Nonsurgical Focal Therapy for Renal Tumors

As has been highlighted in the accompanying article on the Epidemiology and Etiology of Kidney Cancer, cancers of the kidney and renal pelvis comprise the 6th most common newly diagnosed tumors in men and 10th most common in women.1 With the increasing use of abdominal imaging, a growing number of small renal masses are being detected. In fact, 13 to 27% of abdominal imaging studies demonstrate incidental renal lesions unrelated to the reason for the study2 and approximately 80% of these masses are malignant.3Thus, a large number of small, incidentally-detected renal masses are now being diagnosed. Due to the increase in diagnosis of small renal masses and the general predilection for diagnosis of renal tumors in older adults (typically diagnosed between age 50 and 70 years), the paradigm for treatment of renal tumors has focused on minimally invasive approaches and nephron sparing in the past few years.

According to the American Urological Association guidelines on the management of stage 1 renal tumors, nephron sparing surgery (partial nephrectomy) is recommended.4 However, renal mass ablation is considered an alternative, particularly among the elderly and comorbid.4 Renal ablation may be undertaken by percutaneous approaches (nonsurgical) or through laparoscopic or open approaches.

Rationale for Focal Therapy

As with any tumor site, focal ablative therapies offer several potential advantages to traditional surgical approaches. First, focal ablative therapies are less physiologically demanding on the patient than extirpative surgery. As a result, these may often be performed as ambulatory day surgical procedures with a much shorter convalescence and fewer complications when compared to laparoscopic partial nephrectomy.5 Second, renal mass ablation is associated with comparable post-operative renal function when compared to partial nephrectomy.5,6 Third, while laparoscopic partial nephrectomy is a technically challenging operation, requiring advanced laparoscopic skills for tumour resection and renal reconstruction,7 focal ablation (either via laparoscopic or percutaneous approach) allows minimally-invasive treatment of renal tumors with relative technical simplicity.5 Finally, renal mass ablation may be accomplished by a variety of approaches including open, laparoscopic, and percutaneous approaches.

While long-term data are lacking, intermediate term data (with a median follow-up of approximately 3.5 years) suggest that cancer control is similar between renal tumor ablation (using laparoscopic cryotherapy) and minimally-invasive partial nephrectomy.6

Indications for Focal Therapy of Renal Tumors

Treatment choice in the management of small renal masses depends on a complex interplay of patient preference, tumor characteristics, host (patient) factors including age and comorbidity, and the expertise/ability of the treating physician. A number of indications have been well-recognized for the use of renal tumor ablation. Ablation is indicated for patients with small renal tumors who are: poor surgical candidates or at high risk of renal insufficiency. Patients may be at risk of renal insufficiency due to underlying nephron-threatening conditions such as diabetes or hypertension, due to a solitary kidney (either congenital or due to prior nephrectomy), or due to oncologic factors such as bilateral tumors or hereditary syndromes which predispose to recurrent, multifocal tumors.

However, given the good outcomes of renal mass ablation in the treatment of small renal masses among these patients, a number of authors have now advocated the use of renal mass ablation in otherwise healthy patients.8

Approaches to Focal Therapy

Non-surgical focal therapy refers to a therapeutic strategy, rather than a specific treatment modality. A number of different focal therapy modalities have been employed in the treatment of small renal masses. Foremost among these are cryoablation and radiofrequency ablation (RFA).

Prior to ablation, the American Urologic Association guidelines recommend biopsy of the renal mass either prior to ablation or at the time of treatment.9

Cryotherapy

Cryoablation, also known as cryotherapy, is the therapeutic use of extremely cold temperature. While first employed in the treatment of breast, cervical, and skin cancers, cryoablation has subsequently been used in the treatment of a variety of benign and malignant conditions. Initially, liquified air was used, then solidified carbon dioxide, liquid oxygen, liquid nitrogen, and finally argon gas. Today, the majority of commercially available systems rely on argon gas.

It wasn’t until Onik et al. identified that the cryogenic ice-tissue interface was highly echogenic on ultrasound that an accurate, controlled treatment of intra-abdominal malignancies could be undertaken.10 Today, cryotherapy of renal tumors is undertaken under real-time imaging.

Ablation during cryoablation occurs during both the freezing and thawing phases of the treatment cycle. During freezing, the rapid decrease in temperature immediately adjacent to the probe causes the formation of intracellular ice crystals which lead to mechanical trauma to plasma membranes and organelles and subsequent cell death through ischemia and apoptosis.11 More distal to the probe, a slower freezing process occurs in which extracellular ice crystals form, causing depletion of extracellular water and inducing an osmotic gradient which causes intracellular dehydration. During the thaw cycle, extracellular ice crystals melt leading to an influx of water back into the cells, resulting in cellular edema. In addition to these cellular effects, the freezing cycle results in injury to the blood vessel endothelium resulting in platelet activation, vascular thrombosis and tissue ischemia. The result of these process is coagulative necrosis, cellular apoptosis, fibrosis and scar formation. Due to evidence that multiple freeze-thaw cycles led to larger areas of necrosis, the current treatment paradox suggests a double freeze-thaw cycle.

For optimal cellular death, the preferred target temperature for cryotherapy is at or below -40o C. As temperatures at the edge of the ice ball are 0o C, most authors suggest that the ice ball extends at least 5 or 10mm beyond the edge of the target lesion. In some cases, this will require the use of multiple probes.

Radiofrequency Ablation

In contrast to cryotherapy which utilizes freeze-thaw cycles to induce cellular damage, radiofrequency ablation (RFA) relies upon radiofrequency energy to heat tissue until cellular death. Using monopolar alternating electrical current at a frequency of 450 to 1200 kHz, RFA induces vibrations of ions within the tissue which leads to molecular friction and heat production. The resulting increased intracellular temperature leads to cellular protein denaturation and cell membrane disintegration. The success of RFA treatment depends on the power delivered, the resulting maximal temperature achieved, and the duration of ablation.

A number of variations in RFA delivery have been described: temperature- or impedance-based guidance, single or multiple tines, “wet” vs “dry” ablation, and mono- or bi-polar electrodes.

Unlike cryoablation which relies upon real-time imaging guidance, RFA may be guided by either temperature-based or impedance-based monitoring. Systems which rely on temperature-based guidance measure temperature at the tip of the electrode. However, they do not measure temperature within the surrounding tissue. Systems which rely on impedance-based guidance measure the resistance to alternating current (the impedance). These systems are calibrated to achieve a predetermined impedance level. There is no data to support the superiority of either of these approaches. For temperature-based systems, the target is 105o C with a minimum of 70o C during the heating cycle. For impedance-based systems, the target is 200 to 500 ohms, which is achieved by progressively increasing the power beginning from 40-80W to 130-200W at a rate of 10W/minute.

A number of studies have demonstrated that multi-tine electrodes are associated with more complete tissue necrosis and improved treatment outcomes.12

In addition to the guidance approach and number of tines, RFA technology may be stratified according to “wet” vs. “dry” approach. Through the tissue ablation process, tissue desiccation leads to charring which can increase impedance. This in turn increases the resistance to the current emanating from the electrode and limits the size of the ablation field. A “dry” approach functions within these limitations and cannot treat more than 4cm with a single electrode. In contrast, a “wet” approach continuously infuses saline through the probe tip. This cools the tissue and prevents the tissue charring. As a result, larger ablation zones are possible.

Finally, energy delivery may be either through monopolar or bipolar electrodes. The benefit of bipolar electrodes is both increased temperature generation13 and a larger treatment field.14

The efficacy of RFA is affected not only by the characteristics of the tissue being treated but also by the surrounding tissues. For example, large vessels may dissipate heat and result in relative undertreatment of adjacent tissues.

Monitoring following Focal Therapy

The definition of treatment success following renal mass focal ablation has been controversial. Currently, radiographic assessment utilizing computed tomography or magnetic resonance imaging is considered an accepted measure of treatment effect.15 Typically, this is performed 4-12 weeks following treatment. However, some rely on post-ablation biopsy to confirm treatment success though this is not well accepted.

The most reliable radiographic marker of successful ablation is the lack of contrast enhancement, corresponding to complete tissue destruction.16 Persistent enhancement is considered incomplete treatment and re-treatment or an alternative treatment strategy may be warranted. Alternatively, subsequent enhancement on surveillance imaging in an area with prior loss of enhancement suggests local recurrence.17 Many tumors following cryoablation have a significant reduction in tumor size while this is uncommon following RFA.

The AUA guidelines recommend contrast enhanced CT or MUI at 3 and 6 months following treatment and then each year for the following 5 years.9

Oncologic Outcomes

Long-term outcomes are lacking for renal ablation techniques. The summary data from the AUA guidelines panel suggests local recurrence free rates of approximately 90% for patients undergoing cryoablation and 87% for patients undergoing RFA.4 Outcomes between cryoablation and RFA appear to be comparable. Compared to partial nephrectomy, the available data suggest higher rates of local recurrence despite shorter follow-up. However, metastasis-free survival and cancer-specific survival appear to be comparable.

Complications

Major complications following renal mass ablation are uncommon. Further, percutaneous, nonsurgical ablation has lower complication rates than other approaches.18 As with oncologic outcomes, complication rates are comparable between RFA and cryoablation. Major urologic complications occurred in 3.3-8.2% of patients undergoing ablation while non-urologic complications occurred in 3.2-7.2%. These rates are lower than extirpative approaches including open or laparoscopic nephrectomy.

The most common complication is pain or paresthesia at the percutaneous access site.19 The most concerning complications relate to inadvertent injury to intra-abdominal organs. A variety of tumor characteristics including anterior location, proximity to collecting system and those without easy percutaneous access increase the risk of complications when percutaneous ablation is undertaken. Permanent urologic damage including injury to calyces, the ureteropelvic junction, or the ureter is uncommon.20

Hemorrhage is the most common serious complication of cryoablation. This is less common with RFA. Bleeding is more common when multiple probes are used to treat large tumors.21

Written by: Christopher J.D. Wallis, MD PhD, University of Toronto
References:

1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA: a cancer journal for clinicians 2018;68:7-30.

2. Gill IS, Aron M, Gervais DA, Jewett MA. Clinical practice. Small renal mass. The New England journal of medicine 2010;362:624-34.

3. Frank I, Blute ML, Cheville JC, Lohse CM, Weaver AL, Zincke H. Solid renal tumors: an analysis of pathological features related to tumor size. The Journal of urology 2003;170:2217-20.

4. Campbell SC, Novick AC, Belldegrun A, et al. Guideline for management of the clinical T1 renal mass. The Journal of urology 2009;182:1271-9.

5. Desai MM, Aron M, Gill IS. Laparoscopic partial nephrectomy versus laparoscopic cryoablation for the small renal tumor. Urology 2005;66:23-8.

6. Fossati N, Larcher A, Gadda GM, et al. Minimally Invasive Partial Nephrectomy Versus Laparoscopic Cryoablation for Patients Newly Diagnosed with a Single Small Renal Mass. Eur Urol Focus 2015;1:66-72.

7. Aboumarzouk OM, Stein RJ, Eyraud R, et al. Robotic Versus Laparoscopic Partial Nephrectomy: A Systematic Review and Meta-Analysis. European Urology 2012;62:1023-33.

8. Stern JM, Gupta A, Raman JD, et al. Radiofrequency ablation of small renal cortical tumours in healthy adults: renal function preservation and intermediate oncological outcome. BJU international 2009;104:786-9.

9. Donat SM, Diaz M, Bishoff JT, et al. Follow-up for Clinically Localized Renal Neoplasms: AUA Guideline. The Journal of urology 2013;190:407-16.

10. Onik G, Gilbert J, Hoddick W, et al. Sonographic monitoring of hepatic cryosurgery in an experimental animal model. AJR Am J Roentgenol 1985;144:1043-7.

11. Baust JG, Gage AA. The molecular basis of cryosurgery. BJU international 2005;95:1187-91.

12. Rehman J, Landman J, Lee D, et al. Needle-based ablation of renal parenchyma using microwave, cryoablation, impedance- and temperature-based monopolar and bipolar radiofrequency, and liquid and gel chemoablation: laboratory studies and review of the literature. J Endourol 2004;18:83-104.

13. Nakada SY, Jerde TJ, Warner TF, et al. Bipolar radiofrequency ablation of the kidney: comparison with monopolar radiofrequency ablation. J Endourol 2003;17:927-33.

14. McGahan JP, Gu WZ, Brock JM, Tesluk H, Jones CD. Hepatic ablation using bipolar radiofrequency electrocautery. Acad Radiol 1996;3:418-22.

15. Matin SF, Ahrar K, Cadeddu JA, et al. Residual and recurrent disease following renal energy ablative therapy: a multi-institutional study. The Journal of urology 2006;176:1973-7.

16. Matsumoto ED, Watumull L, Johnson DB, et al. The radiographic evolution of radio frequency ablated renal tumors. The Journal of urology 2004;172:45-8.

17. Matin SF. Determining failure after renal ablative therapy for renal cell carcinoma: false-negative and false-positive imaging findings. Urology 2010;75:1254-7.

18. Johnson DB, Solomon SB, Su LM, et al. Defining the complications of cryoablation and radio frequency ablation of small renal tumors: a multi-institutional review. The Journal of urology 2004;172:874-7.

19. Farrell MA, Charboneau WJ, DiMarco DS, et al. Imaging-guided radiofrequency ablation of solid renal tumors. AJR Am J Roentgenol 2003;180:1509-13.

20. Johnson DB, Saboorian MH, Duchene DA, Ogan K, Cadeddu JA. Nephrectomy after radiofrequency ablation-induced ureteropelvic junction obstruction: potential complication and long-term assessment of ablation adequacy. Urology 2003;62:351-2.

21. Lehman DS, Hruby GW, Phillips CK, McKiernan JM, Benson MC, Landman J. First Prize (tie): Laparoscopic renal cryoablation: efficacy and complications for larger renal masses. J Endourol 2008;22:1123-7.

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