TITLE: Management of Small Renal Masses: American Society of Clinical Oncology Clinical Practice Guideline

Transcription

1 TITLE: Management of Small Renal Masses: American Society of Clinical Oncology Clinical Practice Guideline Table of Contents Data Supplement 1: Additional Evidence Table(s) Characteristics of Studies Identified in the Search of the Literature Study Quality Assessment Data Supplement 2: QUOROM Diagram Data Supplement 3: Search Strategy String and Dates

2 Data Supplement 1: Additional Evidence Table(s) Different treatment modalities Table 1. Systematic /meta-analysis Author Year Breda 2009 European urology Kim 2012 J Urol Interventions/ Comparisons Laparoscopic radical Laparoscopic partial Laparoscopic ablative therapies (cryotherapy and radiofrequency) PN Vs RN Objective To the intraoperative and shortterm and long-term postoperative complications associated with laparoscopic surgery for renal masses, as well as the differences existing between the different approaches systematic and meta-analysis of partial vs radical for localized renal tumors, considering all cause and cancer specific Search range # of studies (# of tumors) Median Age Patient Characteristics Gender Race Tumor size (mean/median) Male Female Disease Characteristics Pathology confirmation Length of f/u (mo) 133 NR NR NR NR NR NR NR 31,729 (77%) 9,281 (23%)

3 Author Year Interventions/ Comparisons Objective Search range # of studies (# of tumors) Median Age Patient Characteristics Gender Race Tumor size (mean/median) Male Female Disease Characteristics Pathology confirmation Length of f/u (mo) Froghi 2013 BJU international Kunkle 2008 The of urology Laparoscopic partial (LPN) Robotic partial (RPN) Partial Cryoablation mortality, and severe chronic kidney disease Meta-analysis of comparative studies Meta-analysis of case series pts (101 RPN; 155 LPN) All:99(6471) 50 (5037) 19 (496) NR 60% 40% NR <4cm NR NR NR NR NR % 82% RFA 21 (607) % 16.4 Active surveillance 10 (331) % 33.3 Volpe 2011 European urology Nabi 2010 The Cochrane database of systematic Partial Radical Ablative therapies Active surveillance Percutaneous biopsy Open radical/partial Vs To systematically indications, techniques, and outcomes of surgical and conservative treatments of SRMs To identify and the evidence from randomised NR NR NR NR NR NR NR 0 3 RCTs comparing different NR NR NR NR NR NR NR

4 Author Year s Zargar 2015 European urology Kunkle 2008 Cancer Dib 2011 BJU international Interventions/ Comparisons Laparoscopic radical/partial Cryoablation Objective trials comparing different surgical interventions in localised renal cell carcinoma. To summarize available evidence for CA for small renal masses (SRMs) and to assess the selection criteria, complications, and functional and oncologic results based on the latest CA Search range # of studies (# of tumors) surgical approaches NR noncomparative 8 comparative Median Age Patient Characteristics Gender Race Tumor size (mean/median) Male Female Disease Characteristics Pathology confirmation Length of f/u (mo) NR NR NR NR NR NR NR literature. Cryoablation or RFA Meta-analysis NR 47 (1375) 67.2 NR NR NR % RCC 12.7 % benign 33.5% unknown Cryoablation (CA) vs. RFA Meta-anlysis of case series studies 20 (CA) 11 (RFA) NR NR NR NR # of pts 457 (CA)

5 Author Year Interventions/ Comparisons Objective Search range # of studies (# of tumors) Median Age Patient Characteristics Gender Race Tumor size (mean/median) Male Female Disease Characteristics Pathology confirmation Length of f/u (mo) 426 (RFA) Klatte 2014 The of urology Laparoscopic cryoablation (LCA) Vs Meta-analysis NR % 30.5% NR Wang 2014 Chinese Medical Smaldone 2011 Cancer laparoscopic partial (LPN/RPN) RFA Partial Active surveillance Systematic and meta-analysis to evaluate the perioperative complication rates and oncological results on RFA and PN of case-series studies Meta-analysis of case series NR caseseries studies (62 RFA, 83 PN) 2355 SRMs 6 (284) 259 pts % 38.8% NR NR NR 2.44 NR NR 66.6 NR NR NR Initial: 2.3 Conclusion: NR 27.5 Asimakopoulos 2014 BMC urology Robotic radical To provide a systematic of the current evidence on the role of robotic radical (RRN) and to NR NR NR NR NR NR NR

6 Author Year Interventions/ Comparisons Objective Search range # of studies (# of tumors) Median Age Patient Characteristics Gender Race Tumor size (mean/median) Male Female Disease Characteristics Pathology confirmation Length of f/u (mo) Katsanos 2014 Cardiovascular and interventional radiology Thermal ablation vs. surgical analyze the comparative studies between RRN and open (ON)/LRN. Meta-analysis NR 6 (1 RCT, 5 cohort) 587 pts NR NR NR NR 2.5cm NR Up to 5 yrs Maclennan 2012 European urology Radical Partial (NSS) Laparoscopic surgery for radical or partial Hand-assisted laparoscopic surgery for radical or partial Robot-assisted laparoscopic surgery for radical or partial Complete regional (extended) lymphadenectomy Partial regional (limited) lymphadenectomy Adrenalectomy RFA Cryoablation HIFU. Systematically relevant literature comparing oncological outcomes of surgical management of localised RCC (T1 2N0M (6 RCTs, 28 NRSs) NR NR NR NR NR NR NR

7 Author Year Interventions/ Comparisons Objective Search range # of studies (# of tumors) Median Age Patient Characteristics Gender Race Tumor size (mean/median) Male Female Disease Characteristics Pathology confirmation Length of f/u (mo) Maclennan 2012 European urology Hui 2008 Radical Partial (NSS) Laparoscopic surgery for radical or partial Hand-assisted laparoscopic surgery for radical or partial Robot-assisted laparoscopic surgery for radical or partial Complete regional (extended) lymphadenectomy Partial regional (limited) lymphadenectomy Adrenalectomy RFA Cryoablation HIFU. Percutaneous Vs Surgical Renal Tumor Ablation Systematically relevant literature comparing oncological outcomes of surgical management of localised RCC (T1 2N0M0 To determine the effectiveness and complication rates of ablation of renal cell carcinoma (RCC) performed with a percutaneous approach versus a (7 RCTs, 22 NRSs) 46 case series NR NR NR NR NR NR NR NR NR NR

8 Author Year Interventions/ Comparisons Objective Search range # of studies (# of tumors) Median Age Patient Characteristics Gender Race Tumor size (mean/median) Male Female Disease Characteristics Pathology confirmation Length of f/u (mo) surgical approach.

9 Table 2. Data on Outcomes of Interest Author Year Breda 2009 European urology Kim 2012 J Urol Interventions/ Comparisons Laparoscopic radical Laparoscopic partial Laparoscopic ablative therapies (cryotherapy and radiofrequency) PN Vs RN Survival Major complications # of studies OS CSS Urological Non-urological 133 NR NR Vascular injury Organ injury BRT Postoperative ileus DVT Incisional hernia Mortality 31,729 (77%) 9,281 (23%) NR 29% risk reduction in cancer specific mortality (HR 0.71, p = ) Summary of result Laparoscopic radical (LRN), whether transperitoneal or retroperitoneal, can be performed safely. The overall complication rate is low and does not significantly differ from that of the open experience. Laparoscopic partial Bleeding (LPN), in contrast, is a technically Urine leakage challenging procedure. Positive margins Although the intermediate oncologic Warm ischemia outcomes are comparable to those of time the open experience, there are concerns related to warm ischemia Bleeding Pain & paresthesia time, and there is a risk of major Urine leak at insertion site complications such as urinary leakage Organ injury and hemorrhage requiring transfusion. Cardiovascular Laparoscopic-assisted ablative complications therapies (cryotherapy and Pneumonia radiofrequency) are being performed Postoperative ileus more commonly for the treatment of small exophytic renal lesions with a low complication rate and intermediate oncologic outcomes similar to LRN and LPN. NR NR Data from 21, 21 and 9 studies were pooled for all cause and cancer specific mortality, and severe chronic kidney disease, respectively. partial correlated with a 19% risk reduction in all cause mortality (HR 0.81, p <0.0001), and a 61% risk reduction in severe chronic kidney disease (HR 0.39, p <0.0001). pooled estimate of cancer specific mortality for partial was limited by the lack of robustness in

10 Author Year Froghi 2013 BJU internation al Kunkle 2008 The of urology Interventions/ Comparisons Laparoscopic partial (LPN) Robotic partial (RPN) Partial Cryoablation RFA Active surveillance # of studies pts (101 RPN; 155 LPN) All:99(6471) 50 (5037) 19 (496) 21 (607) 10 (331) Survival Major complications OS CSS Urological Non-urological Summary of result consistent findings on sensitivity and subgroup analyses. NR NR conversion to open postoperative blood There was no significant different in transfusion estimated blood loss (P = 0.12, 95% pulmonary embolism confidence interval [CI] to Cardio-respiratory ). complications. Similarly, there was no significant different in warm ischemic time between the groups (P = 0.23, 95% CI to 3.70). Also, length of stay (P = 0.22, 95% CI 0.38 to 0.09). Overall postoperative complication rates were not significantly different between the groups (P = 0.84, 95% CI 0.05 to 0.06). NR NR NR NR Significant differences in mean patient age (p<0.001), tumor size (p<0.001) and followup duration (p<0.001) were detected among treatment modalities. The incidence of unknown/ indeterminate pathological findings was significantly different among cryoablation, RFA and observation (p=0.003), and a significant difference in the rates of malignancy among lesions with known pathological results was detected (p=0.001). Compared to nephron sparing surgery significantly increased local progression rates were calculated for cryoablation (RR=7.45) and RFA (RR=18.23). No statistical differences were detected in the incidence of metastatic progression regardless of whether lesions were excised, ablated or observed.

11 Author Year Volpe 2011 European urology Nabi 2010 The Cochrane database of systematic s Zargar 2015 European urology Interventions/ Comparisons Partial Radical Ablative therapies Active surveillance Percutaneous biopsy Open radical/partial Vs Laparoscopic radical/partial Cryoablation 82 Survival Major complications # of studies OS CSS Urological Non-urological Summary of result 134 NR NR NR NR Only one randomized controlled trial comparing the results of elective nephron sparing surgery and radical for low-stage renal tumours is available. Few comparative studies of different treatment options for SRMs have been published. The assessment of oncologic outcomes is therefore based mainly on observational studies. Most series of nonsurgical therapies have strong selection biases and relatively short follow-up. Treatment selection is based on the clinical and histologic characteristics of SRMs, on patient age and comorbidities, and on personal preferences and experience of the urologist. 0 NR NR NR NR Three randomised controlled trials 3 RCTs compared the different laparoscopic comparing approaches to different (transperitoneal versus retroperitoneal) surgical and found no statistical difference in approaches operative or perioperative outcomes between the two treatment groups. There were several non-randomised and retrospective case series reporting various advantages of laparoscopic renal cancer surgery such as less blood loss, early recovery and shorter hospital stay. 11 noncomparative 8 NR NR NR NR The rates of major complications across the CA literature remain relatively low. Studies assessing renal function after CA suggest a degree of functional

12 Author Year Kunkle 2008 Cancer Interventions/ Comparisons Croablation or RFA # of studies comparative 47 studies with 1375 renal tumors Survival Major complications OS CSS Urological Non-urological Summary of result decline following CA because proper application includes freezing of a tumor margin; however, often this is not clinically significant. Specific oncologic outcomes should be evaluated in patients with biopsy proven renal cell carcinoma; when SRM series include benign or unbiopsied tumors, the results of these outcomes are skewed. Although earlier series were suggestive of a higher recurrence rate after CA, some studies have challenged this view reporting recurrence rates comparable with extirpative nephron-sparing surgery. NR NR NR NR No differences were detected between ablation modalities with regard to mean patient age (P =.17), tumor size (P =.12), or duration of follow-up (P =.53). Pretreatment biopsy was performed more often for cryoablated lesions (82.3%) than for RFA (62.2%; P <.0001). Unknown pathology occurred at a significantly higher rate for SRMs that underwent RFA (40.4%) versus cryoablation (24.5%; P <.0001). Repeat ablation was performed more often after RFA (8.5% vs 1.3%; P <.0001), and the rates of local tumor progression were significantly higher for RFA (12.9% vs 5.2%; P <.0001) compared with cryoablation. The higher incidence of local tumor progression was found to be correlated significantly with treatment by RFA on

13 Author Year Dib 2011 BJU internation al Klatte 2014 The of urology Interventions/ Comparisons Cryoablation (CA) vs. RFA Laparoscopic cryoablation (LCA) Vs laparoscopic partial # of studies 31 studies 20 (CA) 11 (RFA) # of pts 457 (CA) 426 (RFA) Survival Major complications OS CSS Urological Non-urological NR NR CA: perinephric haematoma haematuria urinary leak haemorrhage ureteropelvic junction obstruction RFA: haematuria flank numbness perinephric haematoma urinary retention flank bruising urinoma flank pain hydronephrosis ureteral stenosis urinary fistula CA: genitofemoral nerve injury cryoshock respiratory failure postoperative ileus pneumonia and allcauses death RFA: ileus pneumonia haemorrhage neuropathic pain and all-causes mortality Summary of result univariate analysis (P=.001) and on multivariate regression analysis (P =.003). Metastasis was reported less frequently for cryoablation (1.0%) versus RFA (2.5%; P=.06). Cryoablation usually was performed laparoscopically (65%), whereas 94% of lesions that were treated with RFA were approached percutaneously The pooled proportion of clinical efficacy was 89% in cryoablation therapy. There was a statistically significant heterogeneity between these studies showing the inconsistency of clinical and methodological aspects. The pooled proportion of clinical efficacy was 90% in radiofrequency ablation therapy. There was no statistically significant heterogeneity between these studies. There was no statistically significant difference regarding complications rate between cryoablation and radiofrequency ablation. 13 NR NR NR NR Compared with laparscopic partial /robot-assisted laparoscopic partial, laparoscopic cryoablation was associated with significantly shorter operative times (weighted mean

14 Author Year Wang 2014 Chinese Medical Smaldone 2011 Cancer Survival Major complications Interventions/ Comparisons # of studies OS CSS Urological Non-urological Summary of result difference [WMD] minutes), (LPN/RPN) lower estimated blood loss (WMD ml), shorter length of stay (WMD 1.22 days), and a lower risk of total (RR 1.82), urological (RR 1.99) and nonurological complications (RR 2.33). Patients undergoing laparoscopic cryoablation had a significantly increased risk of local (RR 9.39) and metastatic tumor progression (RR 4.68). RFA 58 NR NR NR NR The major complication rate with PN treatment was greater than that with RFA treatment (LPN/RPN: 7.2%, OPN: 10.2%, RFA: 4.3%, both P <0.01). Partial Minor complications occurred more frequently following RFA (RFA: 15.1%, LPN/RPN: 5%, P <0.001; OPN: 10.1%, P=0.058). Active surveillance 6 (284) NR NR NR NR Sixty-five masses (23%) exhibited zero net growth under surveillance, and 259 pts none of those masses progressed to metastasis. A pooled analysis revealed increased age (age 75.1±9.1 years vs 66.6±12.3 years; P =.03) initial greatest tumor dimension (4.1±2.1 cm vs 2.3±1.3 cm; P <.0001), initial estimated tumor volume (66.3±100.0 cm 3 vs 15.1±60.3 cm 3 ; p =.0001) linear growth rate of (0.8± 0.65 cm per year vs 0.3 ±0.4 cm per year; P =.0001) volumetric growth rate of 27.1±24.9 cm 3 per year (vs 6.2± 27.5 cm 3 per year; P <.0001) in the progression

15 Author Year Asimakop oulos 2014 BMC urology Katsanos 2014 Cardiovas cular and interventio nal radiology Interventions/ Comparisons Robotic radical Thermal ablation vs. surgical Survival Major complications # of studies OS CSS Urological Non-urological Summary of result cohort 10 NR NR NR NR Only one prospective study available. Mean operative time (OT) ranges between min. Mean estimated blood loss (EBL) ranges between ml. Mean hospital stay (HS) ranges between days. The comparison between RRN and LRN showed no differences in the evaluated outcomes except for a longer OT for RRN as evidenced in two studies. Significantly higher direct costs and costs of the disposable instruments were also observed for RRN. The comparison between RRN and ON showed that ON is characterized by shorter OT but higher EBL, higher need of postoperative analgesics and longer HS. 6 (1 RCT, 5 cohort) 587 pts NR NR Postoperative decline of egfr was higher in case of (mean difference: ml/ min/1.73 m2, 95 % CI: to -1.23, p = 0.03). Overall complication rate was significantly lower in the ablation group (7.4 vs. 11 %; RR: 0.55, 95 % confidence interval [CI]: , p = 0.04). Local recurrence rate was the same in both groups (3.6 vs. 3.6 %; RR: 0.92, 95 % CI: , p = 0.79) and disease-free survival also was similar up to 5 years (HR: 1.04, 95 % CI: , p = 0.92). Maclenna n 2012 European urology Radical Partial (NSS) Laparoscopic surgery for radical or partial Hand-assisted 34 (6 RCTs, 28 NRSs) NR NR NR NR Open radical and open partial showed similar cancer-specific and overall survival, but when both open and laparoscopic approaches are considered together, the evidence showed improved survival for partial for

16 Author Year Maclenna n 2012 European urology Interventions/ Comparisons laparoscopic surgery for radical or partial Robot-assisted laparoscopic surgery for radical or partial Complete regional (extended) lymphadenectomy Partial regional (limited) lymphadenectomy Adrenalectomy RFA Cryoablation HIFU. Radical Partial (NSS) Laparoscopic surgery for radical or partial Hand-assisted laparoscopic surgery for radical or partial Robot-assisted laparoscopic surgery for radical or partial Complete regional (extended) lymphadenectomy Partial regional (limited) lymphadenectomy Adrenalectomy RFA # of studies 29 (7 RCTs, 22 NRSs) Survival Major complications OS CSS Urological Non-urological Summary of result tumours 4 cm. The overall evidence suggests either equivalent or better survival with partial. Laparoscopic radical offered equivalent survival to open radical, and all laparoscopic approaches achieved equivalent survival. Open and laparoscopic partial achieved equivalent survival. The issue of ipsilateral adrenalectomy or complete lymph node dissection with radical or partial remains unresolved. NR NR NR NR There is good evidence indicating that partial results in better preservation of renal function and better QoL outcomes than radical regardless of technique or approach. Regarding radical, the laparoscopic approach has better perioperative outcomes than the open approach, and there is no evidence of a difference between the transperitoneal and retroperitoneal approaches. Alternatives to standard laparoscopic radical (LRN) such as hand-assisted, robot-assisted, or single- port techniques appear to have similar perioperative outcomes. There is no good evidence to suggest that minimally invasive procedures such as cryotherapy or radio-

17 Author Year Hui 2008 Interventions/ Comparisons Cryoablation HIFU. Percutaneous Vs Surgical Renal Tumor Ablation # of studies 46 case series Survival Major complications OS CSS Urological Non-urological Summary of result frequency ablation have superior perioperative or QoL outcomes to. Regarding concomitant lymphadenectomy during, there were low event rates for complications, and no definitive difference was observed. There was no evidence to base statements about concomitant ipsilateral adrenalectomy during. NR NR NR NR The primary effectiveness rate for the percutaneous group (87%) was significantly lower than that in the surgical group (94%; P <.05). The secondary effectiveness rate in the percutaneous treatment group (92%) was not significantly different from that in the surgical treatment group (95%; P >.05). The major complication rate in the percutaneous treatment group (3%) was significantly lower than that in the surgical treatment group (7%; P <.05). Abbreviations: OS-Overall survival; CSS-Cancer Specific Survival; QOL-Quality of Life; PRO-Patient reported outcomes

18 Table 3. Quality of studies Systematic Reviews (N=7) Patient preferences considered important patient sub-types considered Multidisciplina ry panel Welldescribed and reproducible methods COI's are exam ined Rated quality of the Evidence Rated strength of the evidence Includes a plan for updating Funding Author Year source Breda 2009 Yes No Yes Yes Yes No No No None Intermediate Volpe 2011 Yes No Yes Yes Yes No No No None Intermediate Nabi 2010 No No Yes Yes Yes Yes Yes No None Low Zargar 2015 Yes No Yes Yes Yes No No No None Intermediate Asimakopoul No No Yes Yes Yes Yes Yes No None Low os 2014 Maclennan Yes No Yes Yes Yes Yes Yes No Yes Low 2012 Maclennan 2012 Yes No Yes Yes Yes Yes Yes No Yes Low Note: Y, Yes; -, no/not reported/unable to determine Overall risk of bias assessment Meta-analyses (N=10) Author Year Based on systematic Reproducible methods Quality assessment of included studies Planned pooling stated a priori Limitations of the study Funding source Overall risk of bias assessment yes yes no yes Yes NR/NA Low Froghi 2013 yes yes no yes Yes NR/NA Low Kunkle 2008 Kunkle 2008 yes yes no yes Yes NR/NA Low Dib 2011 Yes yes no yes yes NR/NA Low Klatte 2014 Yes yes Yes yes yes NR/NA Low Wang 2014 Yes Yes No Yes No NR/NA Intermediate Smaldone Yes yes Yes yes yes Yes Low 2011 Katsanos 2014 Yes yes Yes yes yes NR/NA Low Kim 2012 Yes yes Yes yes yes NR/NA Low Hui 2008 Yes yes Yes yes yes NR/NA Low Note: Y, Yes; -, no/not reported/unable to determine

19 Biopsy Author Year He 2015 International braz j urol Volpe 2012 European urology Malley 2012 Can J Urol Table 1. Systematic /meta-analysis Interventions/ Comparisons Percutaneous core biopsy Percutaneous biopsy Percutaneous biopsy Objective To evaluate the accuracy of percutaneous core needle biopsy of small renal masses ( 4 cm), especially for the malignancy. To the current rationale, indications, and outcomes of percutaneous biopsies and histologic characterization of renal tumours. analyses the current role of percutaneous renal biopsy Search range # of studies # of pts/biopsies Median Age Patient Characteristics Gender Race Tumor size (mean/median) Male Female Disease Characteristics Repeat biopsy Length of f/u (mo) 9 788/803 NR NR NR NR <4cm > NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR Table 2. Data on Outcomes of Interest Author Year He 2015 Interventions/ Comparisons Percutaneous core biopsy # of pts/biopsi Pooled es sensitivity 788/ % (95% CI: 91.0%, Pooled specificity 100% (95% CI: 98.4%, Pooled positive likelihood ratio (95% CI: , Pooled negative likelihood ratio 0.09 (95% CI: , p=0.13) Summary of result Failed biopsies without repeated or aborted from follow-up/surgery result

20 International braz j urol Volpe 2012 European urology Malley 2012 Can J Urol Percutaneous biopsy Percutaneous biopsy 95.0%, p=0.28), with I2 of 17.7% 100%, p=1), with I2 of 0% p=0.54) were excluded (232 patients and 353 biopsies). (no likely contributory) (no likely contributory) The pooled DOR was (95% CI: , p=0.36). The overall diagnostic accuracy according to the results of SROC curve analysis was 0.959± the overall diagnostic accuracy (Q*) was 0.903±0.037 NR NR NR NR NR Percutaneous biopsy for diagnostic assessment of SRMs can avoid unnecessary surgeries and support treatment decisions, especially in patients at high surgical risk. Biopsies can confirm histologic success after thermal ablation of SRMs and support the selection of the appropriate systemic therapy for metastatic RCC. There is increasing evidence that further diagnostic and prognostic information can be obtained from renal tumour biopsies with the use of immunohistochemistry, cytogenetic and molecular analysis, and highthroughput gene expression profiling NR NR NR NR NR With the adoption of new biopsy techniques, there is a very low risk of tumor seeding. Symptomatic complications are relatively low; less than 2% require any form of intervention. The accuracy has dramatically improved over the past decade. While about 10%-15% of small renal mass biopsies are indeterminate, the rate of false negative renal biopsies is only 1% in contemporary series. Recent studies suggest that biopsy results can be improved by combining histological and molecular analysis.

21 Table 3. Quality of studies Systematic Reviews (N=2) Patient preferences considered important patient sub-types considered Multidisciplina ry panel Welldescribed and reproducible methods COI's are exam ined Rated quality of the Evidence Rated strength of the evidence Includes a plan for updating Funding Author Year source Volpe 2012 Yes No Yes Yes Yes No No No None Low Malley 2012 No No Yes Yes Yes No No No NR/NA Intermediate Note: Y, Yes; -, no/not reported/unable to determine Overall risk of bias assessment Meta-analyses (N=1) Author Year Based on systematic Reproducible methods Quality assessment of included studies Planned pooling stated a priori Limitations of the study Funding source Overall risk of bias assessment yes yes Yes yes Yes NR/NA Low He 2015

22 Summary of primary studies identified Table 1: Elderly Refid Author, year Intervention s/compariso ns. 98 Kyung 2014 RN vs Study type Retrospectiv e # of patients 82 Mean/Medi an age 75yrs Mean/Median size of tumor (cm) 4.4 Primary outcome reported OS Mean/median F/u time months 202 Becker 2014, SEER database PN Delayed Retrospectiv e 53 73yrs 2.4 6,237 NA NA CSM NA 581 Smaldone 2012 PN vs. Retrospectiv e yrs 2.8 OS NR RN 705 Hillyer 2012 Roboticassisted PN in < 70 Retrospectiv e yrs 60yrs Post-op complications 7.1 months vs > 70yrs old 922 Kates 2011 Age <75 y Retrospectiv e yrs 56yrs NR 9.5 months NR Age>75 y yrs 2.9

23 1207 Deklaj 2010 LRN LPN Retrospectiv e yrs 75yrs Perioperative, surgical, and functional outcomes 21 months LAT 99 Tan 2012 PN Retrospectiv e cohort (27.0%) 76yrs yrs 4cm OS, Kidney CSS 62 months RN 5213 (73.0%) Abbreviations: RN: Radical Nephrectomy; PN: Partial Nephrectomy; OS: Overall Survival; CSS: Cancer Specific Survival; LRN: laparoscopic radical ; LPN: laparoscopic partial ; LAT: laparoscopic ablative techniques; NA: Not Applicable\Available; NR: Not reported

24 Table 2: Active Surveillance Refid Author year Intervention s/compariso ns Study type 40 Dorin 2014 AS 128 Tomaszewski 2014 AS vs Prospective cohort N Of patients Mean/Medi an age of pts Mean/Median size of tumor (cm) Primary outcome reported yrs 2.1 Tumor growth rate yrs 2.2 NA Mean/Median F/u time 4.2 years 25.6 months 267 Brunocilla 2014 Surgery AS vs yrs 76yrs Tumor growth rate 91.5months Surgery 384 Audenet 2014 >75yrs CCI > yrs 79yrs Postoperative outcome 31 months Any age, CCI >4 700 Patel 2012 AS vs yrs 72yrs OS, CSS 34 months RN 41 65yrs months vs

25 PN 90 59yrs months 707 Jacobs 2012 AS vs Treatment yrs 60yrs Patient demographics, clinical factors, tumor and surgeon characteristics NR Abbreviations: AS: Active Surveillance; RN: Radical Nephrectomy; PN: Partial Nephrectomy; OS: Overall Survival; CSS: Cancer Specific Survival; LRN: laparoscopic radical ; LPN: laparoscopic partial ; LAT: laparoscopic ablative techniques; NA: Not Applicable\Available; NR: Not reported

26 Table 3: Biopsy Refid Author, year Interventions/compa risons Study type N of patients Mean/Median age of pts Mean/Media n size of tumor (cm) Primary outcome reported Length of F/u 23 Hu 2015 Percutaneous needle core biopsy Retrospectiv e 269 (187 SRMs) 66 yrs 2.6 Diagnostic accuracy NA 1794 Richard 2015 Renal tumor biopsy Retrospectiv e 509 (529 biopsies) 64 yrs 2.5 Diagnostic accuracy NA 258 Londono 2013 Percutaneou s renal biopsy Retrospectiv e 538 Halverson 2013 Percutaneous biopsy Retrospectiv e 126 pts (132 biopsies) 60 SRMs 65 yrs NA Diagnostic accuracy yrs 2.8 Diagnostic accuracy NA 647 Menogue 2013 Percutaneous core biopsy Retrospectiv e 250 (268 SRMs) 64 yrs 2.5 Diagnostic accuracy NA 781 Tan 2012 Biopsy Retrospectiv e yrs 2.9 NA NA No biopsy 951 Leveridge 2011 Percutaneous biopsy Retrospectiv e 1453 Wang 2009 Percutaneous core Retrospectiv biopsy e (345 biopsies) 106 (110 biopsies) 60 yrs yrs 2.5 Diagnostic accuracy 60 yrs 2.7 Diagnostic accuracy 2 yrs NA

27 1496 Volpe 2008 Percutaneous biopsy Retrospectiv e cohort 91 (100 biopsies) 60 yrs 2.4 Diagnostic accuracy NA

28 Table 4: Surgical Interventions Refid Author, year 1795 Thompson 2015 Interventions/c omparisons. Study type N of patients PN 1057 Mean/Media n age of pts 60 Mean/Media n size of tumor (cm) 2.5 Primary outcome reported OS, RFS Mean/media n F/u time 5.2 yrs RFA Cryoablation 86 Johnson 2014 LC 266 Veltri 2014 RFA 278 Tanagho 2013 Cryoablation vs RPN 297 Ramirez 2014 RFA 328 Ma 2014 RFA (112 SRMs) 60 yrs 2.3 OS, CSS, PFS 97.9 months 137 (67 T1a) 64yrs 3.0 OS, CSS, DFS 39 months yrs 57yrs Peri and post op complications 1 day, 1 month, 3 months, 6 months, 12 months, and then annually 79 64yrs 2.2 RFS 59 months 52 (58 SRMs) 57yrs 2.2 RFS, OS 60 months

29 329 Emara 2013 RPN LC 346 Shuch 2014 PN vs RN 389 Scosyrev 2014 RN Prospective cohort RCT yrs 61yrs 73yrs 75yrs 60yrs NR NR Postoperative complications Cardiovascula r, Renal and secondary cancer events Kidney function 16.5months 31.3 months 4.1 years 6.7 yr NSS 507 Mellon 2012 RPN yrs 58yrs 2.4 Pathological outcomes NR OPN 524 Atwell 2012 RFA vs yrs 69yrs Efficacy & complication rates 2.8yrs Cryoablation 565 Kim 2012 Percutaneous cryoablation yrs yrs 2.7 Perioperative and postoperative outcomes 0.9yrs 30.2 months

30 614 Psutka 2012 RFA 650 Favaretto 2013 LPN yrs 3 Long-term oncologic outcomes including residual tumor, tumor recurrence, 6.43 years yrs 2.5 RFS, CCS, OS 38 months 688 Whitson 2012 NSS vs yrs 2.4 DSS 2.8 yrs Ablation 733 Guan 2012 MWA 1114 RCT 48 68yrs 46yrs OS 1.6 yrs 2 years vs. 794 Guillotreau 2012 PN RPN vs yrs 2.8 NA/NR 2.4 peri & post op complications 4.8 months LCA 827 Haramis 2012 LPN LCA yrs 59 yrs Intraoperative and postoperative outcomes 44.5 months 21.8months 14 months

31 901 Antonelli 2012 RN vs yrs 3.3 CSS 10 yrs PN 1127 Takaki 2010 RFA vs Prospective cohort yrs 69yrs OS 34 months RN yrs months vs PN 1149 Guazzoni 2010 LRC yrs months 123 (131 SRMs) NR/NA 2.14 CSS, OS 46 months 1154 Tracy 2010 RFA 1292 Malcolm 2010 LCA 1395 Stern 2009 RFA 208 (243 SRMs) 64 yrs 2.4 Oncologic outcomes, RFS, CSS yrs 2.3 Renal function outcomes yrs 2.1 Changes in GFR, Radiological recurrence 27months 30months 34 months

32 1436 Zini 2009 PN RN 1446 Zini 2009 Non Surgery vs yrs 61.1 yrs 73 yrs OS, Noncancerrelated Mortality OS, CSS 35 months 46 months 5yrs 1648 Thompson 2008 Nephrectomy PN vs RN 1714 Stern 2007 RFA vs yrs 64yrs 65 yrs 60 yrs OS OS 7.1 yrs 30 months PN 1749 Weld 2007 Laparoscopic cryoablation yrs months 31 (36SRMs) 65 yrs 2.1 CSS 3 yrs 1782 Lane 2007 LPN yrs 2.9 OS, CSS, renal function 5 yrs 76 Van Poppel 2011 EORTC study NSS RN RCT yrs 5cm OS, TPP 9.3 yrs

33 88 Stephenson 2004 PN cohort 357 NR NR Early complications NR RN 692 Abbreviations: RPN: robot-assisted laparoscopic partial ; LC: laparoscopic cryoablation; NSS: nephron-sparing surgery; OPN: open partial ; MWA: Microwave Ablation; NA: Not Applicable\Available; NR: Not reported; RN: Radical Nephrectomy; PN: Partial Nephrectomy; OS: Overall Survival; CSS: Cancer Specific Survival

34 Table 5: Renal function Refid Author, year Interventions/c omparisons. Study type N of patients 61 Lane 2015 Surgery for renal cancer 40 Wehrenberg 2012 Cryoablation vs. Mean/Media n size of tumor (cm) Primary outcome reported Mean/Media n age of pts 4299 NR NR Decline in renal function, allcause mortality, and non-renal cancer mortality 22 73yrs 3.4 Renal function, GFR Mean/media n F/u time 9.4yrs 1yr 34 Sun 2012 SEER database RFA PN NR NR Onset of CKD stage >/=3. NR RN 35 Pignot 2014 PN RN 36 Krebs 2014 OPN 663 (68.1%) 60yrs 4 cm in 665 (68.3%) cases and larger than 4 cm in 308 (31.7%) Renal function, GFR 310 (31.9%) Renal function, GFR NR 12 months after surg

35 LPN ORN Klarenbach 2011 LRN Nephrectomy NR Adverse renal outcomes 32 months 41 Weisbrod 2010 Cryoablation 31 NR 3.0 Renal function, GFR 14 months 42 Raman 2010 RFA Renal function, GFR 18.1 and 30.0 months OPN 43 Mitchell 2011 PCA yrs 2.8 NR NR Renal function, GFR NR PN 62

36 Included Eligibility Screening Identification Data Supplement 2: QUOROM Diagram PRISMA 2009 Flow Diagram Records identified through database searching N = 1791 Additional records identified through other sources N = 5 Records after duplicates removed N = 1796 Records screened N = 1796 Records excluded N = 1547 Full-text articles assessed for eligibility N = 249 Full-text articles excluded N = 166 Studies included in qualitative synthesis N = 83 Studies included in quantitative synthesis (meta-analysis) N = 0

37 Data Supplement 3: Search Strategy String and Dates Population Kidney Neoplasms/pathology Kidney Neoplasms/therapy* Neoplasm Staging Humans Adult, Aged Neoplasm Staging Carcinoma, Renal Cell/pathology* Carcinoma, Renal Cell/therapy* Kidney Neoplasms/surgery* Carcinoma, Renal Cell/surgery T1a renal mass Intervention Analgesics/therapeutic use Cryosurgery/methods* Laparoscopy/statistics & numerical data Length of Stay Middle Aged Pain, Postoperative/prevention & control Recovery of Function Treatment Outcome Biopsy, Needle Disease Progression Active Surveillance

38 Watchful waiting Nephrectomy Nephron sparing surgery Natural history Microwave ablation Search (((((("kidney neoplasms"[mesh Terms] OR kidney neoplasms[text Word])) OR Carcinoma, Renal Cell) OR ((renal mass OR small renal mass OR renal mass*[tiab] OR small renal mass*[tiab]))) OR ((t1a renal OR t1a renal mass)))) AND ((((((((((laparoscopic*[tiab] OR robotic*[tiab]))) AND nephrectom*[tiab])) OR ((ultrasound*[tiab] OR biopsy*[tiab]))) OR (("Computed tomography" OR "magnetic resonance imaging"[tiab]))) OR (("Active Surveillance" OR "watchful waiting"))) OR radiotherapy*[tiab]) OR ((*[tiab] OR Thermal*[tiab] OR ablation*[tiab] OR cryoablation*[tiab] OR radiofrequency*[tiab] OR microwave*[tiab]))) Filters: Publication date from 2000/01/01 to 2015/12/31; Humans; English