Ethanol Ablation of Renal Cell Carcinoma for Palliation of Symptoms in Advanced Disease

Introduction

Renal cell carcinoma (RCC) is one of the leading diseases with significant morbidity and mortality. Despite recent advances in imaging technology and early diagnosis, a significant number of patients (approximately 30%) have metastatic disease among newly diagnosed cases of RCC, and the prognosis in these patients with disseminated disease is poor, with a 5-year survival of less than 20%.^1–3 The treatment of patients having metastatic disease remains difficult because RCC has poor response to chemotherapeutic agents. ⁴ Standard treatment for localized disease is radical nephrectomy, but in advanced disease with dissemination, surgery may not always be possible. Immunotherapy using interleukin-2 and interferon may be offered to these patients but the response remains poor.^5,6 As the disease progresses these patients may present with hematuria or intractable flank pain or both for which immediate intervention is required and most patients are not fit for surgery. Other therapeutic options for these symptoms include procedures such as renal artery embolization. Here we report our experience with transcatheter arterial embolization (TAE) using ethanol in cases of advanced RCC presenting with hematuria, flank pain, or both.

Patients and Methods

This was a retrospective study conducted over a period of 3 years from January 2006 to December 2008. The study group consisted of eight patients (7 males and 1 female) ranging from 38 to 69 years of age with mean age of 57.5 years. Seven of the eight patients were referred to our institute from nearby hospitals with the diagnosis of metastatic RCC based on imaging and histopathologic findings. One patient presented directly to the urology department of our institute with the symptom of hematuria and was later diagnosed to have advanced RCC. Robson staging was used and three patients were found to have stage IVa while five had stage IVb disease. Three patients had hematuria and flank pain, four had only frank hematuria, and one presented with recurrent severe flank pain (Table 1), however, hematuria was the predominant indication for embolization in seven patients while one patient was treated for severe flank pain. No specific tool was used to quantify the symptoms of the patients and the decision for embolization was based on patients' low hemoglobin level requiring frequent blood transfusions or the patient having recurrent severe pain requiring high-dose opioid analgesics for pain relief.

All patients underwent TAE using ethanol for the RCC followed by embolization by gelatin sponge pledgets. In six patients ethanol was mixed with ionic water soluble contrast media while in the remaining two iodized oil-based contrast (lipiodol; Andre Gurbet, Aulnay-sous-Bois, France) was used along with the ethanol. The amount of ethanol used ranged from 15–20 mL, depending upon the weight of the patient, with maximum amount not exceeding 0.3 mL/kg body weight. In all patients the renal artery was cannulated using 5F renal double-curve (RDC) catheter (Cook, Bloomington, IN) and was exchanged with a 4F straight-tip Slip Cath (Cook) if required.

After embolization, 3-month follow-up was done and patients were reviewed by the urologist as well as an interventional radiologist. Patients were asked if they had any visible hematuria and/or flank pain and hemoglobin level was assessed during follow-up. However, no specific tool was used to quantify the symptoms.

Results

All patients undergoing TAE were reviewed periodically at 3-month intervals up to 1 year. Of seven patients who were primarily treated for hematuria, six patients had no visible hematuria at 3 and 6 months after embolization and their hemoglobin levels were found to be above 9.0 g/dL. One patient developed hematuria at 4 months and succumbed to the disease at 5 months. At 9 months follow-up five patients did not had macroscopic hematuria, while one patient developed hematuria after 6 months and later died of disease at 8 months. Furthermore, at 1-year follow-up, three patients had no visible hematuria with stable hemoglobin levels. One patient who developed hematuria after 9 months died at 11 months, while one patient died of cardiac arrest after 10 months of treatment (Table 2). The only patient who was primarily treated for severe flank pain denied having pain on periodic follow-up, up to 1 year, and did not require medication for the same.

Overlap of symptoms like hematuria and flank pain was seen in three patients who were treated primarily for hematuria. These patients experienced significant pain relief and did not require analgesics for pain control. Although no specific tool/scale was used to measure pain in these patients, these patients denied having pain after embolization up to 1 year or the time until they survived (Table 2).

At 1-year follow-up four of the eight patients were alive and had minimal or no symptoms for which they were treated. Three patients died as a result of disease dissemination while one died of cardiac arrest.

Postembolization syndrome in the form of fever, pain, and vomiting was seen in three of the eight patients, which persisted for 1 to 2 days. These symptoms subsided with oral antibiotics, antipyretics, analgesics, and antiemetics. The average length of hospital stay was 4 days, ranging from 3 to 7 days.

Discussion

RCC can remain clinically occult for most of its course and significant numbers of patients remain asymptomatic until late in its course. This is the possible reason for the high percentage of newly diagnosed patients having distant metastasis. Disseminated RCC is difficult to treat and has a poor prognosis. There are few therapeutic options for symptomatic patients with advanced RCC. Palliative nephrectomy along with immunotherapy may be offered to this group of patients. However, a large number of patients are not fit for nephrectomy and also have poor response to immunotherapy. TAE may be the only treatment possible for control of symptoms in these patients.

Previous studies have shown survival benefit in patients with metastatic RCC who underwent palliative nephrectomy.^7,8 The role of TAE in the management of RCC remains controversial. There are various initial studies showing encouraging results of TAE followed by nephrectomy,^9–11 however, a later study by Gottesman et al. ¹² did not find better survival in patients treated with TAE followed by delayed nephrectomy. Similar findings were observed by Flanigan. ¹³ Although TAE has not been established as a treatment modality in advanced RCC it is considered effective treatment in controlling symptoms due to primary disease such as hematuria and pain.^14–18

Nurmi et al. ¹⁵ showed successful palliation of symptoms following TAE. Park et al. ¹⁹ found there was improved median survival of patients with unresectable RCC who underwent TAE. Onishi et al. ¹⁷ reported significant survival benefit for patients undergoing TAE with good control of local symptoms. Similarly Munro et al. ¹⁸ showed renal artery embolization to be an effective treatment for palliation of symptoms derived from primary tumor in advanced disease. Maxwell et al. ²⁰ used polyvinyl alcohol (PVA) particles for embolization of unresectable RCC and concluded it to be an alternative management option for inoperable disease. Recently Murata et al. ²¹ described a new technique of embolization under closed renal circuit for large RCC. In this TAE is performed and simultaneously aspiration of blood from occluded renal vein is done using a balloon catheter. They concluded that higher doses of ethanol may be delivered safely using this technique.

In our study, TAE showed excellent control of hematuria and/or flank pain. We had seven patients with stage IV disease presenting with hematuria who underwent TAE. Only one patient had recurrent hematuria at 4 months; he died at 5 months. Another two patients had few episodes of hematuria after 6 months, but the hemoglobin levels of these two patients were always maintained until they survived. Three patients died within the 6- to 12-month period. One of these patients died of cardiac arrest while the other two died because of dissemination of the disease. The only patient who was treated for recurrent severe flank pain responded very well to the treatment and denied having pain until 12-month follow-up.

One of the main limitations of this study is the absence of a symptom assessment tool for quantification of pain or hematuria before treatment and on follow-up. This is primarily due to retrospective nature of this study and all the data of patients were obtained from the patient's record.

Although our study consisted of a small group of patients the results appear very promising. All patients had disseminated disease and were not suitable for palliative surgery. So, transarterial alcohol ablation of the tumor was performed, which is a minimally invasive technique requiring a short hospital stay. The only complication encountered was postembolization syndrome in three patients that persisted for 1–2 days for which symptomatic treatment was given.

We observed excellent control of hematuria and/or flank pain in patients with advanced disease undergoing alcohol ablation of primary tumor. Not only were patients relieved of their local symptoms but four of the eight patients were alive and well at 12 months. However, exact survival benefit could not be calculated because the patients were only reviewed up to 1 year as a result of the study design.

In conclusion, transarterial alcohol ablation of RCC is very effective in controlling local symptoms such as hematuria and pain caused by primary disease in inoperable metastatic cases (stage IV). Moreover it is minimally invasive causing less morbidity and so is better accepted and tolerated by patients.