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Original Research |
1 Department of Radiology, Wake Forest University Health Sciences, Medical
Center Blvd., Winston-Salem, NC 27157-1008.
2 Department of Urology, Wake Forest University Health Sciences, Winston-Salem,
NC.
3 Present address: Department of Urology, Vanderbilt University School of
Medicine, Nashville, TN.
Received December 3, 2006;
accepted after revision March 28, 2007.
Address correspondence to R. J. Zagoria.
Abstract
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MATERIALS AND METHODS. Data from 125 RCCs in 104 patients treated with curative intent was reviewed. Radiofrequency ablation treatments were performed using conscious sedation and local anesthesia. Patients were followed with contrast-enhanced CT or MRI. Tumor control was defined as the absence of contrast enhancement in the tumor on CT or MRI.
RESULTS. Tumor size ranged from 0.6 to 8.8 cm (mean, 2.7 cm; SD, 1.5 cm). Of the 125 treated tumors, 116 (93%) were completely ablated (109 in a single ablation session, seven after a second ablation session) with a mean follow-up interval of 13.8 months. All 95 RCCs smaller than 3.7 cm were completely ablated, and 21 (70%) of 30 larger tumors were completely ablated, with nine showing evidence of residual viable tumor on follow-up scans. Tumor size smaller than 3.7 cm was significantly associated with achieving complete tumor eradication (p < 0.001). With each 1-cm increase in tumor diameter over 3.6 cm, the likelihood of tumor-free survival decreased by a factor of 2.19 (p < 0.001). There were 8 (8%) complications, none of which resulted in long-term morbidity.
CONCLUSION. CT-guided percutaneous radiofrequency ablation is a safe method to treat small RCCs. This study indicates that radiofrequency ablation can reliably eradicate RCCs smaller than 3.7 cm. Treatment of larger RCCs will result in an increased risk of residual RCC.
Keywords: interventional radiology • radiofrequency ablation • renal neoplasms
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The standard therapy for RCC has been radical nephrectomy [4]. Nephron-sparing approaches have proven to have equivalent oncologic outcomes in select (tumor diameter less than 4 cm) renal tumors [5, 6]. A dilemma is created when patients are unwilling or unable to undergo surgical tumor resection or they are prone to recurrent renal surgery due to a hereditary predisposition to develop multifocal RCC (von Hippel-Lindau disease and hereditary papillary RCC). Radiofrequency ablation has been used for the treatment of solid organ tumors, primarily hepatic tumors, since the 1990s [7-9], and CT-guided percutaneous radiofrequency ablation has been shown to be a promising alternative treatment option for problematic patients with RCCs [10-14].
Radiofrequency ablation is generally an outpatient procedure that offers the advantage of being a minimally invasive procedure that does not require general or regional anesthetic and results in a short convalescence with minimal morbidity [10-13]. First introduced in 1997 for the treatment of renal neoplasms [15], this technique has had encouraging early results [10-17]. However, previous studies have been small series; have reported on treatment of renal masses, many of which were not proven RCC; and follow-up intervals were short [10-17]. The current study was designed to analyze the results of CT-guided percutaneous radiofrequency ablation on a consecutive series of patients with biopsy-confirmed RCC who were treated at one institution from May 2000 through June 2006.
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All radiofrequency ablation procedures were performed by a single radiologist. Radiofrequency ablation treatment of all tumors in this study was completed with a system using a 200-W generator and saline-cooled treatment probes (Cool-Tip, ValleyLab). We have previously reported the percutaneous radio-frequency ablation technique adhered to in this series [11] (Fig. 2A, 2B, 2C, 2D, 2E, 2F). Three lengths of active electrode tips were used: 2.5-cm electrode tips with three electrode cluster arrays and single probes with 2.0- and 3.0-cm electrode tips. The tip length was selected based on tumor size. The largest possible electrode tips were selected without being greater than 1 cm longer than the diameter of the neoplasm. For neoplasms larger than 2 cm, the cluster electrode was used. Overlapping ablations were performed based on tumor size and shape, with the intent to destroy the entire mass.
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A small number of patients in this study had pacemakers. These patients were not excluded. Immediately before treatment, patients with pacemakers were seen by a cardiologist, and a doughnut-shaped magnet was placed on the skin overlying the pacemaker to deactivate the sensing feature of the pacemaker. After the radiofrequency ablation session, patients with pacemakers were reevaluated by a cardiologist, who interrogated and reset the pacemakers.
Immediately after the completion of the radiofrequency ablation procedure, patients were transferred to a short-stay area in the hospital where their vital signs were monitored hourly; antiemetics and analgesics were administered on an as-needed basis in this area. A CBC was obtained 5 hours after completion of the radiofrequency ablation procedure. Patients were discharged if they had no sign of complications with stable vital signs, no evidence of active bleeding (stable blood pressure, pulse, hematocrit, and hemoglobin level), and no pain requiring IV analgesics.
Patients were followed up with CT or MRI before and after injection of IV contrast material 1-3 months after the procedure (initial tumor control). At regular intervals thereafter patients were reevaluated with CT or MRI before and after injection of IV contrast material in addition to a complete serum metabolic panel and a chest radiograph. For all scans obtained for follow-up, an electronic region of interest was used to interrogate each treated tumor on the scans before and after IV contrast material injection to assess for evidence of tumor enhancement. When scans obtained after IV contrast injection showed lack of contrast enhancement (< 10 H for CT or < 15% signal increase on MRI) in the treated RCC compared with the precontrast-enhanced scans (Fig. 2A, 2B, 2C, 2D, 2E, 2F), this lack of contrast enhancement was considered as no evidence of disease (NED). Presence of enhancement in the treated tumor on the first follow-up, or on a subsequent follow-up, scan was interpreted as residual tumor (Fig. 3A, 3B, 3C). The length of time, measured in months, from the procedure to the most recent follow-up scan was recorded.
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Patients with recurrent disease were assessed as candidates for further percutaneous radiofrequency ablation therapy. If feasible, an additional radiofrequency ablation session was completed. Beginning in late 2005, percutaneous cryoablation was used to treat some patients with residual disease after radiofrequency ablation. This subset of patients is described further in the Results section of this article.
Patient records and scans made during the procedure and throughout the follow-up period were reviewed and all complications attributable to the radiofrequency ablation procedure were recorded.
Analysis of the data included review of pretreatment, treatment, and follow-up scans for each treated tumor. The diameter of each treated tumor was measured using electronic calipers on the scan slice showing the greatest diameter. To determine if tumor position affected radiofrequency ablation results, the tumor position was categorized using two different tumor features from the pretreatment scans. Location of the tumor was classified by dividing the cephalocaudal length of the kidney into thirds: upper, middle and lower. Each third was then divided into four quarters: posteromedial, posterolateral, anteromedial, and anterolateral. The position of each tumor was categorized based on one of these 12 areas using the segment containing the largest volume of each tumor. Second, tumor location was categorized as being exophytic, parenchymal, central, or mixed, based on a previously described classification system [18]. If a tumor was completely surrounded by renal parenchyma with no contact with the perirenal fat, it was classified as a parenchymal tumor. Tumors that grew into the renal sinus but not beyond the renal capsule were classified as central tumors. Tumors with greater than 25% of their circumference contacting perirenal fat were classified as exophytic. Tumors that contacted both the renal sinus and the perirenal fat were classified as mixed tumors.
The effects of location, type, and size of tumors on disease-free survival time were assessed by a Cox regression analysis. Survival time was compared across poles (lower, middle, and upper), positions (medial vs lateral, anterior vs posterior), and tumor types (exophytic vs other). The association between the size of tumors and survival time was also assessed. In the Cox regression analysis, the residual tumors detected on the first follow-up scan were considered to have zero disease-free times.
Furthermore, the association between the likelihood of complications and variables named above was also assessed. Fisher's exact test was used to investigate whether the likelihood of complications differed across poles, positions, and tumor locations. A logistic regression analysis was used to assess the association between the size of tumors and the likelihood of complications. All the statistical analyses were performed with the SAS package, version 9.1 (SAS Institute), on a PC.
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After radiofrequency ablation treatment of RCCs, follow-up with CT or MRI and clinical assessment ranged from 1 to 75.8 months (mean, 13.8 months; median, 9.8 months). Tumor-free survival was obtained in 116 (93%) of 125 tumors. Tumors in the medial half of the kidney had marginally worse disease-free survival compared with tumors in the lateral position (p = 0.05), with the relative risk of 2.65 (95% CI, 0.99-7.12). Tumor-free survival was not influenced by sex (p = 0.16), side of tumor (p = 0.75), tumor type (exophytic, central, parenchymal, or mixed) (p = 0.21), or cephalocaudal tumor location (p > 0.99) within the kidney. Tumor size was highly significantly associated with achieving tumor-free survival (p < 0.001).
After a single ablation session, tumor-free survival was achieved in 95 (100%) of 95 tumors 3.6 cm or smaller (mean, 2.4 cm) versus 14 (47%) of 30 tumors larger than 3.7 cm in size (mean, 4.7 cm) (Table 1). As a tumor increased 1 cm in size, the likelihood of residual tumor increased 2.19 times (95% CI, 1.74-2.76). Table 2 shows the results from the Cox regression analysis and Figure 4 shows Kaplan-Meier plots of tumor-free survival probabilities for various tumor sizes.
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Seven of the 16 initial treatment failures were successfully retreated with percutaneous ablation (four with radiofrequency ablation and three with cryoablation) with NED on follow-up scans. Of the remaining nine patients, two underwent nephrectomies and two were retreated with radiofrequency ablation. Of those two retreated with radiofrequency ablation, one was lost to follow-up and one was found to still have residual RCC on follow-up scans. Two patients were retreated with percutaneous cryoablation and were found to still have residual RCC on follow-up scans, and three other patients were followed conservatively due to their poor overall health status.
In 12 of the 16 patients with residual tumor, the viable tumor was detected on the first surveillance scan obtained after radiofrequency ablation. In four patients, the residual disease was detected on the second surveillance scan at a mean follow-up of 7.7 months (range, 3-11.9 months) for the second scan after radiofrequency ablation (Fig. 2A, 2B, 2C, 2D, 2E, 2F). Two (1.9%) patients developed evidence of metastatic disease after treatment. One patient with a 2.6-cm RCC and with two other malignancies, prostate adeno-carcinoma and a poorly differentiated thyroid carcinoma, had tiny nodules in his lung bases detected on pretreatment abdominal CT. At the time of his radiofrequency ablation treatment, these pulmonary nodules could not be diagnostically determined as either metastases or granulomas, so radiofrequency ablation was undertaken with curative intent. These nodules have grown gradually over 6 years of follow-up surveillance imaging, indicating that they are likely metastases that were preexisting at the time of RCC ablation. These pulmonary metastases have not been biopsied, so the source of the metastases remains undetermined.
A second patient with a 5.3-cm RCC had a normal chest radiograph but no other thoracic imaging before radiofrequency ablation that resulted in residual tumor in the treated kidney. The patient elected for no further treatment of his kidney tumor, and he was found to have multiple pulmonary nodules on a chest CT scan obtained for an unrelated reason 11 months after the radiofrequency ablation. A tissue diagnosis of these nodules has not been obtained, but they have been presumptively diagnosed as metastases from RCC.
A total of 8 (8%) patients experienced complications. There were four complications that occurred the day of the radiofrequency ablation procedure. These included two (2%) small pneumothoraces and one (1%) perirenal hemorrhage requiring transfusion and one patient (1%) who developed apnea during the radiofrequency ablation procedure. The pneumothoraces were discovered on the CT images obtained at the end of the radiofrequency ablation procedure. These patients were observed with follow-up chest radiographs 1 and 3 hours after radiofrequency ablation. Chest radiographs showed no progression of the pneumothorax in either of these two patients and both remained asymptomatic and were discharged the afternoon of the radiofrequency ablation procedure without the need for a chest tube or further treatment. The patient requiring transfusion developed tachycardia and severe right flank pain several hours after radiofrequency ablation treatment, and he was found to have a large perinephric hematoma on a CT scan obtained at that time. He was treated with a transfusion of 2 units of packed RBCs. The episode of apnea during radiofrequency ablation in one patient was due to narcotization during the procedure. The patient was resuscitated with naloxone, the procedure was completed, and the patient was discharged after an uneventful period of observation.
There were two patients who experienced evidence of complications after leaving the hospital but within 30 days of the radiofrequency ablation procedure. One (1%) patient was found to have pneumonia 3 days after radiofrequency ablation. This was successfully treated with antibiotics without sequela. One (1%) patient experienced severe neuropathic pain beginning a few days after the radiofrequency ablation procedure, which resulted in several emergency department and clinic visits. This pain was treated with narcotic pain medicine until the pain spontaneously resolved 3 months after the procedure. All six patients experiencing immediate and short-term complications made full recoveries.
Long-term complications (> 30 days after radiofrequency ablation) occurred in two (2%) patients who developed proximal ureteral strictures with concomitant hydronephrosis. Both of these patients' RCCs originated in the lower pole. One of these patients declined any further intervention and died of an unrelated cardiac event before undergoing evaluation and treatment. The second patient with a ureteral stricture has been asymptomatic and opted for observational management instead of therapy.
Fisher's exact tests (Table 3) revealed that tumor location within the kidney, tumor type (exophytic, central, parenchymal, or mixed), side, and patient sex were not significantly associated with increased likelihood of complication. The logistic regression analysis failed to find a significant association between the tumor size and the likelihood of complications (p = 0.91).
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Traditionally, standard therapy for RCC has been radical nephrectomy [4]. Management of RCC has evolved with the advent of laparoscopic and nephron-sparing approaches [6, 21-23]. Unfortunately, it is not rare to encounter a patient with a small RCC who is unwilling or, due to comorbidities, unable to undergo standard therapy. On the basis of a mean growth rate of 3-4 mm per year, one could argue that follow-up imaging of small incidental renal neoplasms in older patients could be advisable [24, 25]. However, a patient's life expectancy and the metastatic potential of small RCCs cannot be reliably predicted. Also, some patients desire definitive treatment or are at risk for multiple renal tumors and prone to recurrent morbid surgery secondary to a hereditary predisposition to RCC (von Hippel-Lindau or hereditary papillary RCC) [6]. CT-guided percutaneous radiofrequency ablation is a treatment option for these select patients.
The pathophysiology of radiofrequency ablation involves thermal energy generated from ionic agitation from the transfer of high-frequency AC within the treatment area. As temperatures increase, cellular proteins denature, and lipid components melt, leading to tissue destruction. Much of the early clinical experience with radiofrequency ablation was derived from the treatment of liver tumors. Primary liver tumors have been successfully treated, with low morbidity in patients unable to undergo primary resection [26, 27]. Many of the initial and current treatment protocols are derived from the liver experience.
It is difficult to apply the liver experience to the renal model because the kidney differs in its hemodynamic and electrical characteristics compared with the liver. The architecture of the blood flow is segmental and is greater per gram of tissue in the kidney than in the liver [28]. Electrical conductivity is greater in the kidney compared with the liver [29]. Because of the nonextirpative nature of radiofrequency ablation, contemporary series measure outcomes by the presence or absence of enhancement on follow-up imaging, with the lack of enhancement indicating lack of viable tumor.
One series, using an ablation device different from the one used in this study, showed pathologic skip areas that survived the ablation procedure, with 5% viable tumor volume, in seven of nine treated renal tumors [30]. A second in vivo study, using the device and technique used in our series showed uniform tumor destruction without skip areas [31]. Therefore, we think the lack of contrast uptake on CT or MRI indicates the absence of viable tumor; however, surveillance imaging is required because most radiofrequency ablation series are not mature in terms of proving long-term control. In this series, all RCC recurrences were detected within 11.9 months of radiofrequency ablation treatment. This finding is similar to a multicenter study that found 92.1% of renal tumor recurrences were detectable 12 months or fewer after thermal ablation [32].
Several series have shown favorable initial and short-term tumor control [10-13]. Recently, McDougal et al. [33] examined a small subset of their radiofrequency ablation experience with greater than 4-year follow-up. They showed successful outcomes in exophytic masses smaller than 5 cm. The 11 patients reviewed had a mean tumor size of 3.2 cm and a mean follow-up of 4.6 years. Twelve (92.3%) of the 13 masses treated had no evidence of disease. This is further evidence of the durability of oncologic control after radiofrequency ablation for treatment of RCCs.
In this series, results were limited to patients with a tissue diagnosis of RCC, and, of treated RCCs, tumor-free status was obtained in 116 (93%) of 125 tumors. When stratified for size, initial control was shown in 100% of tumors 3.6 cm or smaller versus 47% of tumors larger than 3.7 cm. In addition, there have been no RCC recurrences when the treated RCC was smaller than 3.7 cm. Of the 16 patients with residual tumor after one session of radiofrequency ablation treatment, seven were successfully retreated (four with radiofrequency ablation and three with percutaneous cryoablation) and are currently without evidence of disease. Three of the 16 patients declined retreatment, two underwent nephrectomies, and four had second ablation treatments (two radiofrequency ablation and two cryoablation), but three had residual viable tumor detected on later scans and one patient was lost to follow-up.
On long-term follow-up imaging, two patients were found to have evidence of metastatic disease, both with multiple pulmonary nodules. One of these two patients, with a 5.4-cm RCC, was found to have pulmonary nodules on a chest CT scan 1 year after radiofrequency ablation treatment. It is possible that this patient developed metastatic RCC after the radiofrequency ablation treatment or he may have had preexisting metastatic disease that was undetected on his pretreatment chest radiograph. A second patient also was found to have pulmonary metastases after radiofrequency ablation. These pulmonary nodules were present before radiofrequency ablation treatment, indicating that these metastases developed before radiofrequency ablation. On the basis of this series, at least in the short term, the risk of developing metastatic disease after percutaneous radiofrequency ablation is very low.
There are some limitations in this study. The lack of enhancing tumor detectable with CT and MRI is taken to be equivalent to no residual neoplasm. It is possible that microscopic foci of viable neoplasm are present in some treated tumors but are undetectable with CT and MRI. However, an in vivo study evaluating the efficacy of radiofrequency ablation in treating RCCs showed uniform ablation of the tumors without skip areas of viable tumor within the ablation zone [31]. This indicates that it is unlikely that viable tumor exists within the ablation zone but does not exclude the possibility of residual tumor outside the margin of the ablation zone.
In addition, one multicenter study showed that after thermal ablation of RCCs, nearly all recurrences were detectable within 12 months, less than the mean time of follow-up in the current study [32]. This suggests that additional patients with residual tumor at the ablation margins would likely have been detected, if present, in the current study. In addition, because these patients have serious comorbidities, the effect of microscopic RCC, if present, on overall survival may be insignificant. There is a lack of a large series of patients with long-term (> 5 years) follow-up, so it is not possible to prove, from this study, that the tumor eradication results will be durable over a period of many years.
This study shows that the procedure, CT-guided percutaneous radiofrequency ablation, as described in this article has a very low rate of complications. Eight complications resulted from 131 radiofrequency ablation sessions in this series. None of the complications in this series resulted in long-term morbidity and most were minor complications. Likewise, we can only speculate on the reason for the increased rate of residual tumor in the patients with medially located RCCs. This may be a statistical aberration related to the small number of incompletely treated RCCs. Alternatively, medial tumors are more likely to be located near large vessels, such as the aorta and vena cava, than are lateral tumors. These vessels serve as heat sinks and may decrease the efficacy of radiofrequency ablation. Also, medial tumors may be close to the ureter, a structure at risk for stricturing if it is in the ablation field. This may lead to less aggressive ablation of these tumors and result in a higher risk of incomplete ablation.
The results of this study support the use of CT-guided percutaneous radiofrequency ablation for the treatment of RCCs in a defined group of patients: those with increased risk of complications from surgery and those with a condition predisposing them to continual development of RCCs that will require repeated treatments. RCCs that are smaller than 3.7 cm in diameter can be reliably and safely eradicated with percutaneous radiofrequency ablation. This result is valid regardless of the location or position of the RCC in the kidney.
Larger tumors can also be eradicated with percutaneous radiofrequency ablation, but with each 1-cm increase in tumor diameter over 3.6 cm, there is a consequent decrease in the likelihood of tumor-free survival by a factor of 2.19. Also, tumors located in the medial half of the kidney and larger than 3.6 cm may have an increased likelihood of incomplete ablation. After radiofrequency ablation, surveillance imaging is justified to detect residual or recurrent RCC. Because tiny foci of residual tumor may be undetectable, surveillance imaging should be performed for a prolonged period after percutaneous radiofrequency ablation, similar to the approach used after partial nephrectomy [34]. If residual tumor is present, it can be retreated, resulting in eradication in many cases. In this series, all residual viable tumors were detected on the first or second surveillance scans after radiofrequency ablation treatment, and no residual tumor was detected greater than 11.9 months after radiofrequency ablation. Most were detected on the first follow-up CT or MRI.
In conclusion, CT-guided percutaneous radiofrequency ablation is a reliable and safe method to treat small RCCs. The results of this study show that radiofrequency ablation can be used to reliably eradicate RCCs smaller than 3.7 cm in diameter. Treatment of larger RCCs will result in an increased risk of residual and recurrent RCC, but larger tumors can be successfully treated with percutaneous radiofrequency ablation. Serious complications are rarely caused by this procedure.
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