Abstract
Background/Aim: To survey the safety and efficacy of percutaneous cryoablation for renal tumors under local anesthesia and pain control by using the −40°C lethal isotherm of the ice ball to cover the tumor margin as well as the coaxial cryoablation technique. Patients and Methods: All procedures were performed between February 2014 and November 2021 with computed tomography (CT) guidance. All tumors were ablated by following the aforementioned plan, according to which tumor margins were covered by the −40°C lethal isotherm. Hydrodissection and coaxial cryoablation were performed in some cases to avoid organ injury and massive bleeding. 2% xylocaine was used for local anesthesia and 50 mg of pethidine (meperidine) was injected intramuscularly for pain control and sedation. The complications were evaluated and the Kaplan–Meier method was used to estimate local recurrence-free survival (LRFS). Results: Sixty-five tumors [49 renal cell carcinomas (RCC) and 16 angiomyolipomas] were ablated in 55 patients (median Charlson Comorbidity Index=5.0). Local recurrence occurred in three of the 49 RCC cases. Two received a second cryoablation. LRFS at three and five years were both 91%. LRFS at three and five years reached 100% in tumors <3 cm. A large tumor (≥3 cm) was observed in the recurrence group. Hemorrhage was the most common complication (76.9%). Two patients who needed blood transfusion did not receive coaxial cryoablation. Three (4.6%) major complications (Clavien–Dindo grade ≥3) occurred. Conclusion: By using −40°C as the pre-plan tumor coverage, with the aid of coaxial cryoablation and multiplanar reconstruction method, CT-guided percutaneous renal cryoablation under local anesthesia is a safe and effective procedure in patients with many comorbidities.
The incidence of malignant renal tumors is continuously increasing in Taiwan. According to the 2019 Taiwan Cancer Registry Annual Report, the most common malignant renal tumor is renal cell carcinoma (RCC; 93.1% of cases), with slightly more males predominant (1). Although partial nephrectomy or radical nephrectomy is the first choice for the management of RCC, in the updated guidelines of the American Urologic Association (AUA) and the European Association of Urology, thermal ablation, including cryoablation and radiofrequency ablation (RFA), is recommended as an alternative management for patients who have a high risk of postoperative morbidity (2-4).
Cryoablation for RCC has revealed a better result than RFA in local tumor control (5.2% vs. 12.9%, p<0.0001) as well as a lower risk of metastasis progression (1% vs. 2.5%, p=0.06) (5). Another advantage of cryoablation for RCC, as compared with other thermal ablation methods, is that the ice ball or ablation zone can be monitored during the procedure on computed tomography (CT) or sonography (6). Furthermore, there are less requirements for pain control compared to other thermal ablation methods (7, 8).
The best image-guiding method for percutaneous renal cryoablation is CT scan, as the cryoprobe insertion can be planned and traced well and the ice ball can be monitored in multiple directions on reconstructed CT images. Since the ice ball margin is larger than the lethal zone of the renal cells and the temperature should be lower than −25°C to reach the lethal point (9, 10), a smaller distance between the ice ball margin and the tumor margin is a major factor of local residual and local recurrence (10).
Cryoablation is also an alternative treatment for renal angiomyolipoma (AML). Indications for treating AMLs include relieving symptoms, reducing bleeding risk from hypervascularity, and managing malignant potential, such as epithelioid-type AMLs (11, 12).
General anesthesia is recommended for percutaneous renal cryoablation in the literature (13). Although renal tumor cryoablation is available in Taiwan, the insurance coverage for percutaneous renal tumor cryoablation is limited to patients who are at high risk for traditional surgery or general anesthesia according to the National Health Insurance Administration (14). To avoid the risks of deep sedation in general anesthesia and keep good communication with the patient during the procedure (15), we performed cryoablation with local anesthesia and pain control instead of general anesthesia in our institute. The technique of percutaneous renal cryoablation under local anesthesia was different from that performed under general anesthesia, presenting additional challenges. Here, we illustrate our single-center experience with CT-guided percutaneous cryoablation for renal tumors under local anesthesia in Taiwan.
Patients and Methods
Patient selection. This retrospective study was approved by the institutional review board in our institute, and written informed consent was obtained from each patient enrolled in this study. All patients and their percutaneous cryoablation procedures were discussed in a multidisciplinary meeting with urologists and interventional radiologists. Pre-procedural images were obtained using either CT or magnetic resonance imaging (MRI). The preprocedural diagnoses of renal tumors included any types of RCC and AML. The inclusion criteria were the following: having a high risk for general anesthesia or surgery and selecting percutaneous cryoablation as the first choice for treating renal tumors. The exclusion criterium was uncorrectable coagulopathy.
Percutaneous cryoablation procedure. Cryoablation procedures were performed between February 2014 and November 2021 by two experienced interventional radiologists (one with 30 and one with 9 years of experience). The patient’s position and the decision concerning the cryoprobe size and number were planned according to the −40°C isotherm of the ice ball coverage, based on the tumor size of the pre-procedure images. These were adjusted depending on the repeated CT scan during the procedure.
The patients received an intramuscular injection of 50 mg pethidine (meperidine, The Pharmaceutical Plants of Controlled Drugs, Taiwan Food and Drug Administration, Ministry of Wealth and Health, Taipei city, Taiwan, R.O.C.) for pain control. All procedures were performed under local anesthesia by injecting 5-7 ml of 2% xylocaine (Recipharm Monts, Monts, France) in each desired puncture site. Under CT guidance, we inserted coaxial needles (15G × 6 cm or 10 cm) (Merit Medical System, South Jordan, UT, USA) and cryoprobes into the desired puncture site. To protect adjacent thermosensitive organs, we used hydrodissection with normal saline (150-450 ml) through a coaxial sheath (Figure 1). In some tumors, biopsies were also performed using cutting biopsy needles before starting the cryoablation via the coaxial sheath in the same tract.
Illustrations of hydrodissection with coaxial needle sheath. (A) Hypervascular tumor located anteriorly in the right kidney near the pancreas. (B) To protect the pancreas, we injected 450 ml of normal saline into the space between the right kidney and pancreas with a coaxial needle sheath. S: Spleen; P: pancreas; H: hydrodissection; arrowheads: tumor and ice ball.
The cryoablation system used in this study was the Galil Medical/BTG cryoablation system (Galil Medical, Arden Hills, MN, USA). The tumors were treated as following: 10 min freezing, 8 min thawing, and 10 min freezing cycles. In case of an unexpectedly smaller size of the ice ball, an additional 8 min of thawing and 10 min of freezing were used. At the time points of 5 min and 10 min of each freezing period, CT scans for surveying the ablation zone (ice ball coverage) were performed. In case of an incomplete ablation zone, the trajectory of cryoprobes was adjusted or additional cryoprobes were inserted at the end of first 8-min thawing period to cover the whole tumor.
After removal of the coaxial sheath and cryoprobes, an immediate follow-up CT scan was performed in the arterial phase to detect immediate complications, such as active bleeding, adjacent organ injury, and residual tumor. In the case of a residual tumor, an additional two cycles of cryoablation were performed. During the entire procedure, vital signs were monitored every 10 min, including electrocardiogram, heart rate, blood pressure, and oxygen saturation. The patients were returned to the ward after the procedure and stayed overnight. They were discharged on the next postoperative day if no significant perioperative complications developed.
Follow-up. We surveyed local recurrence in RCC (diagnosed by either imaging or pathologic results). The patients underwent follow-up images every 3-6 months after the procedure. Patients with normal renal function underwent contrast-enhanced CT. Otherwise, for those with renal insufficiency, non-contrast-enhanced MRI was performed. MRI pulse sequences included diffusion-weighted images (b=0, 50, 100, 200, 500, 800, and 1,000) and the apparent diffusion coefficient.
Data collection. The patient data was collected from medical charts, including medical history, operation history, number of kidneys, renal transplant history, Charlson Comorbidity Index (CCI) (16), and estimated glomerular filtration rate (ml/min/1.73 m2) before and after cryoablation. The tumor size and tumor locations (right or left kidney, anterior or posterior, medial or lateral, upper or lower pole) as well as tumor staging (T1a: ≤4 cm, T1b: >4 cm and ≤7 cm) were obtained from the pre-cryoablation CT images. The procedure detail was extracted from the procedure notes, including cryoprobe number, hydrodissection, the use of coaxial needles, and the number of the freezing and thawing cycles.
Technical success and local recurrence were recorded. Technical success was considered when the procedure was completed with at least two cycles of 10-min freezing and 8-min thawing. The local recurrence of RCC was defined as any new enhancing foci in the ablation zone on follow-up CT or any diffusion-restricted foci in the ablation zone on follow-up MRI by excluding false-positive enhancement with predominant peripheral enhancement of the tumors within one-year of follow-up (17, 18). Intraoperative and post-operative complications were recorded according to the Clavien–Dindo classification and stratified into minor (Clavien–Dindo grades I and II) and major (Clavien–Dindo grades III, IV, and V) complications (19).
The primary outcome of this study was to evaluate the feasibility and safety of CT-guided percutaneous renal cryoablation under local anesthesia. The secondary outcome was to evaluate the local tumor control of RCC, including local recurrent rate and local recurrence-free survival (LRFS).
Statistical analyses. Normally distributed continuous variables are expressed as mean±standard deviation and non-normally distributed continuous variables are expressed as median±interquartile range. The categorical variables are presented as frequencies and/or percentages. We used the Kaplan–Meier method to estimate local recurrence-free survival (LRFS), which was calculated from the date of cryoablation and the date of the first local recurrence. To analyze the differences between the local recurrent group and the non-local recurrent group, the Mann–Whitney U-test was used to compare the continuous variables. The same methods were used to compare the biopsy results of the non-diagnostic specimens and complications. The chi-square test was used to compare the categorical variables. If the sample size was small (≤5) and had low expected cell frequency, the Fisher’s exact test was used. All statistical analyses were performed using SPSS 23.0 (Chicago, IL, USA). For all statistical results, significance was set at p<0.05.
Results
Demographic profile and procedures. Altogether, 54 patients (34 men and 20 women) with a mean age of 65.4±16.4 years were enrolled in this study, including 31 patients (56.4%) aged >65 years. Many of them had a history of several comorbidities, malignancy, and major operations (Table I), while the median CCI was 5.0±3.0. The median CCI was slightly higher in patients with RCC than in those with AML (5 vs. 4.5, respectively), but this difference did not reach statistical significance (p=0.063).
Comorbidities and Charlson Comorbidity Index (CCI) in 55 patients.
Sixty-five tumors were ablated, consisting of 16 AMLs and 49 RCCs (including biopsy proof and image diagnosis). The average tumor size was 3.13±1.58 cm, and the average RENAL nephrometry score (20) was 7.06±1.86. The mean size of the AMLs was larger than that of the RCCs (4.50 cm ±1.97 vs. 2.68 cm ±1.13, respectively, p=0.001). The demographic data of the patients and tumors are shown in Table II. We performed hydrodissection in eight tumors (12.3%) with normal saline (median volume=250 ml). Fifty-eighth tumors (89.2%) were treated with two cycles of freezing and thawing, whereas seven tumors were treated with more than two cycles. The technical success rate was 100%. Percutaneous biopsies were performed for 58 tumors (89.2%), including coaxial biopsies performed for 27 tumors. Among the 58 tumors, histologic results were non-diagnostic in 19 tumors (27.6%). The tumor size of these non-diagnostic tumors was slightly smaller than those with diagnostic histologic results (2.62±1.24 cm vs. 3.41±1.68), without reaching statistical significance (p=0.061). No significant differences were observed between the diagnostic and non-diagnostic results in the coaxial biopsy (p=0.422) or hydrodissection method (p=0.691).
Patient demographic data.
Treatment efficacy. Among the 49 cases of RCCs, 40 had follow-up CT scans or MRIs scans, while 9 (18.4%) were lost to follow-up. The median duration of CT/MRI follow-up was 246 days (range=49-2,134 days). Local recurrence developed in three tumors (6.1%). A second cryoablation was performed in two tumors, and no recurrence developed after the second cryoablation. Compared with non-recurrent tumors, the recurrent tumors were significantly larger in size (4.13±0.20 cm vs. 2.49±1.04, p=0.008). No significant difference was observed in cryoprobe number, tumor location, or use of coaxial cryoablation or hydrodissection (Table III).
Comparing recurrent and non-recurrent tumors in the renal cell carcinoma (RCC) group.
Using the Kaplan–Meier method, the estimated 3-year and 5-year LRFS rates were 91.0% and 91.0%, respectively (Figure 2A). The tumors were classified into <3 cm and ≥3 cm groups and the Kaplan–Meier estimates of the LRFS rates were higher in tumors <3 cm than ≥3 cm at three years (100% vs. 76%, p=0.018) and five years (100% vs. 76%, p=0.018) (Figure 2B).
Local recurrence-free survival (LRFS) of RCC. (A) Kaplan–Meier curve showing LRFS in the whole RCC population. Kaplan–Meier estimates of LRFS at three and five years were both 91.0%. (B) Kaplan–Meier estimates of the LRFS of tumors <3 cm at three and five years were both 100% (blue line), while that of tumors ≥3 cm at three and five years were both 76.0% (green line) (p=0.018).
Complications. The most common complication was hemorrhage at the ablation site and adjacent perirenal space (Table IV). We recorded any perirenal hematoma or active contrast extravasation identified on the immediate follow-up CT scan after the procedure and disclosed that hemorrhage occurred after 50 procedures (76.9%). Up to 72.0% of the hemorrhage episodes were associated with tumor biopsies practically before the freezing cycle. Tumors with larger size (≥3 cm) and higher complexity (RENAL nephrometry score ≥7) had a significantly higher frequency of bleeding (p=0.016 and 0.006, respectively). No significant difference in the use of coaxial cryoablation (p=0.215) or the hydrodissection method (p=1.000) was observed. Two patients needed blood transfusion (Clavien–Dindo grade II), while no patient required further embolization or surgery. None of the two patients who received blood transfusions underwent coaxial cryoablation.
Episodes of complications (percentage) of 65 procedures according to the Clavien-Dindo classification.
Three major complications (Clavien–Dindo grades III and IV) occurred during the perioperative period and postoperative follow-up. No coaxial cryoablation was performed among these three patients. One patient presented with lethargy and inattention several hours after the procedure. Acute stroke in the watershed territory with typical imaging findings of Moyamoya disease was identified on an MRI survey. One tissue-proven RCC, which was completely ablated and confirmed on the immediate follow-up CT scan, developed into a large necrotic mass with diffusion restriction in the 6-month follow-up MRI. The enhancement pattern could not be evaluated due to poor renal function and no gadolinium contrast media was injected. The mass was confirmed to be xanthogranulomatous pyelonephritis by CT-guided biopsy. Additionally, an abscess formation occurred in one AML, and percutaneous drainage was performed.
Discussion
In this study, we performed CT-guided cryoablation for renal tumors with local anesthesia. The first reason for using local anesthesia was due to the payment range of National Health Insurance for percutaneous cryoablation that didn’t include general anesthesia in Taiwan. The second was that the majority of these patients were not eligible for general anesthesia due to multiple comorbidities (median CCI of 5.0). The third is that we used pethidine (meperidine) for pain control, which also has a moderate sedation effect with a half-life of 2.4-4 hours (21). For an interventional procedure lasting less than 4 hours, meperidine is suitable for both analgesia and sedation.
In addition to reducing the risks of general anesthesia, local anesthesia facilitates adjustment of the patient’s position. We may adjust the patient’s position after CT surveillance and before cryoprobe insertion, considering that many pre-procedure plans were made by reviewing CT or MR images scanned with the patient in supine position. The posterior aspect of the diaphragm was much lower when the patient was in prone than when in supine position. The location of the adjacent intestine changed from the supine to the prone position. Hence, the patient’s position should be altered to a supine oblique, prone oblique, or even a true lateral position. We can also ask patients to hold their breath at the end of inspiration or expiration to prevent the tumor from moving up and down during breathing.
Here, the timing and methods for tumor biopsy changed with time. We performed CT-guided biopsy before cryoprobe insertion at the beginning of the learning curve (2014 to 2015) and observed that the post-biopsy hemorrhage made the tumor margin less visible on CT scan (Figure 3), further resulting in a mismatch between the true tumor margin and ice ball margin. Therefore, a higher incidence of local recurrence (two local recurrences in a total of three local recurrences in this study) was identified in this period. The total recurrence rate was 6.1%, which was similar to other large series (22-25), while some studies revealed a slightly lower recurrence rate from 0% to 4.7% (26, 27). The 5-year LRFS rate in this study was 91.0%, which was also similar to other cohorts (including those operated under general anesthesia), ranging from 79% to 93.9% in the literature (22-24, 28). Compared to operation, the oncological control of percutaneous cryoablation is similar to robot-assisted partial nephrectomy for T1 renal cell carcinoma (29). Our results indicated that using a −40° lethal isotherm of ice ball to cover the tumor margin in the pre-ablation plan ensured a good tumor margin coverage and resulted in a better LRFS.
This posteriorly located tumor in the left kidney was biopsied percutaneously before cryoprobe insertion. A small amount of perirenal hematoma after biopsy needle insertion was observed (A). The size of the perirenal hematoma increased gradually during the cryoprobe insertion (B-C) accompanied by a blurring tumor margin. h: Perirenal hematoma.
We found most perirenal hematomas occurred after the tumor biopsy or after cryoprobe removal. Thus, in 2015, we shifted the timing of the biopsy to the period after cryoprobe insertion, which resulted in less perirenal hematoma. Furthermore, since 2018, most procedures have been performed with a coaxial needle. We noticed that the coaxial sheath did not interfere with ice ball formation. The ice ball size was the same as expected without a coaxial sheath (Figure 4). Therefore, ice ball coverage can be predicted as in those without a coaxial sheath, and the treatment efficacy can be confirmed. Performing coaxial biopsy followed by coaxial cryoablation via the same coaxial sheath shortened the cryoprobe insertion time. After removal of the cryoprobe, gel foam cubes were injected into the coaxial sheath before coaxial sheath removal, ceasing hemorrhage by local hemostasis. The two patients who required blood transfusion due to post-procedural hemorrhage did not undergo coaxial cryoablation, suggesting that coaxial cryoablation immediately after coaxial biopsy can reduce massive hemorrhage and prevent further additional management.
Coaxial cryoablation utilizing a coaxial sheath. Due to the beam hardening artifacts, the distal edge of the coaxial sheath (open arrow) presents as a black point on the computed tomography (CT) scan. This image demonstrates that the ice ball (arrowheads) covers the distal edge of the coaxial sheath (open arrow), confirming that the coaxial sheath did not affect the ice ball formation.
Some authors have suggested transarterial embolization before percutaneous cryoablation to prevent hemorrhage in larger renal tumors (30). We performed transarterial embolization for one tissue-proven AML located centrally in the left renal hilum and the results revealed a smaller ice ball formation than expected. Although an additional third freezing period was performed, the ice ball coverage did not match the expected size. Hence, the embolized tumor may be too dry to provide sufficient water, resulting in a smaller ice ball.
Herein, patients with a larger tumor size (≥3 cm) or higher tumor complexity (RENAL nephrometry score ≥7) experienced a higher frequency of tumor bleeding because increasing cryoprobe numbers and repeated trajectories were necessary for targeting these tumors. According to a large cohort study by Bhindi et al. (31), a higher renal tumor complexity using the RENAL nephrometry score with a large renal tumor size was associated with a higher complication rate after percutaneous cryoablations.
The incidence of major complications (Clavien–Dindo grade ≥III) was 4.6% in our series. Similar to other studies, the major complication rate after percutaneous cryoablation was approximately 0-7% (26, 32-35), which is lower than that of other surgical procedures (10-20%) (35). Moreover, the patients with larger tumors (≥3 cm) also experienced a higher local recurrence rate and lower LFRS than those with smaller tumors. This finding is in line with the AUA recommendations that this treatment is suitable for tumors <3 cm (3). Pickersgill et al. (36) have disclosed that a 1-cm increase in tumor size was associated with a 1.3-fold increase of disease progression.
In this study, we chose CT-guided rather than US-guided procedures to perform renal tumor cryoablation. By performing CT-guided cryoablation with multidetector CT, we discovered that tumor location was not associated with local recurrence or complications. Utilizing the multiplanar reconstruction technique, we can predict and ensure the path of cryoprobes, avoiding non-target cryoablation and injury to adjacent organs (37). In addition, it is also a useful method to recognize the effect range of the −40° lethal zone. This is particularly useful for tumors located at the upper pole or anterior aspect of the kidneys.
Nevertheless, targeting endophytic tumors and treating post-biopsy hemorrhages is challenging in CT-guided procedures. The margins of the endophytic tumors and the margins between the tumors and the perirenal hematoma were less visible without contrast medium injection. To concur with this situation and to reduce contrast media injection, we injected half-doses of contrast media (i.e., 50 ml of iodine contrast media) and scanned the kidneys at a lower tube voltage (i.e., 100 kVP) in our institute. The lower tube voltage is close to the k-absorption edge of iodine, which is approximately 33.2 keV. This results in a greater enhancement in vessels and enhanced tissue than the traditional 120 kVP (38), resulting in a clear view of tumor margins.
Our results revealed that CT-guided percutaneous cryoablation is safe for patients with a single kidney, grafted kidney, or metachronous and/or synchronous RCCs. Moreover, performing repeated percutaneous cryoablation for recurrent RCCs in hereditary syndromes, such as the von Hippel Lindau syndrome (VHL), seems to be safe (39). In our series, one patient with VHL underwent four repeated procedures between 2018 and 2021, and five tumors were ablated. Although a slight decline in glomerular filtration rate was noted between the first cryoablation and the last follow-up (from 103.27 to 88.24 ml/min/1.73 m2), the result of the preservation of renal function was acceptable after repeated cryoablations.
This study had some limitations. Firstly, this was a single-center retrospective study with a small study population. A larger study population and a longer follow-up period are needed to evaluate LRFS and overall survival in RCCs. Secondly, the biopsy timing and the coaxial cryoablation method were different from the beginning of the learning curve. With continuous modifications of the procedures, local recurrence has decreased. Thirdly, because we performed percutaneous cryoablation under local anesthesia only, subjective discomfort should be a concern. Pain assessment was not performed in this series. However, in a previous study, de Kerviler et al. (40) evaluated the procedure pain of percutaneous renal cryoablation with the Visual Analog Score (range=1 to 10) and their result revealed that the mean procedure pain score was 2.0 in patients under local anesthesia and pain control was performed via paracetamol. This confirms that the procedure pain is mild and well tolerated. As mentioned in the introduction section, cryoablation is less painful than RFA or microwave ablation.
Conclusion
It is safe and effective to perform CT-guided percutaneous renal cryoablation under local anesthesia, especially for patients with multiple comorbidities. We recommend using a low kVP scanning method and the multiplanar reconstruction technique during the CT-guided procedures. The treatment efficacy of percutaneous renal cryoablation can be ensured by using a −40° lethal isotherm of ice ball to cover the tumor margin. Furthermore, the massive bleeding can be prevented with coaxial cryoablation.
Footnotes
Authors’ Contributions
YTL collected the data and wrote the manuscript; SWH conceived and performed the analysis; MCL reviewed the literature and collected the data; KYC collected the data, reviewed, and edited the manuscript; JWC and JCL reviewed and edited the manuscript.
Conflicts of Interest
The Authors have no conflicts of interest to declare in relation to this study.
- Received January 31, 2023.
- Revision received February 14, 2023.
- Accepted February 16, 2023.
- Copyright © 2023 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
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