thermal versus impedance-based ablation of renal cell carcinoma: a meta-analysis

CLINICAL INVESTIGATION INTERVENTIONAL ONCOLOGY

Thermal Versus Impedance-Based Ablation of Renal CellCarcinoma: A Meta-analysis

Milad Modabber • Jason Martin • Sriharsha Athreya

Received: 19 May 2013 / Accepted: 9 August 2013 / Published online: 4 October 2013

� Springer Science+Business Media New York and the Cardiovascular and Interventional Radiological Society of Europe (CIRSE) 2013

Abstract

Background Percutaneous radiofrequency ablation (RFA)

of renal carcinoma has become an established treatment

modality. However, thermal (TB) versus impedance-based

(IB)-RF generators have not been previously compared.

Methods A literature search on the application of RFA

for renal masses using TB or IB-RF generators was per-

formed. The safety, efficacy, and long-term outcomes of

TB versus IB-based RFA were assessed using the outcome

measures of technical success, local recurrence rate, com-

plications, and preservation of renal function.

Results Across the 27 included studies, pooled results

suggested comparable results for technical success (TB-

RFA 98.53 % vs. IB-RFA 98.78 %, P = 0.9813). Clinical

efficacy results were also similar across both generators

(91.0 % TB-RFA vs. 91.5 % IB-RFA; P = 0.73). At fol-

low-up, no differences in renal function (relative risk [RR]

0.5, 95 % confidence interval [CI] 0.45–5.48), and local

recurrence (RR 0.717, 95 % CI 0.49–1.50) were observed.

The pooled proportion of overall complication rates was

13.1 % for TB-RFA and 11.5 % for IB-RFA.

Conclusion No differences in the observed parameters

were found either during surgery or at follow-up.

Introduction

Advancements in imaging techniques have led to increased

diagnoses of small early-stage renal cell carcinomas (RCCs)

in asymptomatic patients [1]. The treatment of such tumors

using nephron-sparing surgery has shown similar long-term

cancer control to that of radical nephrectomy [2]. However,

the emerging role of minimally invasive ablative therapies for

the treatment of RCC’s has provided an established alternative

for the elderly and patients with comorbidities [3].

The primary goal of radiofrequency ablation (RFA) is to

cause thermal necrosis of the renal tumor and a small

surrounding margin of normal kidney parenchyma [3].

RFA creates an alternating electrical current that induces

ionic agitation and frictional heating ([60 �C) of the tissue

immediately surrounding the probe [4]. This causes tissue

desiccation and coagulative necrosis of the ablated tissue as

well as decreased microvascular perfusion resulting in

delayed ischemia within the ablated zone. Temperatures

[105 �C can cause tissue charring, thus preventing

effective ablation by increasing tissue resistance and pre-

venting the current dissemination within the targeted tissue

[3]. Clinically, RFA of RCC offers a number of advantages

for patients considered to be at higher surgical risk due to

other comorbidities, such as multifocal RCC or patients

with a solitary kidney, as well as those who refuse surgery

[5]. Because it is an outpatient procedure, percutaneous

RFA is associated with decreased postoperative morbidity

and faster recovery [6].

The radiofrequency energy can be applied using either

temperature-based (TB; RITA Medical Systems, Mountain

M. Modabber � J. Martin

DeGroote School of Medicine, McMaster University, Hamilton,

ON, Canada

e-mail: [email protected]

J. Martin


S. Athreya

Faculty of Health Sciences, McMaster University, Hamilton,

ON, Canada

S. Athreya (&)

St. Joseph’s Healthcare Hamilton, 50 Charlton Ave. E., Rm.

T0112, Hamilton, ON L8N 4A6, Canada


123

Cardiovasc Intervent Radiol (2014) 37:176–185

DOI 10.1007/s00270-013-0743-7

View, CA) or impedance-based (IB; Cooltip [Valley Lab-

oratory/Tyco Health Systems, Boulder, CO] or Radiother-

apeutics [Boston Scientific, Natick, MA]) generator

systems. Whereas TB-RFA delivers sufficient energy to

increase the tissue temperature to a predetermined level to

cause necrosis, IB-RFA applies increasing energy until

tissue impedance exceeds a certain threshold, signifying

tissue desiccation [6]. However, to date, no human study

has directly compared the two generator types with regard

to their procedural and long-term outcomes. This has led to

a variety of RFA treatment algorithms based on user

preference rather than an evidence-based treatment

approach. Moreover, the majority of data for RFA are

derived from the treatment of liver masses [7, 8]. However,

the renal system has a unique milieu of conductive, elec-

trical, and hemodynamic characteristics, and the impact of

these factors may contribute to a different ablation profile

in this organ system [9]. In the kidney, TB ablation systems

may not accurately reflect the heating occurring at the

tissue away from the tines [9]. With IB ablation systems,

carbonization of tissue, bubble formation, and tissue

charring may all prematurely increase impedance with

heterogeneous ablation zones [10]. Hence, the purpose of

this article is to provide a review of the current literature

comparing the overall safety, efficacy, and long-term out-

comes of TB versus IB-RFA for the treatment of small

renal masses. Furthermore, we seek to establish whether

differences in ablation zone heterogeneity translate into

differences in clinical outcomes.

Materials and Methods

A literature search was performed on the application of

RFA for renal masses using TM- or IB-based RF genera-

tors. The primary study objective was to assess the safety

and efficacy of the two modalities based on the outcome

measures of technical success, local recurrence rate, com-

plications, and preservation of renal function.

Original scientific articles were retrieved from PubMed,

Medline, Cochrane, and CINAHL databases, and a search

of relevant citations in appropriate articles was performed.

Search keywords included ‘‘radiofrequency ablation,’’

‘‘RFA,’’ ‘‘small renal masses,’’ ‘‘renal cell carcinoma,’’

‘‘nephrectomy,’’ and ‘‘partial nephrectomy.’’ Articles were

manually selected from the results as they pertained to the

treatment of small renal masses with RFA. Literature

comparing RFA with conventional surgery was included,

and only data from the RFA group were used. Because no

randomized trials were found, preference was given to

nonrandomized prospective comparative series.

The retrieved articles were separated into three groups:

TB-RFA, IB-RFA, and a combination of both modalities.

Studies that did not differentiate their findings according to

the generator type (‘‘combination group’’) were excluded

from data analysis. Studies not written in English and those

pertaining to nonhuman subjects were excluded also. In

cases of overlapping patient populations, the most recent

data were used to prevent double-counting of patients. Data

were collected and compiled by one coder but also

reviewed by the primary investigator to check for consis-

tency and completion. Results were cross-referenced with

review articles to check for accuracy. Clinical efficacy and

complication rates were treated as dichotomous variables.

Clinical efficacy was defined as the percentage of tumors

treated successfully by the procedure. Local recurrence was

defined as any detectable local disease at follow-up,

occurring either alone or in conjunction with generalized

recurrence, in patients who have undergone RFA treat-

ment. Change in renal function was defined as [5 %

change in serum creatinine levels after the RFA procedure.

Statistical heterogeneity was assessed using the I2 sta-

tistic with significance set at [50 %. This shows the pro-

portion of variability resulting from heterogeneity between

patient populations and study techniques. Studies without

significant heterogeneity (I2 \ 50 %) were analyzed with a

fixed-effects model, and studies with significant heteroge-

neity (I2 [ 50 %) were analyzed using a random-effects

model to perform a proportional meta-analysis. The soft-

ware STATSDIRECT (StatsDirect Ltd., Cheshire, UK) was

used to plot the studies into a meta-analysis and generate

forest plots to summarize the data. For a given forest plot,

each horizontal line represents a case series. The length of

the line corresponds to the 95 % confidence intervals (CIs)

of the respective effect estimate. The effect estimate is

marked with a solid black square. The size of the square

represents the weight that the corresponding study exerts in

the meta-analysis, thus reflecting the number of subjects in

that study. The pooled estimate is labeled as an unfilled

diamond at the bottom of the forest plot. CIs of pooled

estimates are displayed as a horizontal line through the

diamond. Analyses of the funnel plots were performed

Table 1 Patient demographics

Temperature Impedance

# of studies (publication year

range)

12

(2005–2012)

17

(2004–2011)

# of prospective/retrospective 6/6 9/8

# of patients 574 571

% Male (N) 63.82

(N = 246)

69.05

(N = 475)

Mean age (range) 64 (28–91) 65.9 (38–84)

Total # of tumours (N) 647 (N = 574) 525 (N = 520)

Tumour size (range) 2.455 (0.8–7.5) 2.791 (0.6–8.8)

M. Modabber et al.: Thermal Versus Impedance-Based Ablation of RCC 177

123

using Egger test to assess publications bias. The statisti-

cally significant difference between both interventions

studied was defined if their combined 95 % CIs did not

overlap. We considered P = 0.05 as statistically signifi-

cant for the calculation of heterogeneity.

Results

A total of 42 studies were retrieved. Of these, 13 studies

did not stratify their results based on generator modality or

failed to provide raw data [1, 10–21]. They were therefore

excluded from further analysis. Of the remaining articles,

12 studies reported exclusively on TB-based RF genera-

tors, and 17 studies reported used only IB-based models.

No significant differences in patient demographics across

the two modalities were observed (Table 1).

A total of 12 TB-RFA studies, published between 2005

and 2011, comprising 574 patients were analyzed [22–33].

Of these, 6 were prospective studies, and 6 were retro-

spective studies (Table 2). The mean age of patients was

64 (range 28–91), and 64 % were male. A total of 647

tumors were treated using TB-RFA with a mean tumour

size of 2.46 cm (range 0.7–5.5). The majority of patients

(402 patients, 70 %) were treated percutaneously by

computed tomography (CT) guidance, whereas 172

patients (30 %) had either a percutaneous or laparoscopic

approach (breakdown not provided). The majority of

patients (561 patients, 97.7 %) were primarily monitored

by way of CT with the remaining 13 patients (2.3 %)

receiving ultrasound (US).

The pooled proportion of clinical efficacy was 91 % (95 %

CI 0.86–0.94) (Fig. 1). There was significant heterogeneity

among the studies (I2 = 82 %, 95 % CI 0.67–0.88), thus

highlighting the inconsistency of clinical and methodological

components of the included studies in this meta-analysis

(P = 0.001). Therefore, a random-effects model was used.

Figure 2 represents an asymmetric funnel plot for clinical

effectiveness of the temperature-based case series (Egger test)

that indicates a relationship between treatment effect and study

size. This suggests the possibility of publication bias

(P = 0.0005). The pooled proportion of complication rates for

TB-RFA was 13.1 % (95 % CI = 0.098–0.168). There was no

significant heterogeneity for complication rates (I2 = 31 %).

Therefore, a fixed-effects model was used (Fig. 3). The most

common complication in TB-RFA was hematoma with 20

reported cases (51.3 % of total complications). Hematomas

included perirenal, subscapular, and retroperitoneal; however,

the literature did not stratify based on location.

Seventeen IB-RFA articles were published between 2004

and 2011. Nine studies were prospective, and eight studies

were retrospective (Table 3) [34–50]. In total, 571 patients

were included with a mean age of 65.9 years (range 38–84), Ta

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178 M. Modabber et al.: Thermal Versus Impedance-Based Ablation of RCC

123

and 69 % of patients reported were male. A total of 525

tumors (N = 520) were treated using IB-RFA with a mean

tumor size of 2.79 cm (range 0.6–8.8 cm). The majority of

patients (513, 89.5 %) were treated percutaneously by CT

guidance, 41 patients were treated laproscopically (7.0 %),

and 20 patients (3.5 %) were treated with a combination of

both (breakdown not provided). The monitoring modalities

comprised of CT in 459 patients (80.3 %), US in 58

(10.2 %), magnetic resonance imaging (MRI) in 10 (1.7 %),

and the remainder as combined (7.7 %).

The pooled proportion of clinical efficacy in the IB-RFA

was 91.5 % (95 % CI 0.871–0.951) (Fig. 4). A random-

effects model was used because there was significant heter-

ogeneity (I2 = 61.8 %, P = 0.0006). Figure 5 represents an

asymmetric funnel plot for clinical effectiveness of the

impedance-based case series suggesting the possibility of

publication bias (P = 0.0391). The pooled proportion of

complication rate for IB-RFA was 11.5 % (95 % CI

0.089–0.144). There was no significance regarding hetero-

geneity (I2 = 29.6 %, P = 0.1336). Thus a fixed-effects

model was used (Fig. 6). The most common complications

were both hematoma and pain in 13 reported cases (21.7 %

each of total complications).

Technical success between TB-RFA and IB-RFA was

comparable (TB-RFA 98.53 % vs. IB-RFA 98.78 %,

P = 0.9813). When considering the change in renal func-

tion, no significant differences across the two generators

were observed (RR 0.5, 95 % CI 0.45–5.48). Mean follow-

up duration in was 33.2 months (range 11–61) in TB-RFA,

whereas a mean duration of 17.1 months (range 9–56) was

noted for IB-RFA. This was not statistically significant

(P = 0.5190). During the follow-up period, the reported

local recurrence rate in the TB-RFA group was 8.4 %,

whereas it was 11.7 % in the IB-RFA group (RR 0.717,

95 % CI 0.49–1.50).

Discussion

This study is a review of the literature evaluating imme-

diate and long-term findings of TB versus IB-RF generators

Proportion meta-analysis plot [random effects]

0.3 0.5 0.7 0.9 1.1

combined 0.91 (0.84, 0.96)

Veltri et al. 0.85 (0.55, 0.98)

Matsumoto et al. 0.98 (0.92, 1.00)

Memarsadeghi et al. 0.81 (0.54, 0.96)

Hegarty et al. 1.00 (0.95, 1.00)

Stern et al. 0.93 (0.80, 0.98)

Levinson et al. 0.90 (0.74, 0.98)

Turna et al. 0.62 (0.42, 0.79)

Gupta et al. 0.97 (0.92, 0.99)

Zurera et al. 0.69 (0.39, 0.91)

Ferakis et al. 0.90 (0.74, 0.98)

Tan et al. 1.00 (0.91, 1.00)

proportion (95% confidence interval)

Fig. 1 Proportional meta-

analysis of case series studies

regarding clinical efficacy in

TB-RFA therapy

Bias assessment plot

0.5 0.7 0.9 1.1 1.30.15

0.10

0.05

0.00

Proportion

Sta

ndar

d er

ror

Fig. 2 Funnel plot of case series regarding clinical efficacy in TB-

RFA therapy


123

for the ablation of human RCC. No significant differences

were observed in the technical success and clinical efficacy

of the RFA procedures. Moreover, at follow-up, no dif-

ference in renal function and local recurrence rate was

observed. Complication rate was comparable across the

two modalities with no significant differences noted in the

overall rate. The most common complication observed was

postoperative pain. However, the type of pain was not

documented within the assessed literature. Pain from RFA

modalities primarily comprise acute intraoperative pain,

neuropathic pain, and pain secondary to complications

[51]. The revised Society of Interventional Radiology

(SIR) standards for the classification of complications

should be used in future studies to accurately document

pain and other adverse outcomes [52].

The safety and efficacy of RFA for the treatment of RCC

has been previously established [17]. Given the present

study results, both TB and IB-RFA show comparable

procedural and long-term outcomes. With increasing

healthcare expenditure and shifts in healthcare demo-

graphics, elderly patients will represent an even larger

population of patients who will be amenable to RFA in the

years to come. The current findings are thus of particular

interest to physicians, administrators, and patients alike

because given the comparable outcomes, physicians may

opt to incorporate technology that is less expensive to

administer without reservations regarding differing clinical

outcomes. The comparable findings across the two RFA

generator modalities warrant consideration of additional

procedural innovations to optimize outcome. Specifically,

the introduction of multiple tined probes has enabled the

delivery of energy across a greater tissue volume without

causing periprobe charring [6]. Similarly, with the infusion

of saline into the probe, wet electrodes (StarBurst XLi-

Enhanced and Talon, RITA Medical Systems), and Cool-

tip electrode (Valleylab) are also hypothesized to minimize

charring. To date, no controlled human clinical studies

have tested these hypotheses.

Both laparoscopic and percutaneous RFA techniques are

employed in the treatment of RCC with tumour location

and configuration being the primary determinant of the

chosen approach [53]. Laparoscopic RFA allows for iso-

lation of the tumour to avoid adjacent organ damage.

However, percutaneous RFA, as a true minimally invasive

approach that is feasible with the patient under conscious

sedation, is the preferred approach [53]. This is in agree-

ment with our current report where the majority of TB-

RFA (70 %) and IB-RFA patients (89.5 %) were treated

percutaneously.

Current analyses demonstrate significant heterogeneity

between TB-RFA and IB-RFA studies regarding clinical

efficacy. Reasons for this heterogeneity may include clin-

ical and methodological aspects. The studies differed

considerably in their patient population, disease severity,

approach (laparoscopic, percutaneous, or open), and dura-

tion of follow-up. There were also methodological differ-

ences in the handling of losses to follow-up. Funnel plots

suggest the possibility that publication bias may have

occurred in both the TB (Fig. 2) and IB-RFA groups

(Fig. 5). The current report is also constrained by incon-

sistent reporting standards of the original articles, which

may limit generalizability of the current findings. Of the

Proportion meta-analysis plot [fixed effects]

0.0 0.2 0.4 0.6 0.8

combined 0.131 (0.098, 0.168)

Veltri et al. 0.077 (0.002, 0.360)

Matsumoto et al. 0.121 (0.062, 0.206)

Memarsadeghi et al. 0.438 (0.198, 0.701)

Hegarty et al. 0.097 (0.040, 0.190)

Stern et al. 0.125 (0.042, 0.268)

Levinson et al. 0.194 (0.075, 0.375)

Turna et al. 0.069 (0.008, 0.228)

Zurera et al. 0.077 (0.002, 0.360)

Tan et al. 0.098 (0.027, 0.231)




regarding complication rate in

TB-RFA therapy


123

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123

original 40 articles reporting on the use of RFA on RCC, 13

(33 %) had used a combination of TB and IB-RFA without

differentiating their results per modality, thus making it

difficult to draw conclusions based on their findings. In

addition, given the established role of tumour size on the

success of the RFA procedure, the lack of raw data from

the original studies prevented subgroup analysis based on

tumour size. Several studies did not offer pertinent details

of the tumour (i.e., type, location) and ablation technique

(frequency and duration of ablation per tumour, size of

ablation zone). Follow-up duration and intervals also var-

ied considerably across the analyzed reports ranging from 9

to 60 months. Variable definitions in what constituted

major and minor complications were noted across indi-

vidual studies, thus affecting their reported rates. Alto-

gether, adherence to the SIR reporting standards for the

ablative treatment of renal carcinomas is warranted to

minimize future reporting incongruities. Specifically,

standardized disclosure of patient demographics and well-

defined exclusion criteria, tumour characteristics (size,

location, proximity to organs/vessels), description of the

ablation technique (energy source and applicator, treatment

algorithm), follow-up on clinical status (disease-free and

overall survival as per Kaplan–Meier technique), and a

thorough description of all perisurgical and postsurgical

complications is indicated. Through adherence to uniform

reporting standards, the safety and efficacy of RFA as a

minimally invasive therapy for patients with RCC can be

better delineated and effectively compared with other

nephron-sparing approaches.



regarding clinical efficacy in IB-

RFA therapy

Bias assessment plot

0.6 0.8 1.0 1.2 1.40.138

0.108

0.078

0.048

0.018

Proportion

Sta

ndar

d er

ror

Fig. 5 Funnel plot of case series regarding clinical efficacy in IB-

RFA therapy


123

Conclusion

In the current meta-analysis, no statistical differences

between TB and IB-RF generators were observed imme-

diately after the procedure or at follow-up. Future pro-

spective multicenter RCTs using the recent SIR reporting

standards may further shed light on any differential effi-

cacy across the two modalities. Moreover, future cost-

benefit analysis will help delineate the utility and efficacy

of the various RFA generator models for the clinician and

hospital administrator alike.

Conflict of interest The authors have no conflict of interest to

disclose.

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thermal versus impedance-based ablation of renal cell carcinoma: a meta-analysis

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