Original Study
Small Renal Masses Managed With Active Surveillance: Predictors of Tumor Growth Rate After Long-Term Follow-Up Riccardo Schiavina,1 Marco Borghesi,1 Hussam Dababneh,1 Lorenzo Bianchi,1 Barbara Longhi,1 Davide Diazzi,1 Carlo Monti,2 Gaetano La Manna,3 Giuseppe Martorana,1 Eugenio Brunocilla1 Abstract Active surveillance (AS) could be a valid alternative for the management of small renal masses (SRMs) in elderly or comorbid patients. The natural history of SRMs has not been completely clarified and, to date, no convincing predictors of tumor growth rate or biological behavior of small cortical neoplasms have been described. In our cohort, male sex (hazard ratio [HR], 1.70; P [ .04) and symptomatic presentation (HR, 1.85; P [ .02) were found to be significant predictors of tumor growth rates during AS. Background: The purpose of the study was to evaluate the relationships between the patients’ clinical characteristics and the growth pattern of SRMs, and to investigate the predictive factors of tumor growth rates in patients initially managed with AS. Materials and Methods: We retrospectively reviewed data from our prospectively collected database of 70 patients diagnosed with 72 SRMs between 1996 and 2013. Clinical and demographic data, and linear and volumetric growth rates were recorded for each patient. A Pearson correlation test was used to evaluate initial tumor size and linear or volumetric growth rate. Logistic regression models were used to evaluate the predictive factors affecting tumor growth kinetics. Results: The mean age was 76 6.8 years, and 47 (67.1%) of patients were male. The mean ( SD) and the median (interquartile range [IQR]) tumor size at presentation were 2.1 1.3 and 2.7 (1.8-3.7) cm, respectively. The mean ( SD) and the median (IQR) linear growth rate were 0.5 0.3 and 0.6 (0.4-1.5) cm per year, respectively. Patients treated with delayed surgery experienced a significantly greater mean linear growth rate (1.4 vs. 0.3 cm per year) than those observed in the AS group (P < .001). Male sex (HR, 1.70; P ¼ .04) and symptomatic presentation (HR, 1.85; P ¼ .02) were found to be significant predictors of tumor growth rates during AS. Conversely, age, Charlson Comorbidity Index, and initial tumor size failed to predict growth kinetics. Conclusion: Male sex and symptomatic presentation are associated with faster growth rates in patients managed with AS after long-term follow-up. Clinical Genitourinary Cancer, Vol. -, No. -, --- ª 2014 Elsevier Inc. All rights reserved. Keywords: Delayed surgery, Predictors, Renal cell carcinoma, Small cortical tumors, Surveillance protocol
Introduction Riccardo Schiavina and Marco Borghesi contributed equally to this work. 1 Department of Urology, University of Bologna, S. Orsola-Malpighi Hospital, Bologna, Italy 2 Department of Radiology, M.F. Toniolo Hospital, Bologna, Italy 3 Department of Nephrology, University of Bologna, S. Orsola-Malpighi Hospital, Bologna, Italy
Submitted: May 23, 2014; Revised: Aug 9, 2014; Accepted: Aug 25, 2014 Address for correspondence: Marco Borghesi, MD, Department of Urology, University of Bologna, S. Orsola-Malpighi Hospital, Palagi 9 St, 40134 Bologna, Italy Fax: þ390516362733; e-mail contact: [email protected]
1558-7673/$ - see frontmatter ª 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clgc.2014.08.006
Renal cell carcinoma (RCC) accounts for 3% to 4% of all adult malignant neoplasms,1 with a growing incidence among the Western population in the most recent years.2 The widespread use of noninvasive abdominal imaging has led to a significant detection of small renal masses (SRMs),3 and a nonnegligible amount of those tumors are currently diagnosed in patients who are poor surgical candidates, because of relevant comorbidities or older age.4 Nephron-sparing surgery is considered the standard of care for clinically localized RCC whenever technically feasible,2 with excellent oncological results,5 even in the most challenging and complex
Clinical Genitourinary Cancer Month 2014
-1
Growth Rate Predictors of SRMs procedures,6 with less renal function impairment compared with radical nephrectomy.7 However, there is growing awareness that competing risks related to medical comorbidities in elderly patients might outweigh the potential benefits of surgical intervention,8 especially when considering that approximately 20% to 30% of SRMs will prove to be benign at final histological examination, and will show low metastatic potential during surveillance.9 Thermal ablations (cryotherapy or radiofrequency ablation) and active surveillance (AS) could be valid alternatives in those selected patients.4 Although the radiographic linear and volumetric growth pattern demonstrated as useful indicators for aggressive behavior of SRMs initially managed with AS,10-12 no convincing predictors of tumor growth rate or biological behavior of small cortical neoplasms have been described. The aim of this retrospective study was to evaluate the relationships between the patients’ clinical characteristics and the growth pattern of SRMs, and to investigate whether these features could serve as useful predictors of growth kinetics in patients managed with AS.
Materials and Methods
2
-
We retrospectively reviewed our prospectively collected database of 70 patients diagnosed with renal cortical tumors at our institution, and we extracted only data for patients with SRMs in whom an initial surveillance protocol was scheduled. Therefore, an overall amount of 72 SRMs suspected to be RCC, detected during imaging procedures between January 1996 and August 2013 constituted the definitive cohort of the present study. An AS protocol was proposed for patients with relevant comorbidities, advanced age, or patient refusal of surgery. Patients with Von HippeleLindau syndrome, history of hereditary RCC, and metastatic disease at presentation were excluded from the study cohort. All patients had been followed according to our AS protocol.10-12 In detail, we performed physical examination, blood sampling, and imaging studies every 3 or 6 months for the first year, and then annually; chest x-ray (especially in the first years of study), chest and abdomen computed tomography (CT; 5-mm slice thickness, with and without intravenous iodine contrast) scans, magnetic resonance or ultrasound imaging were used for radiological evaluations. Tumor size was defined as the largest diameter of the tumor, measured in axial or coronal planes; whenever available, anteroposterior, transverse, and craniocaudal diameters were measured. Tumor volume was calculated based on the available dimensions reported in imaging studies. An ellipsoid volume formula (0.5326xyz) was used if 3 dimensions were present; the formula 0.5326xy (x þ y/2) was used if 2 dimensions were available, and the formula for the volume of a sphere (0.5326 x3) was used if only 1 dimension was reported by radiologists.13 Anatomical tumor complexity was evaluated basing on 2 of the most used nephrometric scores, the Preoperative Aspects and Dimensions Used for an Anatomical classification (PADUA)14 and the R.E.N.A.L. nephrometry score.15 Percutaneous CT-guided biopsy were performed at the time of presentation or during follow-up in case of rapid growth rate according to the physician’s preference. The Charlson Comorbidity Index (CCI) was determined in every patient. The end of follow-up was defined by either patient death or surgical intervention. The study was performed according to the Declaration of Helsinki and the national regulations. All patients provided an informed consent for participation and anonymous publication of the data.
Clinical Genitourinary Cancer Month 2014
A Pearson correlation test was used to evaluate initial tumor size and linear or volumetric growth rate. Categorical and continuous data were evaluated using the c2 and the Student t test, respectively. The Wilcoxon/KruskaleWallis test was used for growth rate comparisons between groups. Logistic regression models were used to evaluate the predictive factors affecting the tumor growth rates. SPSS version 22 (IBM Corp, Armonk, NY) was used for statistical analysis. Two-tailed P values < .05 were considered statistically significant.
Results Seventy patients were diagnosed with 72 SRMs in the study period. The mean age at the time of presentation was 76 6.8 years, and 67.1% of patients were male. In 65 (92.9%) cases, the small cortical tumors had been incidentally diagnosed during imaging procedures performed for other medical reasons; the other 5 cases (7.1%) had been diagnosed in patients who complained of abdominal or back pain, without other apparent medical or surgical explanations. The mean ( SD) and the median (interquartile range [IQR]) follow-up duration were 92.7 5.2 and 61 (38-150) months, respectively. The mean CCI was 3 (range, 1-6). The most common comorbidities were: congestive heart failure, coronary artery disease, chronic renal failure, respiratory insufficiency, and dementia. At the time of presentation, the mean ( SD) and the median (IQR) tumor size at presentation were 2.1 1.3 and 2.7 (1.8-3.7) cm, respectively, and the mean ( SD) and the median (IQR) estimated tumor volume were 4.9 2.5 and 8.2 (2.5-20.6) cm3, respectively. The median PADUA and RENAL score in the overall population were 7 (IQR, 6-8). The mean ( SD) and the median (IQR) linear growth rate were 0.5 0.3 and 0.6 (0.4-1.5) cm per year, respectively, and the mean ( SD) and the median (IQR) volumetric growth rate were 4.5 2.2 and 7.9 (2.3-18.5) cm3 per year, respectively (Table 1). The linear growth pattern of the small cortical tumors is shown in Figure 1. Percutaneous CTguided biopsy of the renal neoplasm were performed in 28 patients; of them, 8 underwent percutaneous biopsy at the time of diagnosis, and the other 20 during follow-up, because of a fast growth rate or the urologist’s preference. Clear-cell RCC was found in 16 (57.1%) cases, papillary RCC in 3 (10.7%) cases, benign findings in 7 (5 oncocytomas and 2 angiomyolipomas; 25%) and inconclusive findings in 2 cases (7.2%). Four patients underwent immediate nephron-sparing surgery after a positive percutaneous CT-guided biopsy and, among these patients, 3 pT1a clear-cell RCC and 1 pT1a papillary-type 1 RCC were found. The other 15 patients with positive percutaneous biopsy findings were not treated, and AS was continued. During follow-up, 18 (25.7%) patients were treated with delayed surgical excision, because of a fast growth rate in 15 cases or the patient’s preference; partial nephrectomy was performed in 14 cases. The pathological examination of the SRMs revealed 12 (66.7%) clear-cell RCC, 4 (22.2%) papillary RCC, and 2 (11.1%) benign oncocytomas. According to the tumor, node, metastases staging system, 15 patients were classified as pT1a (83.3%), 2 patients were classified as pT1b (11.1%), and only 1 patient was classified as pT3a (5.6%). Of patients who underwent delayed surgical treatment, 1 patient died from metastatic lung and liver disease after 14 months from surgery; no evidence of disease recurrence or progression was found in the remaining 18 patients
Riccardo Schiavina et al treated with delayed nephron-sparing surgery or radical nephrectomy. The remaining 48 patients (68.6%) were included in the AS protocol, according to our follow-up scheme. Eighteen patients (37.5%) died during the observation period. The reasons for death were acute coronary disease in 11 patients, respiratory insufficiency in 5 patients, pulmonary embolism in 1 patient, and metastatic (liver and lung) disease after 20 months of follow-up in 1 patient. The remaining 30 (62.5%) patients were still alive and free from disease progression or metastases at the end of follow-up. The cancer-specific mortality was observed only in 2 patients (2.8%) of the entire study population; death was from metastatic disease
(1 patient in the surveillance group died after 20 months of followup and another patient died because of disease progression after 14 months from radical nephrectomy). A comparison between the delayed surgical intervention group and AS group is reported in Table 1. No statistically significant differences were found in terms of age, CCI, follow-up duration, tumor size, volume at presentation, and nephrometric scores (PADUA and RENAL scores) measured at the time of diagnosis (P > .05). Conversely, patients included in the AS protocol were more likely to be male (70.8% vs. 61%; P ¼ .04) and to be incidentally diagnosed with SRMs (95.8% vs. 83.3%; P ¼ .04) compared with patients treated with delayed
Table 1 Clinical, Demographic, and Tumor Characteristics of the 70 Patients Diagnosed With 72 SRMs, and Comparison Between the Delayed Surgical Intervention Group and Active Surveillance Group Overall (n [ 70)
Variables
Delayed Surgical Intervention Group (n [ 18)a
Active Surveillance Group (n [ 48)
P .06
Age at Presentation, Years Mean SD
76 6.8
75 6.2
77 6.8
Median (IQR)
77 (68-82)
76 (68-80)
78 (71-88)
Male Sex, n (%)
47 (67.1)
11 (61)
34 (70.8)
.04 .04
Mode of Presentation, n (%) Incidental
65 (92.9)
15 (83.3)
46 (95.8)
Local symptoms
5 (7.1)
3 (16.7)
2 (4.2)
Mean CCI (Range)
3 (1-6)
3
4
.15
27.4 4.4
.23
Body Mass Index Mean SD
27.0 4.3
28.1 5.0
Median (IQR)
26.6 (23.5-30.3)
27.1 (24-31)
Mean SD
92.7 5.2
90.1 5.0
Median (IQR)
61 (38-150)
60 (38-148)
63 (36-150)
26.8 (24-31)
Follow-Up Duration, Months 93 5.5
.23
Tumor Size at Presentation, cm Mean SD
2.1 1.3
2.1 1.2
2.0 1.4
Median (IQR)
2.7 (1.8-3.7)
2.8 (1.8-3.8)
2.5 (1.7-4.1)
.14
Estimated Tumor Volume at Presentation, cm3 Mean SD
4.9 2.5
4.9 2.6
4.6 2.3
Median (IQR)
8.2 (2.5-20.6)
8.8 (2.8-21)
8.4 (2.2-19.5)
Median PADUA Score (IQR)b
7 (6-8)
8 (7-9)
b
7 (6-8)
Median RENAL Score (IQR)
.24
7 (6-8)
.36
7.5 (7-8.7)
7 (5.7-7)
.52
26 (37.2)
16 (80.9)
6 (12.5)
.005
9 (12.8)
2 (11.1)
7 (14.6)
Pathological Findings, n (%) Bx or histologically proven RCC Benign Unknown
35 (50)
0 (0)
35 (72.9)
Linear Growth Rate, cm/years Mean SD
0.5 0.3
1.4 0.5
0.3 0.4
Median (IQR)
0.6 (0.4-1.5)
1.6 (0.3-2.5)
1 (0.3-1.6)
.05). Unsurprisingly, the histological status (proven RCC vs. unknown tumor) did not predict the tumor growth rates in the overall population (P ¼ .08), nor in the AS group (P ¼ .09). Notably, in 35 patients (72.9%) enrolled in the surveillance protocol, the bioptical discrimination between benign or malignant lesion had not been obtained, and therefore the number of undiagnosed renal cancers could have been quite higher in this group. This reflection, together with the awareness of the extremely heterogeneous biology of small cortical tumors could be a possible explanation of such a result. Organ and coworkers, in their multi-institutional, prospective phase II clinical trial from the Renal Cell Carcinoma Consortium of Canada, conducted on 207 SRMs initially managed with AS with a median follow-up of 603 days,20 found no significant clinical or radiological predictors of growth kinetics. The predictive role of tumor dimension at the time of presentation has been matter of debate in the literature. In the present study, the SRM size was not a significant predictor of growth kinetics (P > .05). Similar results have been reported by others.13,16,21,22 Conversely, several investigators showed that the
tumor size could predict the tumor growth rate. Mason et al showed that larger ( 2.45 cm) renal masses grow more quickly than smaller (< 2.45 cm) ones, with a greater risk to develop to metastatic disease.23 AS could be a reasonable option in the management of SRMs in selected patients, even considering the low rate of metastatic spreading of the tumor and the low risk of cancer-specific death. In the present study, only 2 (2.8%) patients experienced metastatic disease (1 after delayed surgery, and the other during AS). In both of these cases, the patients died from causes related to kidney cancer. Several other studies demonstrated that SRMs managed with AS have a low (1%-2%) metastatic potential.9,22-25 These data are comparable with those shown in the meta-analysis by Chawla et al.13 In this remarkable report, indeed, progression to metastatic disease was described in 3 patients, representing only 1% of the entire cohort of patients. The main strength and advantage of this study are based on the longterm follow-up, by which stronger correlations between clinical predictors and tumor growth kinetics have been found. However, the retrospective design, with the inherent related biases, together with the quite low number of enrolled patients are the most important limitations.
Conclusion Male sex and symptomatic presentation are associated with faster growth rates in patients managed with AS after long-term follow-up. These data add new important knowledge to the body of literature, even if larger studies with longer follow-up are needed to confirm these results.
Clinical Practice Points The detection of SRMs is increasing over time, and a non-
negligible amount of these tumors are diagnosed in patients unsuitable for surgery, because of relevant comorbidities or older age. Linear and volumetric growth patterns could be useful indicators for aggressive behavior of SRMs initially managed with AS, but no convincing predictors of tumor growth rate have been described. In this study, male sex (HR, 1.70; P ¼ .04) and symptomatic presentation (HR, 1.85; P ¼ .02) were found to be significant predictors of tumor growth rates during AS. Conversely, age, CCI, and initial tumor size failed to predict growth kinetics. A better understanding of growth kinetics of SRMs would help clinicians in choosing the best management in each patient. This study adds important knowledge to the body of literature, but larger studies are needed to confirm these results.
Disclosure The authors have stated that they have no conflicts of interest.
References 1. Siegel R, Ma J, Zou Z, et al. Cancer statistics, 2014. CA Cancer J Clin 2014; 64: 9-29. 2. Ljungberg B, Campbell SC, Choi HY, et al. The epidemiology of renal cell carcinoma. Eur Urol 2011; 60:615-21. 3. Hollingsworth JM, Miller DC, Daignault S, et al. Rising incidence of small renal masses: need to reassess treatment effect. J Natl Cancer Inst 2006; 98:1331-4. 4. Kunkle DA, Egleston BL, Uzzo RG. Excise, ablate or observe: the small renal mass dilemmaea meta-analysis and review. J Urol 2008; 179:1227-33.
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Growth Rate Predictors of SRMs 5. Van Poppel H, Da Pozzo L, Albrecht W, et al. A prospective, randomised EORTC intergroup phase 3 study comparing the oncologic outcome of elective nephronsparing surgery and radical nephrectomy for low-stage renal cell carcinoma. Eur Urol 2011; 59:543-52. 6. Borghesi M, Schiavina R, Gan M, et al. Expanding utilization of robotic partial nephrectomy for clinical T1b and complex T1a renal masses. World J Urol 2013; 31:499-504. 7. Scosyrev E, Messing EM, Sylvester R, et al. Renal function after nephron-sparing surgery versus radical nephrectomy: results from EORTC randomized trial 30904. Eur Urol 2014; 65:372-7. 8. Kutikov A, Egleston BL, Wong YN, et al. Evaluating overall survival and competing risks of death in patients with localized renal cell carcinoma using a comprehensive nomogram. J Clin Oncol 2010; 28:311-7. 9. Smaldone MC, Kutikov A, Egleston BL, et al. Small renal masses progressing to metastases under active surveillance: a systematic review and pooled analysis. Cancer 2012; 118:997-1006. 10. Brunocilla E, Borghesi M, Monti C, et al. Surveillance for small renal masses: retrospective analysis of a cohort of 42 patients with long-term follow-up. Int Urol Nephrol 2013; 45:307-12. 11. Brunocilla E, Borghesi M, Schiavina R, et al. Active surveillance for small renal masses diagnosed in elderly or comorbid patients: looking for the best treatment strategy. Actas Urol Esp 2014; 38:1-6. 12. Brunocilla E, Borghesi M, Schiavina R, et al. Small renal masses initially managed using active surveillance: results from a retrospective study with long-term followup. Clin Genitourin Cancer 2014; 12:178-81. 13. 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; 175:425-31. 14. Ficarra V, Novara G, Secco S, et al. Preoperative aspects and dimensions used for an anatomical (PADUA) classification of renal tumors in patients who are candidates for nephron-sparing surgery. Eur Urol 2009; 56:786-93.
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15. Kutikov A, Uzzo RG. The R.E.N.A.L. nephrometry score: a comprehensive standardized system for quantitating renal tumor size, location and depth. J Urol 2009; 182:844-53. 16. 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; 115:2844-52. 17. Borghesi M, Della Mora L, Brunocilla E, et al. Warm ischemia time and postoperative complications after partial nephrectomy for renal cell carcinoma. Actas Urol Esp 2014; 38:313-8. 18. Matsumoto R, Abe T, Shinohara N, et al. RENAL nephrometry score is a predictive factor for the annual growth rate of renal mass. Int J Urol 2014; 21: 549-52. 19. Tomaszewski JJ, Uzzo RG, Kocher N, et al. Patients with anatomically “simple” renal masses are more likely to be placed on active surveillance than those with anatomically “complex” lesions. Urol Oncol, Published online June 6, 2014; http:// dx.doi.org/10.1016/j.urolonc.2014.05.003. 20. Organ M, Jewett M, Basiuk J, et al. Growth kinetics of small renal masses: a prospective analysis from the Renal Cell Carcinoma Consortium of Canada. Can Urol Assoc J 2014; 8:24-7. 21. Abouassaly R, Lane BR, Novick AC. Active surveillance of renal masses in elderly patients. J Urol 2008; 180:505-8. 22. Rosales JC, Haramis G, Moreno J, et al. Active surveillance for renal cortical neoplasms. J Urol 2010; 183:1698-702. 23. Mason RJ, Abdolell M, Trottier G, et al. Growth kinetics of renal masses: analysis of a prospective cohort of patients undergoing active surveillance. Eur Urol 2011; 59:863-7. 24. Volpe A, Panzarella T, Rendon RA, et al. The natural history of incidentally detected small renal masses. Cancer 2004; 100:738-45. 25. Jewett MA, Mattar K, Basiuk J, et al. Active surveillance of small renal masses: progression patterns of early stage kidney cancer. Eur Urol 2011; 60: 39-44.
Small Renal Masses Managed With Active Surveillance: Predictors of Tumor Growth Rate After Long-Term Follow-Up Riccardo Schiavina,1 Marco Borghesi,1 Hussam Dababneh,1 Lorenzo Bianchi,1 Barbara Longhi,1 Davide Diazzi,1 Carlo Monti,2 Gaetano La Manna,3 Giuseppe Martorana,1 Eugenio Brunocilla1 Abstract Active surveillance (AS) could be a valid alternative for the management of small renal masses (SRMs) in elderly or comorbid patients. The natural history of SRMs has not been completely clarified and, to date, no convincing predictors of tumor growth rate or biological behavior of small cortical neoplasms have been described. In our cohort, male sex (hazard ratio [HR], 1.70; P [ .04) and symptomatic presentation (HR, 1.85; P [ .02) were found to be significant predictors of tumor growth rates during AS. Background: The purpose of the study was to evaluate the relationships between the patients’ clinical characteristics and the growth pattern of SRMs, and to investigate the predictive factors of tumor growth rates in patients initially managed with AS. Materials and Methods: We retrospectively reviewed data from our prospectively collected database of 70 patients diagnosed with 72 SRMs between 1996 and 2013. Clinical and demographic data, and linear and volumetric growth rates were recorded for each patient. A Pearson correlation test was used to evaluate initial tumor size and linear or volumetric growth rate. Logistic regression models were used to evaluate the predictive factors affecting tumor growth kinetics. Results: The mean age was 76 6.8 years, and 47 (67.1%) of patients were male. The mean ( SD) and the median (interquartile range [IQR]) tumor size at presentation were 2.1 1.3 and 2.7 (1.8-3.7) cm, respectively. The mean ( SD) and the median (IQR) linear growth rate were 0.5 0.3 and 0.6 (0.4-1.5) cm per year, respectively. Patients treated with delayed surgery experienced a significantly greater mean linear growth rate (1.4 vs. 0.3 cm per year) than those observed in the AS group (P < .001). Male sex (HR, 1.70; P ¼ .04) and symptomatic presentation (HR, 1.85; P ¼ .02) were found to be significant predictors of tumor growth rates during AS. Conversely, age, Charlson Comorbidity Index, and initial tumor size failed to predict growth kinetics. Conclusion: Male sex and symptomatic presentation are associated with faster growth rates in patients managed with AS after long-term follow-up. Clinical Genitourinary Cancer, Vol. -, No. -, --- ª 2014 Elsevier Inc. All rights reserved. Keywords: Delayed surgery, Predictors, Renal cell carcinoma, Small cortical tumors, Surveillance protocol
Introduction Riccardo Schiavina and Marco Borghesi contributed equally to this work. 1 Department of Urology, University of Bologna, S. Orsola-Malpighi Hospital, Bologna, Italy 2 Department of Radiology, M.F. Toniolo Hospital, Bologna, Italy 3 Department of Nephrology, University of Bologna, S. Orsola-Malpighi Hospital, Bologna, Italy
Submitted: May 23, 2014; Revised: Aug 9, 2014; Accepted: Aug 25, 2014 Address for correspondence: Marco Borghesi, MD, Department of Urology, University of Bologna, S. Orsola-Malpighi Hospital, Palagi 9 St, 40134 Bologna, Italy Fax: þ390516362733; e-mail contact: [email protected]
1558-7673/$ - see frontmatter ª 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clgc.2014.08.006
Renal cell carcinoma (RCC) accounts for 3% to 4% of all adult malignant neoplasms,1 with a growing incidence among the Western population in the most recent years.2 The widespread use of noninvasive abdominal imaging has led to a significant detection of small renal masses (SRMs),3 and a nonnegligible amount of those tumors are currently diagnosed in patients who are poor surgical candidates, because of relevant comorbidities or older age.4 Nephron-sparing surgery is considered the standard of care for clinically localized RCC whenever technically feasible,2 with excellent oncological results,5 even in the most challenging and complex
Clinical Genitourinary Cancer Month 2014
-1
Growth Rate Predictors of SRMs procedures,6 with less renal function impairment compared with radical nephrectomy.7 However, there is growing awareness that competing risks related to medical comorbidities in elderly patients might outweigh the potential benefits of surgical intervention,8 especially when considering that approximately 20% to 30% of SRMs will prove to be benign at final histological examination, and will show low metastatic potential during surveillance.9 Thermal ablations (cryotherapy or radiofrequency ablation) and active surveillance (AS) could be valid alternatives in those selected patients.4 Although the radiographic linear and volumetric growth pattern demonstrated as useful indicators for aggressive behavior of SRMs initially managed with AS,10-12 no convincing predictors of tumor growth rate or biological behavior of small cortical neoplasms have been described. The aim of this retrospective study was to evaluate the relationships between the patients’ clinical characteristics and the growth pattern of SRMs, and to investigate whether these features could serve as useful predictors of growth kinetics in patients managed with AS.
Materials and Methods
2
-
We retrospectively reviewed our prospectively collected database of 70 patients diagnosed with renal cortical tumors at our institution, and we extracted only data for patients with SRMs in whom an initial surveillance protocol was scheduled. Therefore, an overall amount of 72 SRMs suspected to be RCC, detected during imaging procedures between January 1996 and August 2013 constituted the definitive cohort of the present study. An AS protocol was proposed for patients with relevant comorbidities, advanced age, or patient refusal of surgery. Patients with Von HippeleLindau syndrome, history of hereditary RCC, and metastatic disease at presentation were excluded from the study cohort. All patients had been followed according to our AS protocol.10-12 In detail, we performed physical examination, blood sampling, and imaging studies every 3 or 6 months for the first year, and then annually; chest x-ray (especially in the first years of study), chest and abdomen computed tomography (CT; 5-mm slice thickness, with and without intravenous iodine contrast) scans, magnetic resonance or ultrasound imaging were used for radiological evaluations. Tumor size was defined as the largest diameter of the tumor, measured in axial or coronal planes; whenever available, anteroposterior, transverse, and craniocaudal diameters were measured. Tumor volume was calculated based on the available dimensions reported in imaging studies. An ellipsoid volume formula (0.5326xyz) was used if 3 dimensions were present; the formula 0.5326xy (x þ y/2) was used if 2 dimensions were available, and the formula for the volume of a sphere (0.5326 x3) was used if only 1 dimension was reported by radiologists.13 Anatomical tumor complexity was evaluated basing on 2 of the most used nephrometric scores, the Preoperative Aspects and Dimensions Used for an Anatomical classification (PADUA)14 and the R.E.N.A.L. nephrometry score.15 Percutaneous CT-guided biopsy were performed at the time of presentation or during follow-up in case of rapid growth rate according to the physician’s preference. The Charlson Comorbidity Index (CCI) was determined in every patient. The end of follow-up was defined by either patient death or surgical intervention. The study was performed according to the Declaration of Helsinki and the national regulations. All patients provided an informed consent for participation and anonymous publication of the data.
Clinical Genitourinary Cancer Month 2014
A Pearson correlation test was used to evaluate initial tumor size and linear or volumetric growth rate. Categorical and continuous data were evaluated using the c2 and the Student t test, respectively. The Wilcoxon/KruskaleWallis test was used for growth rate comparisons between groups. Logistic regression models were used to evaluate the predictive factors affecting the tumor growth rates. SPSS version 22 (IBM Corp, Armonk, NY) was used for statistical analysis. Two-tailed P values < .05 were considered statistically significant.
Results Seventy patients were diagnosed with 72 SRMs in the study period. The mean age at the time of presentation was 76 6.8 years, and 67.1% of patients were male. In 65 (92.9%) cases, the small cortical tumors had been incidentally diagnosed during imaging procedures performed for other medical reasons; the other 5 cases (7.1%) had been diagnosed in patients who complained of abdominal or back pain, without other apparent medical or surgical explanations. The mean ( SD) and the median (interquartile range [IQR]) follow-up duration were 92.7 5.2 and 61 (38-150) months, respectively. The mean CCI was 3 (range, 1-6). The most common comorbidities were: congestive heart failure, coronary artery disease, chronic renal failure, respiratory insufficiency, and dementia. At the time of presentation, the mean ( SD) and the median (IQR) tumor size at presentation were 2.1 1.3 and 2.7 (1.8-3.7) cm, respectively, and the mean ( SD) and the median (IQR) estimated tumor volume were 4.9 2.5 and 8.2 (2.5-20.6) cm3, respectively. The median PADUA and RENAL score in the overall population were 7 (IQR, 6-8). The mean ( SD) and the median (IQR) linear growth rate were 0.5 0.3 and 0.6 (0.4-1.5) cm per year, respectively, and the mean ( SD) and the median (IQR) volumetric growth rate were 4.5 2.2 and 7.9 (2.3-18.5) cm3 per year, respectively (Table 1). The linear growth pattern of the small cortical tumors is shown in Figure 1. Percutaneous CTguided biopsy of the renal neoplasm were performed in 28 patients; of them, 8 underwent percutaneous biopsy at the time of diagnosis, and the other 20 during follow-up, because of a fast growth rate or the urologist’s preference. Clear-cell RCC was found in 16 (57.1%) cases, papillary RCC in 3 (10.7%) cases, benign findings in 7 (5 oncocytomas and 2 angiomyolipomas; 25%) and inconclusive findings in 2 cases (7.2%). Four patients underwent immediate nephron-sparing surgery after a positive percutaneous CT-guided biopsy and, among these patients, 3 pT1a clear-cell RCC and 1 pT1a papillary-type 1 RCC were found. The other 15 patients with positive percutaneous biopsy findings were not treated, and AS was continued. During follow-up, 18 (25.7%) patients were treated with delayed surgical excision, because of a fast growth rate in 15 cases or the patient’s preference; partial nephrectomy was performed in 14 cases. The pathological examination of the SRMs revealed 12 (66.7%) clear-cell RCC, 4 (22.2%) papillary RCC, and 2 (11.1%) benign oncocytomas. According to the tumor, node, metastases staging system, 15 patients were classified as pT1a (83.3%), 2 patients were classified as pT1b (11.1%), and only 1 patient was classified as pT3a (5.6%). Of patients who underwent delayed surgical treatment, 1 patient died from metastatic lung and liver disease after 14 months from surgery; no evidence of disease recurrence or progression was found in the remaining 18 patients
Riccardo Schiavina et al treated with delayed nephron-sparing surgery or radical nephrectomy. The remaining 48 patients (68.6%) were included in the AS protocol, according to our follow-up scheme. Eighteen patients (37.5%) died during the observation period. The reasons for death were acute coronary disease in 11 patients, respiratory insufficiency in 5 patients, pulmonary embolism in 1 patient, and metastatic (liver and lung) disease after 20 months of follow-up in 1 patient. The remaining 30 (62.5%) patients were still alive and free from disease progression or metastases at the end of follow-up. The cancer-specific mortality was observed only in 2 patients (2.8%) of the entire study population; death was from metastatic disease
(1 patient in the surveillance group died after 20 months of followup and another patient died because of disease progression after 14 months from radical nephrectomy). A comparison between the delayed surgical intervention group and AS group is reported in Table 1. No statistically significant differences were found in terms of age, CCI, follow-up duration, tumor size, volume at presentation, and nephrometric scores (PADUA and RENAL scores) measured at the time of diagnosis (P > .05). Conversely, patients included in the AS protocol were more likely to be male (70.8% vs. 61%; P ¼ .04) and to be incidentally diagnosed with SRMs (95.8% vs. 83.3%; P ¼ .04) compared with patients treated with delayed
Table 1 Clinical, Demographic, and Tumor Characteristics of the 70 Patients Diagnosed With 72 SRMs, and Comparison Between the Delayed Surgical Intervention Group and Active Surveillance Group Overall (n [ 70)
Variables
Delayed Surgical Intervention Group (n [ 18)a
Active Surveillance Group (n [ 48)
P .06
Age at Presentation, Years Mean SD
76 6.8
75 6.2
77 6.8
Median (IQR)
77 (68-82)
76 (68-80)
78 (71-88)
Male Sex, n (%)
47 (67.1)
11 (61)
34 (70.8)
.04 .04
Mode of Presentation, n (%) Incidental
65 (92.9)
15 (83.3)
46 (95.8)
Local symptoms
5 (7.1)
3 (16.7)
2 (4.2)
Mean CCI (Range)
3 (1-6)
3
4
.15
27.4 4.4
.23
Body Mass Index Mean SD
27.0 4.3
28.1 5.0
Median (IQR)
26.6 (23.5-30.3)
27.1 (24-31)
Mean SD
92.7 5.2
90.1 5.0
Median (IQR)
61 (38-150)
60 (38-148)
63 (36-150)
26.8 (24-31)
Follow-Up Duration, Months 93 5.5
.23
Tumor Size at Presentation, cm Mean SD
2.1 1.3
2.1 1.2
2.0 1.4
Median (IQR)
2.7 (1.8-3.7)
2.8 (1.8-3.8)
2.5 (1.7-4.1)
.14
Estimated Tumor Volume at Presentation, cm3 Mean SD
4.9 2.5
4.9 2.6
4.6 2.3
Median (IQR)
8.2 (2.5-20.6)
8.8 (2.8-21)
8.4 (2.2-19.5)
Median PADUA Score (IQR)b
7 (6-8)
8 (7-9)
b
7 (6-8)
Median RENAL Score (IQR)
.24
7 (6-8)
.36
7.5 (7-8.7)
7 (5.7-7)
.52
26 (37.2)
16 (80.9)
6 (12.5)
.005
9 (12.8)
2 (11.1)
7 (14.6)
Pathological Findings, n (%) Bx or histologically proven RCC Benign Unknown
35 (50)
0 (0)
35 (72.9)
Linear Growth Rate, cm/years Mean SD
0.5 0.3
1.4 0.5
0.3 0.4
Median (IQR)
0.6 (0.4-1.5)
1.6 (0.3-2.5)
1 (0.3-1.6)
.05). Unsurprisingly, the histological status (proven RCC vs. unknown tumor) did not predict the tumor growth rates in the overall population (P ¼ .08), nor in the AS group (P ¼ .09). Notably, in 35 patients (72.9%) enrolled in the surveillance protocol, the bioptical discrimination between benign or malignant lesion had not been obtained, and therefore the number of undiagnosed renal cancers could have been quite higher in this group. This reflection, together with the awareness of the extremely heterogeneous biology of small cortical tumors could be a possible explanation of such a result. Organ and coworkers, in their multi-institutional, prospective phase II clinical trial from the Renal Cell Carcinoma Consortium of Canada, conducted on 207 SRMs initially managed with AS with a median follow-up of 603 days,20 found no significant clinical or radiological predictors of growth kinetics. The predictive role of tumor dimension at the time of presentation has been matter of debate in the literature. In the present study, the SRM size was not a significant predictor of growth kinetics (P > .05). Similar results have been reported by others.13,16,21,22 Conversely, several investigators showed that the
tumor size could predict the tumor growth rate. Mason et al showed that larger ( 2.45 cm) renal masses grow more quickly than smaller (< 2.45 cm) ones, with a greater risk to develop to metastatic disease.23 AS could be a reasonable option in the management of SRMs in selected patients, even considering the low rate of metastatic spreading of the tumor and the low risk of cancer-specific death. In the present study, only 2 (2.8%) patients experienced metastatic disease (1 after delayed surgery, and the other during AS). In both of these cases, the patients died from causes related to kidney cancer. Several other studies demonstrated that SRMs managed with AS have a low (1%-2%) metastatic potential.9,22-25 These data are comparable with those shown in the meta-analysis by Chawla et al.13 In this remarkable report, indeed, progression to metastatic disease was described in 3 patients, representing only 1% of the entire cohort of patients. The main strength and advantage of this study are based on the longterm follow-up, by which stronger correlations between clinical predictors and tumor growth kinetics have been found. However, the retrospective design, with the inherent related biases, together with the quite low number of enrolled patients are the most important limitations.
Conclusion Male sex and symptomatic presentation are associated with faster growth rates in patients managed with AS after long-term follow-up. These data add new important knowledge to the body of literature, even if larger studies with longer follow-up are needed to confirm these results.
Clinical Practice Points The detection of SRMs is increasing over time, and a non-
negligible amount of these tumors are diagnosed in patients unsuitable for surgery, because of relevant comorbidities or older age. Linear and volumetric growth patterns could be useful indicators for aggressive behavior of SRMs initially managed with AS, but no convincing predictors of tumor growth rate have been described. In this study, male sex (HR, 1.70; P ¼ .04) and symptomatic presentation (HR, 1.85; P ¼ .02) were found to be significant predictors of tumor growth rates during AS. Conversely, age, CCI, and initial tumor size failed to predict growth kinetics. A better understanding of growth kinetics of SRMs would help clinicians in choosing the best management in each patient. This study adds important knowledge to the body of literature, but larger studies are needed to confirm these results.
Disclosure The authors have stated that they have no conflicts of interest.
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