadily by an average of 2-3% annually during the past 3 decades.1 The increased incidence of RCC can mainly be attributed to the widespread use of cross-sectional abdominal imaging during evaluation of nonrelated abdominal symptoms, leading to the incidental detection of asymptomatic small renal masses. The increase has been more notable in patients ⬎70 years, an age group that typically presents with significant medical comorbidities.2 The accepted standard of treatment of RCC has traditionally been radical nephrectomy. The evolution of nephron-sparing surgery, along with the emergence of minimally invasive techniques such as cryotherapy and radiofrequency ablation, has dramatically changed the From the Department of Urology, Columbia University Medical Center, New York, New York Reprint requests: Georgios Haramis, M.D., Department of Urology, Columbia University Medical Center, 161 Fort Washington Avenue, Room 1154, New York, NY 10032. E-mail: [email protected] Submitted: June 7, 2010, accepted (with revisions): September 18, 2010
© 2011 Elsevier Inc. All Rights Reserved
available treatment options in the past few years. However, despite the earlier diagnosis and treatment, the cancer-specific death rates have failed to decrease, suggesting a probable overtreatment of a slow-growing disease with low metastatic potential.3 Furthermore, approximately 20% of clinical Stage 1 renal masses will be benign, and only 20-30% of malignant tumors in this size range will demonstrate potentially aggressive features, providing the rationale for noninterventional management for selected patients.4,5 Although not recommended for young, relatively healthy patients, active surveillance (AS) is considered a reasonable treatment option for selected patients. AS has generally been recommended for patients with a limited life expectancy or those who are unfit for a surgical procedure.6 In the present data, a number of series have provided important information regarding the natural history of renal cortical neoplasms (RCNs) during surveillance. However, most AS series have been small retrospective studies with limited follow-up. To date, no series has presented longer term AS data.7,8 As such, we report on 0090-4295/11/$36.00 doi:10.1016/j.urology.2010.09.031
787
what is, to our knowledge, the largest, single-center series of patients with RCN who continued in surveillance for ⬎5 years.
MATERIAL AND METHODS We retrospectively reviewed our institutional review boardapproved renal cell neoplasm database and identified 223 patients undergoing AS. Among this population, 44 patients with 51 RCNs remained under AS for a minimal period of 5 years. For each patient, a complete record was maintained, including an initial contrast-enhanced axial imaging study (computed tomography [CT] or magnetic resonance imaging). The initial images were reviewed by the treating urologist to evaluate the solid mass features, enhancement, tumor size, and maximal cross-sectional dimension. All patients with strong suspicion of metastatic disease, as indicated by the clinical symptoms or laboratory findings, underwent metastatic evaluation with additional diagnostic procedures (chest CT, bone scan) before enrollment to AS. The exclusion criteria included patients with suspected transitional cell carcinoma, a history of hereditary RCC syndrome, metastatic disease at diagnosis, or cystic renal masses (except for Bosniak IV cysts). The decision to proceed with AS was not determined by prospectively established selective criteria. Instead, the patients underwent an extensive discussion of all available treatment options. The decision to proceed with AS was a consensus between the treating surgeon and the patient according to the patient factors, including age, comorbidities, overall surgical risk, tumor metrics, and the patient’s willingness to undergo surgery. The Charlson comorbidity index was determined for all patients. No standardized imaging protocol was used. However, after the first 3 years of AS, all patients underwent an annual follow-up evaluation consisting of axial abdominal imaging (CT or magnetic resonance imaging), chest radiography, and blood chemistry. The tumor size at the initial and follow-up evaluations was measured as the maximal cross-sectional diameter. All radiologic evaluations that were not performed at our medical center were obtained and evaluated by the treating urologist. The measurements were performed at consistent anatomic levels within the kidney by direct comparison with existing studies. The patient and tumor characteristics, including age, sex, comorbidities, tumor growth rates, and survival data, were recorded. Failure of AS was defined as either progression to metastatic disease or a change in management from AS to delayed intervention.
RESULTS A total of 44 patients with 51 RCNs receiving AS with ⱖ60 months of follow-up were identified. The median patient age was 71.7 years (range 55-92). Of the 44 patients, 21 (47.7%) were men and 23 (52.3%) were women. The Charlson comorbidity index was evaluated for the entire cohort, with 32 patients (72.7%) having an index of ⱖ2 and 12 (27.3%) a Charlson index of 1. The median duration of AS was 77.1 months (range 60-137), and the median number of overall imaging studies performed per patient was 9 (range 6-14; Table 1). All 51 tumors were incidentally diagnosed; no patient had presented with clinical symptoms. Of the 44 patients, 788
Table 1. Patient and tumor characteristics Characteristic
Value
Age (y) Median Range Sex (n) Male Female Charlson index (n) ⱖ2 1 Multifocal disease (n) Bilateral disease (n) Initial tumor size (cm) Median Range Ending tumor size (cm) Median Range Lesion type (n) Solid Cystic Patients with biopsy (n) Overall mean growth rate (cm/y) Follow-up (mo) Median Range Imaging studies/person (n) Median Range Patients withdrawn from AS (n) Progression/metastasis Cancer-related deaths Noncancer-related deaths (n)
71.7 55-92 21 (47.7) 23 (52.3) 32 (72.7) 12 (27.3) 7 (15.9) 4 (9) 2.67 0.9-8.6 4 1-10.7 36 (70.6) 15 (29.4) 17 (38.6) 0.15 77.1 60-137 9 6-14 2 (4.5) 0 0 1 (2.2)
Data in parentheses are percentages.
7 (15.9%) had been diagnosed with multiple lesions and 4 (9%) had bilateral tumors. Most RCNs were solidenhancing masses (n ⫽ 36, 70.6%), and the remaining lesions were Bosniak IV cysts (n ⫽ 15, 29.4%). The median tumor size on axial imaging at diagnosis was 2.67 cm (range 0.9-8.6), with 41 tumors (80.3%) measuring ⬍4 cm (Stage cT1a). The median tumor size at the end of the observation period was 4 cm (range 1-10.7). The overall mean tumor growth rate was 0.15 cm/y (range 0-1.73), with larger tumors (⬎4 cm) exhibiting a faster growth rate at 0.31 cm/y (range 0-1.73). Of the 51 tumors under AS, 15 (29.4%) did not demonstrate any interval growth. Of the 44 patients, 17 (38.6%) underwent biopsy of their renal mass. The histopathology report confirmed malignant pathologic features in all the cases. More specifically, 15 biopsy specimens (88.2%) demonstrated clear cell RCC and 2 (11.8%) revealed papillary RCC. The mean growth rate of the pathologically confirmed tumors was 0.25 cm/y. Finally, the median initial and terminal serum creatinine levels were comparable at 1.1 mg/mL (range 0.8-1.4) and 1.2 mg/mL (range 0.9-1.6), respectively. Two patients (4.5%) failed AS. The first patient had an initial tumor size of 8.6 cm that exhibited an average growth rate of 0.44 cm/y. He underwent laparoscopic radical nephrectomy, after spending 60 months on AS. UROLOGY 77 (4), 2011
Histopathologic examination revealed Stage pT2 clear cell RCC. At 24 months postoperatively, no recurrence had been reported. The second patient elected to withdraw from AS because of personal anxiety and despite having stable disease for 72 months. The tumor size was 2.5 cm, and he eventually underwent laparoscopic renal cryotherapy. The intraoperative biopsy demonstrated clear cell RCC, and the patient had had no recurrence at 12 months postoperatively. Only 1 patient died during the course of the present evaluation. That patient (2.2%) died of another medical condition (heart failure) after undergoing AS for 96 months. His tumor demonstrated zero interval growth. No metastases or cancer-related deaths were reported in the entire cohort.
COMMENT The natural history of localized RCN is not well-known because of their early removal after diagnosis in most cases. Although the reference standard has remained surgical excision or ablation, AS has been increasingly implemented in selected patients, with growing published data supporting this management strategy.9-11 Recent guidelines published by the American Urological Association for the management of small renal tumors recommends AS as a reasonable treatment for patients with Stage T1 RCN and decreased life expectancy, or those with increased surgical risk. Despite the growing body of evidence trying to better assess the biology of RCN, very little is known about the natural history of tumors that have remained on AS for a long period. As such, we evaluated patients who continued with AS for a minimal period of 5 years in an effort to optimize patient management decisions. The median patient age in the present study was 71.7 years, similar to that described in other major studies.9,10,12 Of the 44 patients, 32 (75.7%) had a Charlson comorbidity index of ⱖ2. A recently published report by Berger et al13 reported that advanced patient age and medical comorbidities can independently reduce the overall survival benefit of patients who undergo nephrectomy for renal tumors. Despite the lack of strict selective criteria, we believe that elderly patients with severe comorbidities are ideal candidates for AS, because they have a significantly greater surgical risk and can be treated with a noninterventional approach. The tumor size has traditionally been used in selecting patients for AS, with many urologists recommending AS for RCNs of ⬍4 cm. The mean tumor size in our population was 2.67 cm (range 0.9-8.6), with 80.3% of the lesions Stage cT1a. Most solid, enhancing renal masses are RCC. Remzi et al14 retrospectively analyzed 287 RCNs ⬍4 cm that underwent surgery. They reported that 81.9% of all small renal masses were RCC.14 However, recent data have suggested that smaller lesions might have a greater chance of being benign. Frank et al15 retrospectively examined 2935 solid renal tumors that were surgically treated during a 30-year period and reUROLOGY 77 (4), 2011
ported that 46.3%, 22.4%, 22%, and 19.9% of renal lesions ⬍1, ⬍2, ⬍3, and ⬍4 cm to be benign, respectively. Gill et al16 treated 100 tumors with a mean size of 2.8 cm with laparoscopic partial nephrectomy and reported that 30% of the lesions were benign. These results have provided a pathologic basis for the use of AS management of RCN. However, the tumor size alone at presentation cannot predict malignancy and progression.17 The individual growth kinetics of suspicious RCNs have been used to determine a possible delayed intervention and eventual withdrawal of patients from AS. Most RCNs grow slowly, with average growth rates ranging from 0.09 to 0.86 cm/y.9,10 In a recently published study, Rosales et al18 examined 223 RCNs in 212 patients on AS and reported a median growth rate of 0.34 cm/y (range 0.29-2.3). In a meta-analysis of several AS studies, Chawla et al17 analyzed 234 lesions and found an overall growth rate of 0.28 cm/y. The observed growth rate in the present study was 0.15 cm/y (range 0-1.73). Although the initial tumor size cannot predict tumor growth, we found interesting that the growth rate of larger tumors (⬎4 cm) was double that of the entire cohort (0.31 cm/y). Mues et al19 recently reported a mean growth rate of 0.57 cm/y for large renal masses (cT1bN0M0 and cT2N0M0) undergoing AS. A total of 15 patients (29.4%) in our cohort exhibited a zero tumor growth rate on follow-up imaging. In the present data, the number of RCNs that remained stable has been 26%-33%.20 However, these findings should be interpreted with caution, because tumors with zero growth rates might also have malignant potential.21 It is likely that the key factor contributing to the slow growth rate in our cohort was that we excluded patients with follow-up of ⬍5 years. It is likely that most faster growing tumors in our overall AS series underwent intervention before the 5-year follow-up period. In our entire AS cohort, we had 212 patients, of whom 11 patients (5.1%) underwent intervention and 4 (1.9%) had progression to metastatic disease. As such, the patients reported in the present series were somewhat selected for the particularly indolent nature of their disease. Taking this into consideration, the results of the present study should not be used to prospectively make treatment decisions regarding patients presenting with RCNs. However, it is of value that once patients have been followed up for 5 years, the probability remains high that they will not require intervention. To date, controversy still exists regarding the value of biopsy for RCNs, with many urologists expressing concerns regarding the overall accuracy and complication rates. However, fine needle aspiration and core biopsy techniques have improved, and they can be applied in an outpatient setting with low morbidity.22,23 Schmidbauer et al24 published a prospective study of 78 patients who had undergone 18-gauge core biopsy under CT guidance. They also used the same sheath for fine needle aspiration and cytologic analysis. The masses were surgically re789
moved, and the histology reports were compared with the preoperative biopsy results. The investigators reported a sensitivity of 93.5% and 90.6% for core biopsy and fine needle aspiration, respectively. In our study, 17 patients (38.6%) underwent biopsy, with all lesions RCC. With improved techniques and the emergence of novel molecular and gene markers, biopsy will not only differentiate between malignant and benign renal masses, but it will also significantly effect clinical management, providing useful information about the aggressiveness and prognosis of RCNs. Also, none of the patients undergoing biopsy in our series experienced a complication or documented tumor seeding. Two patients (4.5%) from our entire cohort elected to stop AS. The first patient underwent ablation of a 2.5-cm tumor despite AS and stable disease for 72 months. This patient was encouraged to continue with AS but refused. This case underscores the fear and anxiety that patients do experience with AS protocols. This factor has yet to be quantified in any RCN AS evaluation. The other patient had an 8.6-cm lesion at presentation, making it highly suspicious for RCC. That patient was observed because of severe comorbidities; however, the tumor demonstrated a growth rate (0.44 cm/y) almost 3 times greater than the rest of the cohort. After 60 months of AS, he underwent laparoscopic radical nephrectomy. The pathology report revealed clear cell RCC in both cases. Although no pre-established cutoff growth rate has been determined for delayed intervention, we believe that rapid growth of RCNs under AS should always be a point of concern and should be treated with surgery or ablation, independent of the tumor’s size. Several studies, including data recently published from our institution, have supported that RCNs under AS can be managed expectantly without compromising the oncologic outcome.6,18,25,26 In the meta-analysis performed by Chawla et al,17 only 3 (1%) of 287 patients had developed metastatic disease during AS. Similar low rates have also been published in other studies.6,8,18,27 A common finding in all series was that no metastasis was reported in the absence of tumor growth. With the longest median follow-up of AS ever reported at 77.1 months (range 60-137) and with a median tumor growth rate of 0.15 cm/y, it was notable that no patient developed metastasis and no cancerrelated deaths were recorded. Again, in our overall series of AS for RCNs, 4 patients (1.9%) progressed to metastatic disease, with 1 patient (0.5%) dying of RCC during AS. Despite the metastatic potential of RCN, tumors with a slow initial growth rate that have remained stable for a long time are less likely to manifest progression or metastasis. As such, we intuitively believe that initial close evaluations (every 3-6 months) should be followed by annual follow-up examinations if the tumor shows an initial slow growth rate, with CT remaining the most accurate imaging modality, despite the radiation dose and intravenous contrast requirement. 790
The present study had several limitations, mostly related to its retrospective nature. It was a single-institution data set in which no well-defined criteria were used for patient selection, surveillance, or intervention. The patients in the present cohort were of a particularly advanced age and represented a group with a heterogeneous population of lesions, with only a part of them having malignant confirmation by biopsy. Finally, it is imperative to note that, by definition, the patient population described in the present series was selected by not having undergone intervention or disease progression in the first 5 years of follow-up. Large, prospective, clinical trials are required to more precisely define the role and safety of AS in the management of RCN.
CONCLUSIONS The results of the present study have shown that RCNs that undergo AS for ⱖ5 years exhibit a minimal growth rate with low metastatic potential. The average growth rate of 0.15 cm/y was one half the average growth rate currently documented in the published data. Although surgical treatment remains the standard therapy, AS can be a viable treatment option for elderly patients with concomitant medical conditions. References 1. Pantuck AJ, Zisman A, Belldegrun AS. The changing natural history of renal cell carcinoma. J Urol. 2001;166:1611-1623. 2. Chow WH, Devesa SS, Warren JL, et al. Rising incidence of renal cell cancer in the United States. JAMA. 1999;281:1628-1631. 3. Parsons JK, Schoenberg MS, Carter HB. Incidental renal tumors: casting doubt on the efficacy of early intervention. Urology. 2001; 57:1013-1015. 4. Pahernik S, Ziegler S, Roos F, et al. Small renal tumors: correlation of clinical and pathological features with tumor size. J Urol. 2007; 178:414-417. 5. Remzi M, Ozsoy M, Klingler HC, et al. Are small renal tumors harmless? Analysis of histopathological features according to tumors 4 cm or less in diameter. J Urol. 2006;176:896-899. 6. Kouba E, Smith A, McRackan D, et al. Watchful waiting for solid renal masses: insight into the natural history and results of delayed intervention. J Urol. 2007;177:466-470. 7. Kato M, Suzuki T, Suzuki Y, et al. Natural history of small renal cell carcinoma: evaluation of growth rate, histological grade, cell proliferation and apoptosis. J Urol. 2004;172:863-866. 8. Lamb GW, Bromwich EJ, Vasey P, et al. Management of renal masses inpatients medically unsuitable for nephrectomy—natural history, complications, and outcome. Urology. 2004;64:909-913. 9. Abou Youssif T, Kassouf W, Steinberg J, et al. Active surveillance for selected patients with renal masses: updated results with longterm follow-up. Cancer. 2007;110:1010-1014. 10. Crispen PL, Viterbo R, Fox EB, et al. Delayed intervention of sporadic renal masses undergoing active surveillance. Cancer. 2008; 112:1051-1057. 11. Kunkle DA, Egleston BL, Uzzo RG. Excise, ablate or observe: the small renal mass dilemma—a meta-analysis and review. J Urol. 2008;179:1227-1233. 12. Abouassaly R, Lane BR, Novick AC. Active surveillance of renal masses in elderly patients. J Urol. 2008;180:505-508. 13. Berger DA, Megwalu VA II, et al. Impact of comorbidity on overall survival in patients surgically treated for renal cell carcinoma. Urology. 2008;72:359-363.
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14. Remzi M, Katzenbeisser D, Waldert M, et al. Renal tumour size measured radiologically before surgery is an unreliable variable for predicting histopathological features: benign tumours are not necessarily small. BJU Int. 2007;99:1002-1006. 15. Frank I, Blute ML, Cheville JC, et al. Solid renal tumors: an analysis of pathological features related to tumor size. J Urol. 2003;170(6 Pt. 1):2217-2220. 16. Gill IS, Matin SF, Desai MM. Comparative analysis of laparoscopic versus open partial nephrectomy. J Urol. 2003;170:64-68. 17. Chawla SN, Crispen PL, Hanlon AL, et al. The natural history of observed enhancing renal masses: meta-analysis and review of the world literature. J Urol. 2006;175:425. 18. Rosales JC, Haramis G, Moreno J, et al. Active surveillance of renal cortical neoplasms. J Urol. 2010;183:1698-1702. 19. Mues AC, Haramis G, Badani K, et al. Active surveillance for larger (cT1bN0M0 and cT2N0M0) renal cortical neoplasms. Urology. 2010;76:620-623. 20. Klaver S, Joniau S, Van Poppel H. Surveillance as an option for the treatment of small renal masses. Adv Urol. 2008:705958: 1-6.
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