Embolization Therapy: Principles and Clinical Applications, 1 Ed.

Renal Cell Carcinoma

Michael Darcy

The standard of care for managing renal cell carcinoma (RCC) is surgical resection, whereas in nonsurgical candidates, small RCCs are commonly treated with percutaneous ablation. So even though embolization of RCC has been around since the initial description in 1973,1 its role is still relatively limited. However, in certain situations, it can be a very useful technique.

DEVICE DESCRIPTION

Catheters needed for embolization are generally not exotic. Standard 5-Fr catheters such as Cobra or Sos-shaped catheters are adequate to engage the main renal artery. If the RCC involves only a portion of the kidney, a microcatheter can be used to advance closer to the tumor’s vasculature. Because coils are rarely used and particles or liquid embolics are favored, microcatheters with larger internal diameters can be useful. Occasionally, if the embolization is to be carried out from the main renal artery and the artery is short, a balloon occlusion catheter can be used to help prevent reflux of embolic materials.

The choice of embolic agent depends somewhat on the goal of the embolization. If you are simply providing preoperative devascularization, occluding the major arterial branches is adequate. Thus, large particles or even coils can be used to rapidly occlude the arteries. If embolization is the definitive therapy, then one wants to occlude very small peripheral branches to maximize the percentage of tumor tissue that undergoes necrosis. The fact that arteriovenous fistulae may sometimes be present in an RCC may guide the selection of embolic agents because particles or liquids could rapidly pass through the fistula.

Particles such as polyvinyl alcohol (PVA) are favored by some because they are readily available, relatively inexpensive, and easy to use. Suspending the PVA in contrast allows fluoroscopic monitoring to ensure that the particles are injected where intended. The size of the particles selected depends on the goal of embolization. Larger particles can easily occlude the major branches and reduce flow for preoperative devascularization. To achieve complete tissue necrosis for definitive therapy, smaller particles (100 to 300 µm) are a better choice.

Alcohol is favored by many because it will penetrate into peripheral small branches, thus reducing the chance of any collateral perfusion keeping the tumor alive. The problem is that alcohol is not radiopaque and therefore more difficult to use. As outlined in Chapter 9, mixing ethanol with Ethiodol provides opacification so the injections can be fluoroscopically monitored. It has an added benefit of allowing more peripheral embolization. Pure ethanol causes spasm, immediate protein denaturation, and thrombus formation. Mixing ethanol with Ethiodol blunts this effect and allows the ethanol to penetrate further into the precapillary arteries.2 Although alcohol can be delivered through a peripherally positioned end-hole catheter, balloon occlusion catheters are favored when alcohol needs to be injected into the main renal artery. This is to prevent reflux from the renal artery into the abdominal aorta. Cyanoacrylate glue or Onyx (Covidien, Irvine, California) can also be used, but the expense of these agents cannot be justified given how easy it is to embolize an RCC with these other less expensive agents.

TECHNIQUE

There are several considerations before starting an embolization for RCC. Preoperative antibiotics are often used to reduce the chance of abscess formation in the necrotic tumor. Although renal embolization can be done with local anesthesia and sedation, general anesthesia should be considered if ethanol is going to be used (especially in larger volumes) because it can be painful. For large tumors extending into the renal vein or inferior vena cava (IVC), one concern is that embolization-induced necrosis will cause the tumor thrombus to become detached and embolize to the heart. Placing a suprarenal IVC filter has been used as a way to protect against embolization.3 In some cases, the tumor thrombus may extend too far into the IVC and there may not be enough room to deploy a filter without extending into the right atrium. In that setting, we have still embolized the kidney and have not seen tumor embolization (Fig. 48.1), although that is still a concern. Use of a large self-expanding stent has been described to hold the tumor against the IVC wall to prevent embolization.4 This has the added benefit of restoring caval patency. However, this technique would primarily be useful during palliative embolization because stenting across the tumor would interfere with a surgical resection. Finally, one may need to address a renal artery stenosis first to allow easier catheterization of the renal artery or to help preserve function of the normal parenchyma.5

An effective embolization always starts with a good diagnostic arteriogram. Although preprocedure cross-sectional imaging will often indicate the number of major renal arteries supplying the kidney, one can miss small accessory renal arteries that might supply the tumor. Also, RCCs can parasitize blood supply from surrounding structures. Thus, diagnostic arteriography is needed to discover all the potential sources of blood supply to the tumor. This is best accomplished with a flush aortogram so that all vessels supplying the tumor will be opacified. Alternatively, in cases of very large RCCs with tortuous and distorted vascular anatomy, it may be difficult to see small arteries supplying the RCC because of overlapping larger vessels. Thus, it may be easier to identify smaller arteries supplying the RCC if you first embolize the major vessels supplying the tumor and then perform an aortogram to search for those vessels (Fig. 48.2).

Catheter choice depends on individual patient anatomy. For RCCs involving only a portion of the kidney, microcatheters are used for superselective catheterization to preserve as much normal renal parenchyma as possible. But even for large RCCs that will require embolizing the whole kidney, some prefer to use microcatheters because positioning them very peripherally in the kidney reduces the chance of reflux and nontarget embolization (Fig. 48.3). The downside to microcatheters for larger tumors is that you have to selectively catheterize multiple branches. When dealing with a large RCC that occupies most of the kidney, it is often more expeditious to embolize from a more proximal position in the main renal artery. It is important to make sure the catheter is positioned far enough into the main renal artery to avoid infusing embolic material into the adrenal arteries (Fig. 48.4), which could cause adrenal dysfunction or hypertensive crisis. When using a balloon occlusion catheter, an initial contrast injection is done with the balloon inflated to see what volume of contrast is needed to fill the renal artery. This is done to gauge how much ethanol needs to be injected. For preoperative devascularization, some interventionalists prefer to just catheterize the main renal artery, inject some PVA peripherally, and then deposit coils in the main renal artery. One caveat is that coils should not be placed too proximally in the renal artery because that can interfere with effective clipping or ligation of the main renal artery during nephrectomy.

CLINICAL OUTCOMES

Embolization for Palliative Therapy of Renal Cell Carcinoma

With laparoscopic surgical techniques or percutaneous ablation, definitive therapy can be accomplished with relatively low risk in most patients. However, there are some patients for whom surgery is still too risky or the tumor is too large to be managed with percutaneous ablation alone. Embolization provides a reasonable alternative in these patients. In solitary kidneys, embolization can also be used as an alternative to surgery to limit loss of functioning parenchyma.

One of the main palliative uses of embolization is relief of symptoms. Serafin et al.6 reported on 73 patients who underwent palliative embolization of advanced RCCs. In their study, 34% and 32% of patients presented with hematuria or flank pain, respectively. Embolization eliminated hematuria and flank pain in 100% and 72% of cases, respectively.

At least one study has shown that embolization can also significantly prolong survival even when distant metastases are present. Onishi et al.7 compared matched cohorts with unresectable RCC and distant metastases. Patients who underwent embolization with ethanol had a median survival of 229 days and 1-, 2-, and 3-year survival rates of 29%, 15%, and 10%, respectively. Those not treated with embolization had median survival of 116 days and 1-, 2-, and 3-year survival rates of 13%, 7%, and 3%, respectively. There have been reports of metastases regressing after embolization of the primary tumor.8 Significant increase in natural killer cell activity has been seen 48 hours after embolization of RCCs.9 Thus, it has been postulated that embolization can upregulate the immune system’s antitumor activity.

Embolization for Rupture of Bleeding

The incidence of spontaneous rupture of RCC is 0.3% to 0.6%. Although radical nephrectomy is typically required in this scenario, embolization may be used to arrest the hemorrhage.10 Aside from stabilizing the patient by reducing blood loss, embolization also provides an important role by converting an emergent nephrectomy into an elective operation. This provides time to be able to medically prepare the patient for the nephrectomy, which is a major operation. For patients who are not surgical candidates, terminating hemorrhage by embolization can be an important lifesaving palliative procedure.

Embolization can also be used to control hemorrhage after radiofrequency ablation (RFA) of an RCC11 or when patients develop pseudoaneurysms after partial nephrectomy. The main benefit here is that embolization can selectively occlude the bleeding vessel while preserving most of the normal renal parenchyma, which is particularly useful after surgery or RFA has already removed some of the functioning parenchyma.

When treating a ruptured RCC, a specific bleeding site is not often visible at angiography, thus embolization of the entire RCC is the preferred technique. However, for postoperative or post-RFA bleeding, the goal is to stop the bleeding and not provide any direct tumor therapy. In this setting, extravasation or pseudoaneurysm can often be seen angiographically. Therefore, superselective embolization through microcatheters is optimal.

Embolization before Nephrectomy

RCCs are highly vascular tumors and thus there is great potential for blood loss during resection. Thus, for larger tumors, preoperative embolization may facilitate surgical resection. Although some studies12have shown that there is no reduction in blood loss compared to nephrectomy without embolization, other studies have shown that preoperative embolization can significantly reduce intraoperative blood loss.13

As mentioned, infarction of RCCs can trigger an immunologic response, which can lead to spontaneous regression of metastases.14 This has led to the hypothesis that embolization should be done before surgical nephrectomy for the immunologic benefits. However, the results have been somewhat mixed. A Southwest Oncology Group study of 30 patients with metastatic RCC treated by embolization followed by delayed nephrectomy reported no complete remissions and only one partial remission.15 Also, 1-year survival and median survival was similar to studies in which no therapy was performed. However, more recently, a large study was done in which 118 patients who underwent embolization before nephrectomy were compared to a matched population of 116 patients who were treated with nephrectomy alone.16The 5- and 10-year survival rates for patients embolized before nephrectomy was 62% and 47%, respectively, compared to 35% and 23% in patients who were not embolized (P = .01).

Embolization as Adjunct to Percutaneous Ablation

Although data are limited, embolization has been used before RFA of RCC. The potential benefit is that devascularizing the tumor should reduce the heat sink effect, which may increase the size of the ablation zone and decrease the chance of local recurrence. It could also reduce the chance of postprocedural hemorrhage and improve visualization of the tumor during computed tomography (CT)–guided puncture. A small pilot17 study of 10 patients reported no major complication and no recurrences during a mean follow-up of 47 months. Yamakado et al.18 treated 12 RCCs all larger than 3.5 cm with RFA after arterial embolization. Even though tumor extended into the renal sinus in 10 of 12, tumor enhancement was completely eliminated after just one RFA session in 75% of tumors.18

POTENTIAL COMPLICATIONS

The largest series that specifically addressed complications of RCC embolization was the study by Lammer et al.19 They noted an overall complication rate of 9.9%, with a mortality rate of 3.3%. An important finding was that the complication rate was five times higher (20% vs. 4.9%) in patients undergoing embolization for palliative therapy versus those undergoing preoperative embolization. This was attributed to the large mass of the tumors and the poor health of the patients in the palliative group. When combining embolization and RFA, minor complications have been reported in as many as 50% of cases.17 These included back pain, subcapsular hematomas, hematuria, or nausea and were all self-limited.

Postembolization syndrome is nearly universal and consists predominantly of pain and fever. Fortunately, symptoms are typically limited to the first few days and are managed with supportive care alone. Transient hypertension is also occasionally seen and treated with short-term antihypertensive agents as needed.

One of the major complications is nontarget embolization, which has been seen in as many as 10% of cases, 4% of which were symptomatic embolization to the lower extremities in that series.6 Two cases of colonic infarction were reported after left renal embolization with ethanol.20 This was presumably due to reflux from the renal artery to the inferior mesenteric artery. The remarkable thing about this report was that large volumes of ethanol (25 and 20 mL) were injected at a fairly high rate (1.5 to 2 mL per second) without opacification of the ethanol or use of a balloon occlusion catheter.

Other major complications are rare. Although devitalized tumor could be a potential nidus for infection to develop, abscess formation requiring drainage has only rarely been reported.18 As mentioned earlier, tumor embolization to the lungs can occur. Although rare, it can be catastrophic. Okuda et al.21 reported a case of fatal massive tumor embolism to pulmonary arteries after an RCC embolization.

TIPS AND TRICKS

• Careful angiography is essential to defining all the arteries supplying the tumor.

• Ethanol is an excellent embolic agent but should either be opacified with Ethiodol or injected with a balloon occlusion catheter to prevent nontarget embolization.

• Embolization can be used as an adjunct to increase the efficacy of RFA.

REFERENCES

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 2. Wright KC, Loh G, Wallace S, et al. Experimental evaluation of ethanol-ethiodol for transcatheter renal embolization. Cardiovasc Intervent Radiol. 1990;13(5):309–313.

 3. Hirota S, Matsumoto S, Ichikawa S, et al. Suprarenal inferior vena cava filter placement prior to transcatheter arterial embolization (TAE) of a renal cell carcinoma with large renal vein tumor thrombus: prevention of pulmonary tumor emboli after TAE. Cardiovasc Intervent Radiol. 1997;20(2):139–141.

 4. Zamora CA, Sugimoto K, Mori T, et al. Prophylactic stenting of the inferior vena cava before transcatheter embolization of renal cell carcinomas: an alternative to filter placement. J Endovasc Ther. 2004;11(1):84–88.

 5. Mondshine RT, Owens S, Mondschein JI, et al. Combination embolization and radiofrequency ablation therapy for renal cell carcinoma in the setting of coexisting arterial disease. J Vasc Interv Radiol. 2008;19(4):616–620.

 6. Serafin Z, Karolkiewicz M, Strzesniewski P, et al. Palliative percutaneous kidney embolization with enbucrilate in patients with renal cell carcinoma: safety and symptom control. Med Sci Monit. 2007;13(suppl 1):98–104.

 7. Onishi T, Oishi Y, Suzuki Y, et al. Prognostic evaluation of transcatheter arterial embolization for unresectable renal cell carcinoma with distant metastasis. BJU Int. 2001;87(4):312–315.

 8. Munro NP, Woodhams S, Nawrocki JD, et al. The role of transarterial embolization in the treatment of renal cell carcinoma. BJU Int. 2003;92(3):240–244.

 9. Bakke A, Gothlin JH, Haukaas SA, et al. Augmentation of natural killer cell activity after arterial embolization of renal carcinomas. Cancer Res. 1982;42(9):3880–3883.

10. Watanabe S, Hama Y, Kaji T, et al. Pre-operative embolization for spontaneous rupture of renal cell carcinoma. Ulster Med J. 2005;74(1):66–67.

11. Roach H, Whittlestone T, Callaway MP. Life-threatening hematuria requiring transcatheter embolization following radiofrequency ablation of renal cell carcinoma. Cardiovasc Intervent Radiol. 2006;29(4):672–674.

12. Lanigan D, Jurriaans E, Hammonds JC, et al. The current status of embolization in renal cell carcinoma—a survey of local and national practice. Clin Radiol. 1992;46(3):176–178.

13. Bakal CW, Cynamon J, Lakritz PS, et al. Value of preoperative renal artery embolization in reducing blood transfusion requirements during nephrectomy for renal cell carcinoma. J Vasc Interv Radiol. 1993;4(6):727–731.

14. Mohr SJ, Whitesel JA. Spontaneous regression of renal cell carcinoma metastases after preoperative embolization of primary tumor and subsequent nephrectomy. Urology. 1979;14(1):5–8.

15. Gottesman JE, Crawford ED, Grossman HB, et al. Infarction-nephrectomy for metastatic renal carcinoma. Southwest oncology group study. Urology. 1985;25(3):248–250.

16. Zielinski H, Szmigielski S, Petrovich Z. Comparison of preoperative embolization followed by radical nephrectomy with radical nephrectomy alone for renal cell carcinoma. Am J Clin Oncol. 2000;23(1):6–12.

17. Nakasone Y, Kawanaka K, Ikeda O, et al. Sequential combination treatment (arterial embolization and percutaneous radiofrequency ablation) of inoperable renal cell carcinoma: single-center pilot study. Acta Radiol. 2012;53(4):410–414.

18. Yamakado K, Nakatsuka A, Kobayashi S, et al. Radiofrequency ablation combined with renal arterial embolization for the treatment of unresectable renal cell carcinoma larger than 3.5 cm: initial experience. Cardiovasc Intervent Radiol. 2006;29(3):389–394.

19. Lammer J, Justich E, Schreyer H, et al. Complications of renal tumor embolization. Cardiovasc Intervent Radiol. 1985;8(1):31–35.

20. Cox GG, Lee KR, Price HI, et al. Colonic infarction following ethanol embolization of renal-cell carcinoma. Radiology. 1982;145(2):343–345.

21. Okuda H, Toda F, Ito F, et al. A case of sudden death by pulmonary embolism after angio-embolization of renal cell carcinoma extending into the inferior vena cava [in Japanese]. Hinyokika Kiyo. 1999;45(1):49–51.