Assessing Outcomes in Probe Ablative Therapies for Small Renal Masses

Abstract

The increasing incidence of renal-cell carcinoma can be largely attributed to the increased detection of small renal masses (SRMs) via abdominal imaging. These lesions tend to have a slow rate of growth and low malignant potential, and hence, minimally invasive treatments and active surveillance have been developed for these low-risk tumors to minimize treatment-related morbidity. Radiofrequency ablation and cryotherapy are the principal less-invasive approaches, and their initial oncologic efficacy and complication profiles have been favorable. Suboptimal definition of the relevant outcomes of treatment, a dearth of prospective and randomized data, and relatively short follow-up in the context of the natural history of SRMs pose challenges in the assessment of the efficacy and outcomes of thermal ablation of renal-cell carcinoma. Better pretreatment characterization of the biology of these tumors, more effective real-time treatment monitoring, and standardization of outcome definitions and follow-up are needed to better clarify the effectiveness and role of these treatments. This review highlights these potential pitfalls in the assessment of outcomes of probe ablation of SRMs.

Introduction

I n the last 20 years, the incidence of renal-cell carcinoma (RCC) in North America has increased by 2.0% per year.¹ Mortality rates, however, have not appreciably changed during the same time. The increased use of abdominal imaging may explain this phenomenon, as it has led to the increased detection of small renal masses (SRMs), most of which are RCC.² SRMs are by definition less than 4 cm in maximal dimension. A pooled analysis of SRMs found a growth rate of 0.28 cm per year, and if RCC, they have a very low rate of progression to metastatic disease during follow-up and a low incidence of metastatic disease at presentation.^3
–5

For these reasons, to minimize treatment-related morbidity, minimally invasive treatments and active surveillance have been developed for these low-risk tumors.^6,7 Thermal or probe ablation (we will use these terms interchangeably) with radiofrequency ablation (RFA) and cryoablation are the principal less-invasive approaches. Their initial oncologic efficacy and complication profiles have been favorable.^3,6 The known natural history of the lesions treated and the absence of pretreatment biopsy make full evaluation of outcomes difficult despite longer follow-up in some published reports. Definition of the relevant outcomes is controversial in comparison to those with the standard surgical treatments of RCC. We will address some of these issues and explore potential pitfalls in the application of standard measures of treatment outcome to thermal ablative therapies.

Defining Success in Probe Ablative Therapy

Surgical treatment of RCC by radical or partial nephrectomy provides well-established metrics for the definition of successful management. Pathological confirmation of RCC is obtained, including histologic subtype, as well as local stage and grade, and margin status as an indicator of the completeness of excision. Disease-specific and progression-free survival can be measured using established follow-up protocols.^8,9 Success is usually defined as the absence of recurrent disease after treatment with acceptable morbidity including preservation of renal function, allowing that open surgery is generally more morbid than a minimally invasive, laparoscopic approach. Surgical complications are well defined and usually reported; most are minor.

Measurement of outcomes with nonsurgical treatments, including probe ablative therapies, may require surrogate endpoints to measure treatment success. Several approaches have been used for RFA and cryoablation. Serial imaging of the kidney is the standard follow-up method (often without reported inclusion of chest and other imaging to rule out distant progression) and consensus is evolving regarding the definition of a successfully ablated versus a persistent lesion over time.^10

–14 Routine posttreatment biopsy is used by some to detect the presence or absence of residual viable cancer but this remains controversial.^3,15,16 Clark et al¹⁷ have published reporting standards for RFA that recommend serial imaging after the procedure, but make no specific recommendation regarding routine postprocedure biopsy. Probe ablation series have generally included fewer patients in comparison to nephrectomy or partial nephrectomy cohorts, and no randomized prospective assessment has been undertaken to assess their efficacy in comparison to these conventional treatments.^3,6 It merits acknowledgment, however, that partial nephrectomy, though extensively analyzed in retrospective cohorts, has not been the subject of randomized comparison to radical nephrectomy. Currently, success for probe ablation is defined as the absence of enhancement on follow-up imaging with or without a negative biopsy of the ablation lesion, which does not increase in size over time. The time frame to achieve this outcome is variably defined as the presence of residual mass and size change.

Technical Issues in Probe Ablation Assessment

To a greater extent than with surgical techniques, thermal ablation technologies may evolve over the time between a patient's procedure and the time of outcome evaluation. Examples include advances in materials, energy delivery, targeting, and monitoring. With longer the follow-up, there is a potential for results that appear suboptimal, to be attributed to earlier or obsolete instrumentation.

Techniques for monitoring thermal ablation procedures during treatment are evolving. They are not standardized and the extent of the acute thermal lesion is not reported although it may be visualized at the time of treatment. Cryoablative treatment is classically monitored with visualization of the ice ball as a marker of the extent of complete freezing.¹⁸ For RFA, the issue is less standardized. The size and completeness of thermal injury is indirectly determined by treatment time, diameter of the deployed RFA tines, tissue impedance, and temperature sensors on the probe.^18,19 Some centers use separately placed temperature probes adjacent to tumor margins.¹⁹ Variations in size and shape of lesions despite using standard technique have been reported in animal experiments.²⁰ There is some experience using magnetic resonance (MR) thermography to monitor thermal injury.^21,22 This may allow real-time monitoring and decision making to optimally position or reposition RFA probes and to better determine treatment intensity and time. MR-guided RFA has been applied in the management of selected liver tumors; however, the relative mobility of the kidney with respiration may result in artifactually incorrect temperature measurement with MR.^22,23 There are several methods and algorithms to map temperature. A reference image must be obtained prior to the ablation procedure and any spatial difference between this and the in-treatment images can result in an inaccurate representation of the thermal gradients. The development of temperature-sensitive contrast media may obviate this problem. Finally, there may be a significant burden of cost associated with MR-assisted RFA, and an incompatibility with currently available MR and RFA systems that may not allow the simultaneous capture of images and application of ablative energy.

It has also been demonstrated that there are significant differences in the ablation lesion created at different sites in the same tissue, or between individuals, despite identical time and amplitude of energy delivery. Pereira et al²⁰ performed RFA on animal liver, with similar energy settings and different probe styles. The result was the creation of different ablation lesions in each case. It may therefore be difficult to specifically target a renal lesion with great accuracy, especially in light of the differences in location of tumors or in intrarenal anatomy between patients that may result in heat-sinking and lower effective temperature in some areas.

Tumor location within the kidney can impose limitations on the ability to successfully and safely perform thermal ablative treatments. This is similar to the experience with partial nephrectomy, which is more difficult for central lesions despite meticulous technique. With probe ablation, proximity of the tumor to large blood vessels can result in a heat-sink effect that lowers (or raises) the actual temperature achieved within the mass at the point adjacent to the vessel. This may result in ineffective local cell kill and may contribute to failure.

The standard follow-up of ablated tumors requires serial cross-sectional imaging. Optimal imaging of a renal tumor requires unenhanced, enhanced, and delayed imaging and can therefore represent a significant radiation exposure. There is no standard or validated protocol for the follow-up but most series have relied on the absence of contrast enhancement as a surrogate for treatment success. Bensalah et al¹¹ imaged patients with computed tomography (CT) at 6 weeks, 3 months, and 6 months after treatment, and then every 6 months subsequent. Gervais et al²⁴ used a similar protocol, with cross-sectional imaging at 1, 3, and 6 months postprocedure, and every 6 to 12 months thereafter. Recent reporting standards for RFA suggest scans at every 6 months up to at least 5 years after the procedure, in addition to an early postprocedure scan.¹⁷ This would represent up to 12 separate scans in the 5 years following the procedure, each ideally requiring contrast to assess for enhancement. This compares to two scans (usually with ultrasound but may require CT) recommended in the first 5 years of follow-up for T1 (tumor ≤7 cm and confined to the kidney) renal masses after partial or radical nephrectomy according to the guidelines of the Canadian Urological Association.⁸ There is concern about diagnostic radiation from CT, as current usage may be responsible for up to 2% of all cancers.^25,26 Opinion leaders have recommended the judicious use of CT with radiation minimization techniques and the exclusion of unnecessary tests. It must be clearly understood, however, that the model for radiation dose and cancer incidence is based on the outcomes following atomic bomb detonations during World War II. The appropriateness of this model has been criticized in the setting of the intermittent low-dose exposure that occurs with repeated CT scans. MR imaging is also employed for follow-up but it can pose problems in the patients with impaired renal function. Nephrogenic systemic fibrosis has emerged with the use of gadolinium-based contrast agents in patients with renal insufficiency.²⁷ There may be a role for contrast-enhanced ultrasonography, with reports of excellent interobserver reliability and concordance with both CT and biopsy in known RCCs.^28,29 It is reasonable to anticipate that with greater experience and longer follow-up, the postprocedure surveillance regimen for thermal ablation will become simplified and the number of imaging studies will decrease. This may abrogate some of the issues of cost and exposure in the follow-up of RFA and cryoablation.

Reported Outcomes in Probe Ablation Series

There have now been numerous published series reporting outcomes in renal masses treated with thermal ablation using RFA or cryoablation. Disease-specific outcomes have been universally excellent within the limited follow-up of these studies (Table 1).^{24,30

–39} Only one study presented follow-up to 5 years, but most series have followed patients for less than 3 years.³⁶ In a multi-institutional study of thermal ablation in 616 patients, 13.4% of RFA patients and 3.9% of cryoablation patients had residual or recurrent disease after treatment (defined as enhancement on the first postprocedure imaging or on later imaging, respectively).⁴⁰ Progression of disease locally occurred in 5.2% of cryoablation patients and 12.9% of RFA patients in a recent combined analysis of series on these modalities.³ Overall, repeat ablation in RFA and cryoablation patients was required in 8.5% and 1.3% of patients, respectively, and progression to metastatic disease was identified in 2.5% and 1%, respectively. It is important to acknowledge the pitfalls in comparing outcomes of RFA and cryoablation in these retrospective analyses. Cryotherapy has been performed with a laparoscopic approach in most series, whereas RFA has been typically undertaken through a percutaneous approach.⁴¹ Differences between image guidance and direct vision guidance, as well as differences in patient compliance and respiration management may impose significant bias on these published results.

Table 1.

Recent Series of Thermal Ablation of Small Renal Masses

Author	No. of patients (no. of tumors)	Energy modality	Mean tumor size (cm)	Median follow-up (months)	Recurrence rate (%)	Cancer-specific survival (%)
Gervais et al²⁴	85 (100)	RFA^a	3.2	28	10	100^b
Park et al³⁰	78 (94)	RFA^c	2.4	25	3.2	NA
Zagoria et al³¹	104 (125)	RFA^a	2.7	13.8	8	NA
Levinson et al³²	31 (31)	RFA^a	2	61.6	9.7	100
Wyler et al³³	14 (14)	Cryo^d	2.8	21	0	100
Weld et al³⁴	31 (36)	Cryo^d	2.1	36	2.8	100
Lehman et al³⁵	23 (30)^e	Cryo^d	1.8	11	0	100
Aron et al³⁶	88	Cryo^d	2.3	min. 60	5.7	95
Atwell et al³⁷	110 (115)	Cryo^d	3.3	13.3	0	100
Caviezel et al³⁸	7 (7)	Cryo^a	2.1	28	0	100
Finley et al³⁹	37 (43)	Cryo^c	2.9	12.8	4.7	100
Permpongkosol et al⁵⁴	21 (23)	Cryo^a	2.1	12.3	9.5	100

Percutaneous approach.

Among patients treated for solitary lesion in the absence of metastatic disease at treatment.

Included percutaneous and laparoscopic/retroperitoneoscopic approaches.

Laparoscopic approach.

Cohort of patients with lesion <3.0 cm.

RFA = radiofrequency ablation; cryo = cryoablation; NA = not available; min = minimum.

Despite the minimally invasive approach, serious adverse events can occur.^17,42 These have generally been reported individually in series, and so an established rate of complications is not available from the literature. Bleeding is the most common complication, but more severe issues can arise, including but not limited to urinary leak, ureteral obstruction, fistula to bowel or other surrounding structures, and loss of the kidney. Partial nephrectomy is associated with complications as well, but the rate of injury to adjacent structures is less. Case volume and complication rates have not been specifically studied with ablation.

Issues in the Interpretation of Current Results

Despite an increasing number of patients and published series on probe ablation of SRMs, significant questions remain. Reports are retrospective reviews of case series, with no control arm or randomization. The same can be said of partial nephrectomy reports. The numbers of patients are relatively small (only two series report on more than 100 patients) and often do not reflect a similar population to surgical studies, with a higher preponderance of medically unfit and elderly patients with limited life expectancy represented. Unlike surgical experience, follow-up in these series has been relatively short, with only one series following patients for at least 5 years. Arguably, at the present time, these data, even when pooled, do not yet provide a reliable or generalizable assessment of probe ablation in the treatment of renal malignancies.^3,6

The very high survival rates in published series are certainly promising, but are less impressive when interpreted in the context of the natural history of the SRMs being treated. SRM surveillance series and meta-analyses have been reported in recent years and have defined the very slow growth rate in the majority of cases, and low rates of progression to metastatic disease in the incidentally discovered, isolated SRMs. A combined analysis of SRMs (median, 2.6 cm) under active surveillance revealed an average growth rate of 0.28 cm per year.⁷ Only 10 cases in the literature have been identified as having progressed from such a mass to metastatic disease.^{4,43

–48} There is therefore some precedent to suggest that many of the lesions treated in the RFA and cryoablation series might have been surveyed instead without a significant impact on the disease-specific survival.

Absence of enhancement on imaging has classically been used as the definition of treatment success in probe ablation of renal masses. Early series in patients undergoing partial nephrectomy immediately or soon after RFA identified viable tumor in a majority of surgical specimens.^49,50 Rendon et al⁵⁰ found viable tumor in four of five patients undergoing immediate post-RFA partial nephrectomy, and in three of six patients treated with RFA a week prior to surgery. Michaels and colleagues⁴⁹ found incomplete tumor kill in 100% of partial nephrectomy specimens obtained immediately after RFA treatment. Some series have explored the success of ablation with immediate or delayed postprocedure biopsy to determine the presence of persistent viable cancer. Weight et al¹⁶ found that while the radiographic success of their RFA patients was 85% at 6 months postprocedure, 35.2% of patients had evidence of persistent carcinoma on biopsy at the same time. No such difference was found between radiographic and biopsy success rates in a cryoablation cohort (90% radiographic and 93.8% negative biopsy at 6 months postprocedure). Raman and colleagues,¹⁵ however, found perfect concordance between negative imaging and negative biopsy in RFA patients undergoing biopsy at more than a year after their procedure.

Other issues regarding the available data in probe ablation relate to the biology of the masses and to the determination of that biology. Reporting biopsy results prior to (to guide the indication for ablation) treatment is inconsistent in the published ablation series. A recent analysis of RFA and cryoablation series noted that pretreatment biopsy was performed in 62.2% of patients undergoing RFA, and 82.3% of those treated with cryotherapy.³ Despite biopsy, pathology was indeterminate or unknown at the time of treatment in 40.4% and 24.5% of RFA and cryoablation patients, respectively. Clearly, benign masses have been ablated and included in the analysis in these series (similar observations apply to some partial nephrectomy reports). This is especially important given the well-established relationship between tumor size and the likelihood of malignancy. In the series of Frank et al,⁵¹ 2770 radical and partial nephrectomy specimens were assessed to determine this relationship. Twenty-five percent of renal masses less than 3.0 cm were found to be benign. Only two series featured an average tumor size of 3.0 cm or greater (exclusive of the cohort of patients with lesions of greater than 3 cm in the series of Lehman et al).^24,35,37 It is also established that SRMs tend to have lower histologic grade than larger masses, further suggesting a more limited malignant potential.⁵² A recent update on reporting standards for RFA suggests that biopsy should be performed at the time of the RFA procedure whenever possible.¹⁷

The size and location of tumors managed with nephron-sparing treatment are important factors in the success of treatment. Kutikov and Uzzo⁵³ have attempted to quantify this in the form of the R.E.N.A.L. nephrometry score, which rates five anatomic and morphologic characteristics of a renal mass to standardize tumor description and to stratify masses based on the complexity of excision. The series of Gervais et al²⁴ found small size and noncentral location to be independent predictors of successful ablation, and all eight incompletely ablated masses (9%) were greater than 4.0 cm. Similarly, Zagoria and colleagues³¹ successfully ablated all tumors less than 3.7 cm, with 70% success in larger lesions with RFA, whereas Permpongkosol et al⁵⁴ found that tumor size and location impacted success in cryoablation. A combined analysis did not find tumor size to be independently predictive of progression or metastasis.³ The impact of tumor size and location will be important parameters in the stratification of outcomes in future prospective analysis of RFA and cryoablation.

Finally, the impact of residual disease on long-term outcomes is unclear. There is an emerging body of literature on outcomes in patients with positive surgical margins (PSMs) at partial nephrectomy. A combined analysis performed on 1344 patients undergoing partial nephrectomy at the Mayo Clinic and the Memorial Sloan-Kettering Cancer Center found no difference in recurrent disease or in progression to metastatic disease between patients with PSMs and negative surgical margins.⁵⁵ Similarly, a pooled European analysis of 111 patients with PSMs at partial nephrectomy compared with 664 patients with negative surgical margins found no differences in disease recurrence or cancer-specific survival.⁵⁶ These data raise the question of the real risks associated with persistent disease and may be relevant in the setting of imperfect tumor cell kill in thermal ablative therapies. Long-term data on recurrence, progression, and survival will be needed to better define the true impact of procedure outcomes on patients.

Conclusions

Thermal ablative therapies and active surveillance have emerged as viable options in the management of patients with SRMs, particularly those who are elderly or infirm or with preexisting renal insufficiency. New insights into the natural history of these SRMs, combined with a dearth of prospective data and an absence of randomized data, limited to relatively short follow-up, make difficult to validate the conclusions about the efficacy of thermal ablation in treating RCC. There is certainly some biological evidence of tumor destruction, but this has not been proven as effective as extirpation.

Prospective and randomized data would be ideal but present series need to be reevaluated with longer follow-up periods. Better pretreatment characterization of the biology of these tumors is critically needed as well. Real-time monitoring is suboptimal with current technologies and may be important in ensuring effective treatment and minimizing treatment-related morbidity. Standardization of follow-up is similarly important and lacking, and current enhanced imaging-intensive regimens are quite burdensome from a resource, and possibly a safety, perspective.

Footnotes

Disclosure Statement

No competing financial interests exist.

Abbreviations Used

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