Ablative Therapies for Small Renal Masses

Michael Palese, MD

About the Authors Affiliation: Kadi-Ann Bryan, MD, is a chief resident in the Department of Urology; and Michael Palese, MD, is the director of Minimally Invasive Surgery at the Mount Sinai Medical Center in New York City.

Disclosures: The author reports no financial interest with any entity that would pose a conflict of interest with the subject matter of this article.

Address correspondence to: Michael Palese, MD, Department of Urology, Mount Sinai Medical Center, One Gustave L. Levy Pl, Box 1272, New York, NY 10029. E-mail: michael.palese@mountsinai.org.

Ablative Techniques

Cryotherapy

Renal cell carcinoma accounts for 2% to 3% of adult malignancies and is the third most common urologic malignancy after prostate and bladder cancer. Over the last 65 years, the rate of diagnosis has increased by approximately 2% per year as the use of cross-sectional diagnostic imaging has increased, largely reflecting the diagnosis of incidental renal masses. Currently, the standard of care for localized renal cell carcinoma is surgical excision as this has demonstrated the most durable oncologic efficacy. Since 1969 when radical nephrectomy was described as the “gold standard” treatment for localized renal cell carcinoma,¹ management of renal masses has evolved to a greater utilization of nephron-sparing techniques for small renal masses. Currently, there are several evolving and emerging techniques that have been successfully employed in the minimally invasive treatment of small renal masses. As long-term data accrue, these techniques are likely to play a greater role in the management of these lesions. This review summarizes the ablative techniques currently available for the treatment of small renal masses.Cryotherapy first emerged as a minimally invasive technique for treating renal masses in 1995. Its oncological efficacy and short-term durability have supported its use as a treatment option for select patients.² Using high-pressure inert gases, most commonly argon, tissues are exposed to temperatures as low as -187°C. This induces mechanical cellular injury due to both the formation of ice crystals intra- and extracellularly, as well as reperfusion vascular injury resulting in cell death, microcirculatory failure, and small-vessel vascular thrombosis.³ Renal cell death occurs at -19.4°C; all human tissues under necrosis at temperatures in excess of -40°C (the preferred target temperature during ablation).⁴

Currently, a double freeze—thaw cycle is used as this achieves superior tumor cell death when compared to a single cycle.⁵ In addition, the propagation of the treatment zone can be observed in real time with ultrasonic imaging, allowing for more precise ablation. The treatment area typically extends approximately 1cm beyond the tumor margin,⁶ as the target temperature is usually achieved within 3 mm of the expanding “ice ball.”

Radiofrequency Ablation

Long-term data on cryoablation for small renal masses has shown an oncologic efficacy comparable to that of partial nephrectomy, with reported cancer-specific survivals of 95% and recurrence-free survivals of 90%.^7-11 Cryoablation may be performed via a laparoscopic or percutaneous approach, with both demonstrating equivalent outcomes. While the percutaneous approach obviates the need for general anesthesia, it may not be suitable for more anterior lesions or patients with prior retroperitoneal surgeries.Radiofrequency ablation (RFA) was first employed experimentally in 1997 for pre-operative ablation of T1a renal masses.¹² RFA induces thermal damage through heat generated by oscillating bipolar or monopolar high frequency alternating currents, achieving temperatures up to 120° C. The current is introduced with needle electrodes inserted into the tissue percutaneously or laparoscopically, resulting in irreversible coagulative necrosis at temperatures above 60° C.¹³ Ideally, core ablation temperatures are maintained at a mean of 105° C. Lower temperatures may result in inadequate tumor death and higher temperatures will increase the impedance of the tissue and decrease the size of the ablation zone.¹⁴

As the temperature gradient decreases farther away from the elelctrode, the tumor margin as well as up to a 1cm rim of normal tissue should be exposed to a minimum temperature of 60° C to ensure adequate cell death. Unlike cryotherapy, reliable real-time monitoring is not currently available for RFA. Treatment efficacy can be compromised by adjacent vasculature (as seen with perihilar lesions), causing a heat-sink phenomenon whereby areas adjacent to such vessels are not exposed to the minimum required ablation temperature.^15,16 This results in areas that are incompletely ablated, or “skip lesions,” and represent areas of potentially viable tumor.

Several studies have demonstrated efficacies of RFA ranging from 80 to 100% in small renal masses.^17-20 Five-year recurrence-free survivals of 80 to 90% have been reported with cancer-specific survival >95%.^17,20 Treatment success, when stratified by tumor size, appears less uniform for lesions >3-4cm.^17,21

High-Intensity Focused Ultrasound

Most centers perform RFA through a percutaneous approach. This has been associated with lower complication rates and efficacy equivalent to the laparoscopic approach when secondary treatment results are included.²²In 1992, Vallancien and colleagues²³ demonstrated the feasibility of extracorporeal ablation of human tissue using high-intensity focused ultrasound (HIFU). HIFU takes advantage of the heat generated by ultrasonic waves as it propagates through tissues and focuses on a target area, causing coagulative necrosis and focal cell death.²⁴ This may be done intra- or extracorporeally, and generates temperatures exceeding 65° C. Unlike diagnostic ultrasound, HIFU uses low frequency (0.8-1.6MHz), high-energy, ultrasound waves with small focal areas for targeted ablation. Outside the focal zone there is minimal transmission of energy. This sharp decrease in temperature spares adjacent normal parenchyma from injury. Unfortunately, when administered with extracorporeal devices, inconsistent treatment is noted due to interference of ultrasonic transmission between different tissue interfaces (such as the abdominal wall and rib cage). In addition, respiratory motion makes it difficult to target lesions, even with single-lung ventilation.

Laser Intersitial Thermal Therapy (LITT)

Microwave Ablation

CyberKnife and Irreversible Electroporation

Small series with extracorporeal HIFU showed a success rate of 66% after 36 months follow-up.²⁵ However, patients with BMI >30 kg/m² showed no evidence of ablation, suggesting limited efficacy in patients with increased adiposity. Laparoscopic approaches may provide improvement in treatment efficacy^26,27 allowing for more targeted ablation under visual guidance. Refinement of the technique is needed to obtain consistent tumor ablation, and further study is needed to demonstrate durable oncological efficacy.Lasers have been employed extensively in urology for the treatment of benign and malignant lesions. Neodymium:yttrium aluminium garnet (Nd:YAG) laser fibers can be placed percutaneously with MRI guidance into target lesions, generating temperatures exceeding 55° C to produce irreversible coagulative necrosis. Recent data from animal models and small case series^28,29 have demonstrated some efficacy in treating renal masses with a decrease in enhancing tumor volume. Unfortunately, data supporting the oncologic efficacy of LITT is currently limited, and it therefore cannot be applied in other than an investigational context.Another technique for the ablation of small renal masses uses heat generated by a microwave antenna introduced into the lesion. Like RFA, the generated electromagnetic field causes rapid ionic oscillations producing temperatures up to 150° C. This technology may prove superior to RFA as it generates higher temperatures faster without susceptibility to heat sinks. This can create more uniform ablation, even in cystic lesions.³⁰ Currently, microwave ablation has only been examined in a few in-vivo animal studies^31,32 and clinical series^33-36 and remains experimental. Retrospective series have reported recurrence-free survival of ranging from 62% to 96% and cancer-specific survival of 100%.^34,35 However, with complication rates of up to 40%, further refinement of the technology is required.Several other ablative techniques include irreversible electroporation and CyberKnife, but these techniques have yet to yield compelling follow-up data. CyberKnife is an image-guided frameless radiosurgical device that delivers high-dose radiation divided into up to 1200 beams that coalesce onto the target tissue. This decreases the individual radiation dose per beam, thereby decreasing the radiation delivered to surrounding tissues.^37,38 Ponsky and colleagues³³ demonstrated a successful proof-of-concept with tumor ablation in one of three patients with T1a lesions confirmed on post-ablation surgical pathology.

Comparison of Ablative Focal Therapies and Nephron-Sparing Surgery

Cryotherapy

Radiofrequency Ablation

Risks and Complications

More recently, irreversible electroporation (IRE) has been described as a nonthermal alternative ablative technique that may induce tissue destruction with superior preservation of adjacent structures.^39,40 Electroporation uses electrical fields of varying magnitudes to create nanopores within cell membranes. At currents of higher magnitude, this process is irreversible and lethal. Several studies have reported preliminary results in ablation of pancreatic, lung, and hepatic tumors with varying success.^41-44 Thomson and colleagues⁴² reported successful ablation (3-month follow-up) in five of seven patients treated with IRE for renal tumors up to 3.1cm. Both techniques remain investigational for ablation of renal masses.Short-term data suggest that ablative techniques have recurrence rates equivalent to partial nephrectomy, but with 50% lower morbidity rates.⁴⁵ Consequently, much attention has been placed on refining ablative techniques and assessing intermediate and long-term oncological outcomes. Currently, there are no randomized studies that compare the efficacy and durability of ablative therapies, and comparative data are derived from meta-analyses of existing studies. One large meta-analysis of 99 studies on focal extirpative and ablative therapies for sporadic small renal masses failed to demonstrate any difference in disease progression between patients treated with partial nephrectomy, cryotherapy, RFA or active surveillance.⁴⁶ However, the analysis did show that focal ablative therapies were associated with an increased risk of local recurrence. Unfortunately, there were too many disparities between the surgical and ablation groups to allow for generalization of these findings.In retrospective reviews of partial nephrectomies and cryoablation, partial nephrectomy was associated with a significant increase in blood loss, delayed postoperative complications (renal hemorrhage, urinary leak, and deep vein thrombosis) and longer hospital stays, while cryotherapy had significantly higher incidence of recurrence.^47-49 Results regarding complications rates have been mixed, with some groups reporting equivalent rates with both treatment approaches and others reporting higher complication rates after partial nephrectomy.^47-50There are limited data directly comparing outcomes after RFA and partial nephrectomy. One single-institution study that compared outcomes after partial nephrectomy versus RFA versus cryoablation showed a significantly higher complication rate for partial nephrectomy (58%) versus ablative treatments (RFA 7%, cryoablation 14%).⁵¹ The partial-nephrectomy group was also noted to have a higher rate of intra-operative adverse events and a longer hospital stay.To date, larger studies have focused primarily on cryoablation and RFA and have improved our understanding of the morbidities associated with these procedures. Again, as there are no randomized studies comparing ablative techniques, the relative risk of complications is derived from meta-analysis of combined series. It is expected that as these techniques are refined and experience continues to grow, the incidence of certain complications are likely to decrease with time.

Post-Ablation Surveillance

In general, all laparoscopic or percutaneous procedures, ablative or extirpative, carry an inherent risk of bleeding and injury to adjacent structures. A meta-analysis of over 30 case series reported an overall 19% complication rate of both cryoablation and radiofrequency ablation.⁵² Inconsistent reporting of complications confounds the valid interpretation of these results, and can only be addressed by a randomized, controlled clinical trial.There is no generally accepted post-ablation surveillance protocol. Such protocols are largely institution- and surgeon-specific and may vary depending on whether the procedure is performed by a urologist or an interventional radiologist. Protocols must consider certain key tenets of oncologic surveillance: (1) follow-up should be more frequent during the period when most recurrences are likely to occur; (2) surveillance techniques should not expose patients to unnecessary risks (such as increased radiation exposure from frequent CT scans); (3) surveillance should image areas where recurrence and/or metastasis are more likely; (4) follow-up imaging should be sufficiently sensitive enough to detect recurrence when potentially curative intervention is still possible; and (5) the decline in frequency of follow-up should be commensurate with the decreasing likelihood of disease recurrence.

Conclusion

Most protocols perform follow-up imaging at 3, 6, and 12 months during the first year, then every 6 to 12 months thereafter, as most studies report the majority of recurrences within 24 months post-ablation.^53,54 Some studies have reported recurrences up to 58 months after ablation, and therefore surveillance should be guided by pathological and clinical findings and should continue for a minimum of 5 years if not longer. As these techniques are more widely applied, long-term data may be used to ascertain the optimal frequency and duration of follow-up post-focal ablation.Data on oncological outcomes after thermal ablation are promising. Although this is largely true for ablative approaches for small renal masses, the consistent lack of prospective randomized, controlled trials demonstrating durable and non-inferior outcomes to surgical excision for these and larger tumors prevents ablation from being extended to become standard of care. Currently, most studies report intermediate cancer-specific survival rates of 90% to 95%, but with higher primary treatment failure rates and local recurrence rates. Ablative therapy will continue to play an evolving role in the management of small renal masses, but further investigation is needed before it becomes standard of care. Prospective randomized controlled trials and multi-institutional registries are necessary to allow validated evaluation of post-ablation outcomes and clarify the future of ablation in the management of small renal masses.

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