Thermal ablation in renal cell carcinoma: What affects renal function?

Abstract

Because of its minimally invasive nature, thermal ablation is increasingly performed in patients with renal cell carcinoma (RCC) who are poor surgical candidates. Thermal ablation has been associated with excellent outcomes, and thus has been regarded as a viable alternative to nephron-sparing surgery. Many papers report minimal to no reduction in renal function after ablation therapies. However, in order to achieve good local control, normal renal tissue must be sacrificed, subsequently leading to reduced renal function. The amount of normal renal tissue to be ablated depends on the size, location, and number of RCCs, as well as the type of thermal ablation applied. However, there are few reports about what reduces renal function following thermal ablation therapies. The purpose of this review was to discuss factors that affect reduction in renal function and to assess the relationship between local tumour control and renal function.

• renal cell carcinoma
• thermal ablation
• renal function

Introduction

The incidence of renal cell carcinoma (RCC) has increased due to the increasing use of cross-sectional imaging studies. Incidental RCC is often characteristic of asymptomatic patients with organ-confined tumours and is typically staged as T1a cancer with a good prognosis [1], [2]. Nephron-sparing surgery is considered the treatment of choice for small RCC but can cause severe morbidity and mortality to patients who are poor surgical candidates.

Currently, thermal ablation is used to treat RCC in selected patients with co-existing medical diseases [3–6]. The long-term outcomes of thermal ablation are not well characterised, [7] but the short-term or intermediate outcomes are excellent [3–6]. To reduce local recurrence, an ablation zone should cover adequate normal renal tissue beyond the edge of the tumour. The loss of renal tissue is necessary to prevent local recurrence, but it may be associated with reduced renal function. Intuitively, the amount of renal tissue to be ablated depends on whether a RCC is small or large, parenchymal or non-parenchymal, and single or multiple. It is still unclear what tumour factors contribute to reduced renal function following ablation therapies [8]. However, many studies report that thermal ablation has minimal effects on renal function [9–13].

The purpose of this review was to discuss changes in renal function related to size, location, tumour number and treatment modality using a theoretical mathematical model. The relationship between local recurrence and renal function was also assessed.

Lesion size

Lesion size is closely related to changes in renal function. As the size of RCCs increases, the amount of normal tissue to be ablated also increases (Table 1). Generally, radiofrequency ablation (RFA) requires a 0.5 cm tumour margin to prevent local recurrence. If spherical parenchymal RCCs of 1−4 cm in diameter are treated with RFA and if the tumour volume is calculated by 4πr³/3, the tumour volume ranges from 0.5–32 cm³ (mean, 12.5 cm³) but the volume of tumour margin ranges from 3.5–30.5 cm³ (mean, 15.5 cm³) on the assumption that 4π/3 out of 4πr³/3 is regarded as 4. In other words, the loss of normal tissue is slightly greater than the corresponding tumour volume.

Table 1.  Comparison of RFA and cryoablation in terms of total ablated volume.

Diameter of tumour (cm)	Volume of tumour (cm^3)	Volume of tumour margin (cm^3)		Volume of tumour + tumour margin (cm^3)
		RFA	Cryoablation	RFA	Cryoablation
1	0.5	3.5	13.0	4.0	13.5
2	4.0	9.5	28.0	13.5	32.0
3	13.5	18.5	49.0	32.0	62.5
4	32.0	30.5	76.0	62.5	108

Notes: There are two hypotheses for Table 1. One is that a renal tumour is completely spherical in shape. The other is that 4π/3 is regarded as 4. The volume of a spherical tumour is calculated from 4π × r³/3 in which “π” and “r” indicates the ratio of the circumference of a circle to its diameter and the radius of the tumour, respectively. The volume of tumour margin is calculated according to the premise that RFA and cryoablation require 0.5 and 1.0 cm tumour margin around the lesion, respectively. Therefore, the total ablation volume minus the tumour volume is the volume of the tumour margin. RFA, radiofrequency ablation.

Ablation of a larger RCC may lead to decreased renal function compared to a smaller RCC because a greater volume of tumour margin is ablated. The loss of renal tissue is not a problem in healthy patients with good renal function, but this is not the case in patients with chronic kidney disease, a solitary kidney, or repeated nephron-sparing surgery. Patients with marginal renal function are more susceptible to renal failure after thermal ablation of a large RCC. Some studies have reported large RCCs being re-treated after a first session of RFA because of higher local recurrence rates [3], [4]. In order to lower rates of local recurrence, re-ablation requires ablation of extended tumour margins, leading to reduction in renal function.

Lesion location

The volume of tumour margin can differ according to lesion location (Figure 1). RCCs can be classified as exophytic, parenchymal, central, or mixed lesions [14]. Although exophytic, parenchymal, central, and mixed RCCs are similar in size, the extent of normal renal tissue adjacent to the tumour varies in volume; thus decreased renal function may vary from one lesion to the other. A round parenchymal RCC of 2 cm in diameter requires 9.5 cm³ of tumour margins. In contrast, a 2 cm exophytic RCC that is projecting 70% out of the kidney requires only 2.9 cm³ of tumour margin (Figure 1).

Figure 1. Schematic diagram of a renal tumour and tumour margin according to the location of the tumour. A parenchymal tumour (A) has a greater volume of tumour margin than an exophytic (B) or central (C) tumour in cases where all the tumours are the same size. The parenchymal tumour requires double the ablation of the tumour margin than an exophytic or central tumour that is projecting 50% from the renal parenchyma to the peri-renal space or renal sinus. RP indicates renal parenchyma.

Previous studies showed that there were different proportions of RCCs in terms of tumour location [9–13]. If there is a higher proportion of exophytic RCC, the reduction in renal function will be minimal compared to other types of RCC. Inversely, if one has a higher proportion of parenchymal RCCs, renal function will be more impaired. It is meaningless to evaluate or compare renal function before and after thermal ablation without matching tumour location.

A central or mixed RCC abuts small vessels in the renal sinus. When an artery measures less than 3 mm in diameter it is likely to be occluded during the ablation, subsequently resulting in segmental renal infarction [15], [16]. To ablate a central or mixed RCC, an applicator should traverse the renal sinus. This procedure may be complicated by an arteriovenous fistula requiring embolisation of the arterial feeder that also supplies normal renal parenchyma [17]. When ablating central lesions, collecting system injury is another potential cause of renal damage. In these clinical situations, inevitable loss of normal renal tissue leads to worsening renal function compared to uneventful RCC ablations.

Lesion number

Lesion number may have a greater influence on renal function than other tumour factors (Figure 2). If there are five parenchymal RCCs 2 cm in diameter, a total of 48 cm³ of normal renal tissue must be ablated to prevent local recurrence. If these RCCs develop in a solitary kidney measuring 150 cm³ and the patient's glomerular filtration rate (GFR) is 80 mL/min/1.73 m², the GFR may drop below 60 mL/min/1.73 m².

Figure 2. Schematic diagram of a renal tumour and tumour margin according to the number of tumours. (A) An exophytic tumour is projecting 50% out from the renal parenchyma. RP indicates renal parenchyma. (B) There are three tumours consisting of one parenchymal tumour (left) and two exophytic tumours, all the same size as figure A. These exophytic tumours are projecting 70% (middle) and 30% (right) from the parenchyma into the peri-renal space, respectively. Renal tumours in figure B require four times the normal renal tissue for thermal ablation than in figure A.

Some studies reported no significant difference in renal function before and after thermal ablation [10], [12]. Paired t-test is frequently used to determine whether renal function decreases after treatment. The values of the paired GFR may not follow a normal distribution in retrospective studies with small populations. Thus, non-parametric tests such as Wilcoxon signed-rank test are preferred for analysis. Because loss of normal renal tissue is accompanied by ablation of tumour margins, GFR will decrease after thermal ablation. If there were no reduction in GFR after thermal ablation, patients with multiple hereditary RCCs would not be reluctant to undergo thermal ablations for fear of impaired renal function. Indeed, patients with von Hippel Lindau disease have gradually worsening renal function as the number of ablation sessions increases [18–20].

Treatment modality

Change in renal function may vary according to type of thermal ablation therapy. Currently, RFA and cryoablation are the main thermal ablation therapies for treating RCC. Cryoablation requires a wider tumour margin than RFA. RFA and cryoablation therapies ablate 1 cm and 0.5 cm tumour margins, respectively [21], [22]. When a spherical parenchymal RCC of 2 cm in diameter is treated, tumour margins are 28 cm³ and 9.5 cm³ for cryoablation and RFA, respectively (Table 1). Therefore, cryoablation requires more renal tissue to be ablated than RFA. Reduction in renal function following cryoablation seems to be more common than in RFA. In contrast, local recurrence rate is lower in cryoablation than RFA [12], [23]. However, comparisons between RFA and cryoablation were not matched for size, location and number of renal tumours.

Indeed, the tumour margin ablation volume in RFA or cryoablation is larger than the theoretical volume of tumour margin described above. The shape of a RFA zone is not spherical but oval (Figure 3). In cases of spherical RCC, the volume of tumour margin to be ablated is different at different points along the lesion. For this reason, some renal tissue around the tumour must be over-ablated beyond the tumour margin in order to achieve a complete ablation. Subsequently, this over-ablation of renal tissue may be involved in reduction of renal function. The shape of a cryoablation zone is also not spherical. Similarly, cryoablation cannot avoid over-ablation of normal renal tissue (Figure 4). Practically, complete ablation of tumour margins requires more injury to normal renal tissue than theoretical tissue loss.

Figure 3. Over-ablation beyond the tumour margin during the RFA procedure. Arrowheads indicate RFA electrodes. (A) For radiofrequency ablation (RFA) of a spherical RCC (red), the shape of ablation zone (yellow) is not a circle but oval. Thus, the lateral areas of the RCC and tumour margin (dotted line) require additional ablations to prevent a residual or recurrent lesion. (B and C) Additional ablations (blue and violet) are performed to completely cover the tumour margin (dotted line) as well as the RCC (red). However, some over-ablation of normal tissue is created beyond the lateral tumour margin.

Figure 4. Over-ablation beyond the tumour margin during the cryoablation procedure. (A) For cryoablation of a spherical RCC (red), the ends (black dots) of three cryoprobes are seen within the tumour. The ice balls (yellow, blue, and violet) do not cover the entire tumour margin (arrowheads). (B) The ice balls grow to completely cover the tumour margin. However, some over-ablation of normal renal tissue (arrows) is noted beyond the tumour margin.

Thermal ablation and compensatory hypertrophy

Compensatory hypertrophy of remaining renal tissue may occur after thermal ablation as well as partial or radical nephrectomy. However, it does not imply the complete recovery of renal function. Hypertrophy improves GFR per renal tissue weight. Therefore, post-ablation or post-surgery GFR may increase but cannot reach pre-treatment status. Several recent studies from the urological literature found that the percentage of remaining renal parenchyma is the most important factor in post-operative renal function [24–26]. These results seem to relate to our results, given that size, location, and number of RCC determine the amount of remaining renal parenchyma following thermal ablation. Many studies dealing with renal function following thermal ablation and/or nephrectomy reported decreased renal function after treatment [27–30]. However, the degree of renal function reduction was much lower after thermal ablation than partial nephrectomy [27–29].

Local recurrence and renal function

The relationship between local recurrence and renal function involves a balancing act between two conflicting goals. Minimising local recurrence requires adequate ablation of tumour margins and subsequently results in the reduction of renal function. Inversely, achieving minimum ablation of tumour margin may be accompanied by unwanted local recurrence. Some studies that achieved an excellent local control rate ranging between 88–92% with thermal ablation showed a significant difference in renal function before and after treatment [31] or did not mention it [7], [32]. In contrast, other studies that achieved low recurrence-free survival rates of 33−70% with thermal ablations reported minimal or no changes in renal function [12], [29].

Local recurrence and renal function should be weighed according to circumstances. In cases of a sporadic RCC in a healthy patient, sufficient ablation of tumour margin around the tumour is acceptable for prevention of locally recurrent tumour. Since sporadic RCC is barely recurrent, even the over-ablation of renal tissue will not lower GFR less than 60 mL/min/1.73 m² [28]. Although thermal ablation therapies sufficiently ablate normal renal tissue, these minimally invasive treatments are more effective than partial nephrectomy in preserving renal function [27–29].

In the case of hereditary RCC in a patient with von Hippel Lindau disease, over-ablation of normal renal tissue is not recommended in order to prolong the dialysis-free survival period. The best approach to manage hereditary RCCs is to simultaneously preserve renal function as much as possible and to remove as many RCCs as possible. For treatment of hereditary RCCs, thermal ablation as well as surgery should be conducted with the understanding that microscopic cancer cells will likely remain [18], [19], [33]. Therefore, the goal of treating hereditary RCCs is not to cure, but to control multifocal or recurrent renal tumours to prevent cancer progression and to delay dialysis as long as possible.

Conclusion

It is difficult to avoid impaired renal function in the setting of thermal ablation since tumours should be ablated with wide tumour margins to prevent local recurrence. The degree of reduced renal function varies according to the size, location and number of RCC and the type of ablation modality. Therefore, thermal ablation therapies should be appropriately designed to achieve complete local control and to minimise loss of normal renal tissue, as well.

Declaration of interest: None of the authors have conflicts of interest or financial support for conducting this study. The authors alone are responsible for the content and writing of the paper.