Transarterial Yttrium-90 Radioembolization Treatment of Patients with Liver-Dominant Metastatic Renal Cell Carcinoma

Abstract

Purpose:

To evaluate safety and efficacy of transarterial hepatic radioembolization treatment of patients with liver-dominant metastatic renal cell carcinoma (RCC).

Materials and Methods:

From July 2010 to December 2014, 18 patients with liver-dominant metastatic RCC were treated with yttrium-90 glass microsphere radioembolization. Retrospective review of medical records and imaging studies was performed to evaluate toxicities, treatment response, and overall survival. The median follow-up period from radioembolization treatment was 17.8 months (range, 3–54.4 months).

Results:

Median overall survival from RCC diagnosis was 64 months (95% confidence interval [CI], 0–144.1 months), from diagnosis of liver metastasis was 29 months (95% CI, 7.2–50.8 months), and from radioembolization treatment was 22.8 months (95% CI, 13.2–32.3 months). After treatment, 10 patients reported grade 1 clinical toxicities, and 8 patients had grade 1 or 2 biochemical toxicities. The best radiographic responses of 17 patients who underwent contrast-enhanced cross-sectional imaging showed complete response in 16 patients and partial response in 1 patient evaluated by modified Response Evaluation Criteria in Solid Tumors (mRECIST) criteria. The last available imaging of these 17 patients demonstrated complete response in 14 patients, partial response in 1 patient, and progression of disease in 2 patients. Images of a patient who underwent noncontrast CT showed stable disease as best response and stable disease on the last available imaging evaluated by RECIST.

Conclusions:

Radioembolization is safe and effective and led to improved hepatic disease control and overall survival in patients with liver-dominant metastatic RCC.

Metastasis develops in approximately 60% of patients with renal cell carcinoma (RCC) (1). Liver metastasis from RCC is uncommon; the rate has been reported to be up to 18% (2). Development of liver metastasis portends a poor prognosis with a median overall survival of 7.6 months, which is shorter compared with survival of patients with other metastases in whom the median overall survival time was 21.4 months (3). Once a tumor metastasizes to the liver, it is often the limiting factor for survival. RCC liver metastasis is relatively resistant to systemic chemotherapy, cytokine therapy, and external radiation (4,5). Hepatic metastasectomy in patients with RCC significantly improved survival (6,7), but < 5% of patients are candidates for resection (8).

Transarterial liver-directed embolization treatment of patients with liver-dominant metastatic disease is increasing worldwide because of the severe prognostic implications of the presence of liver metastasis regardless of the type of primary tumor. Transarterial embolization has lower comorbid risk compared with partial hepatectomy, and a higher fraction of tumors is accessible to transarterial treatment than to resection (9). Transarterial radioembolization with yttrium-90 (⁹⁰Y)-labeled microspheres improved overall survival of patients with liver-dominant metastatic diseases and has a favorable tolerability profile (9,10). Metastatic RCC is an attractive target for transarterial embolization therapies because of its hypervascularity, which ensures efficient delivery of the embolization microspheres to the tumor parenchyma. There is only 1 case series reporting the use of hepatic radioembolization in 6 patients with liver-dominant metastatic RCC (11). The purpose of this study was to evaluate the safety and efficacy of transarterial hepatic radioembolization treatment of patients with metastatic RCC to the liver.

MATERIALS AND METHODS

Patients

This study was approved by the institutional review board. Medical records of 20 consecutive patients with liver-dominant metastatic RCC who underwent radioembolization treatment between July 2010 and December 2014 in a single institution were retrospectively reviewed and analyzed. Criteria for receiving ⁹⁰Y radioembolization treatment included liver-dominant metastases, Eastern Cooperative Oncology Group performance status of ≤ 2, total serum bilirubin ≤ 2 mg/dL, serum creatinine ≤ 2 mg/dL, and international normalized ratio and platelet count correctable to ≤ 1.5 and ≥ 50,000/μL, respectively. Patients were not excluded if they had received previous liver-directed therapy or multiple lines of chemotherapy before radioembolization treatment.

There were 2 patients lost to follow-up; these patients were excluded from the study. Patient demographics are summarized in the Table. The study included 13 men and 5 women with a mean age of 66.1 years ± 9.6. All patients had biopsy-proven RCC; 15 patients had clear cell RCC, 2 patients had papillary RCC, and 1 patient had chromophobe RCC. Four patients presented with synchronous liver metastasis, and the remaining 14 patients developed liver metastasis later during the course of the disease. At the time of radioembolization treatment, 6 patients had hepatic-only metastatic disease, and 12 patients had both hepatic and extrahepatic metastases. Four patients had a solitary liver lesion, but none of the patients was amenable to percutaneous ablation because of the size of the metastasis. Seven patients received systemic treatment before radioembolization, and 13 patients received systemic treatment after radioembolization. One patient underwent intra-operative radiofrequency ablation of 2 liver metastases 23 months before radioembolization, and 1 patient had been treated with transarterial chemoembolization with doxorubicin-loaded drug-eluting beads 7 months after radioembolization.

Table .

Patient Characteristics

Age (y)/ Sex	ECOG*	Histology	Liver mets†	Extrahepatic Disease‡	Systemic treatment before 90Y§	Systemic treatment after 90Y‖
50/F	0	Clear cell	Solitary	None	Sunitinib	None
50/M	0	Papillary	Solitary	Retroperitoneum	None	Temsirolimus, sorafenib, everolimus
69/M	1	Clear cell	Multifocal, bilobar	Retroperitoneum, lungs	IL-2, sunitinib, nivolumab, bevacizumab	Lenvatinib
74/M	0	Clear cell	Multifocal, bilobar	None	None	None
65/M	1	Papillary	Multifocal, unilobar	Retroperitoneum	Temsirolimus	Sorafenib
69/F	0	Clear cell	Multifocal, bilobar	None	None	Sunitinib
67/F	0	Clear cell	Multifocal, bilobar	None	None	Pazopanib
78/M	2	Clear cell	Multifocal, bilobar	Lungs, bones	Sorafenib, everolimus, sunitinib	None
60/M	1	Clear cell	Multifocal, unilobar	Lungs, pancreas	None	Pazopanib
57/F	0	Clear cell	Multifocal, bilobar	Retroperitoneum	IL-2	Sorafenib, everolimus
71/M	1	Clear cell	Multifocal, bilobar	Pancreas, mediastinum	None	Pazopanib
65/M	1	Clear cell	Multifocal, bilobar	IVC	Pazopanib	Pazopanib
48/M	1	Chromophobe	Multifocal, bilobar	Mediastinum, bones	None	Sorafenib, everolimus
70/M	0	Clear cell	Solitary	Lungs, mediastinum	None	Pembrolizumab, axitinib
82/M	0	Clear cell	Multifocal, bilobar	None	None	None
72/F	0	Clear cell	Solitary	None	None	None
74/M	1	Clear cell	Multifocal, bilobar	Pancreas	None	Sorafenib
68/M	1	Clear cell	Multifocal, bilobar	Retroperitoneal, peritoneal, bone	Sunitinib, temsirolimus, pazopanib	Nivolumab, bevacizumab

ECOG = Eastern Cooperative Oncology Group; F = female; IL-2 = interleukin-2; IVC = inferior vena cava; M = male; mets = metastases; ⁹⁰Y = yttrium-90.

^*ECOG scale of performance status.

^†Distribution of liver metastases at the time of radioembolization.

^‡Location of extrahepatic metastases at the time of radioembolization.

^§Systemic treatment before radioembolization.

^‖Systemic treatment after radioembolization.

Radioembolization Procedure

All patients underwent treatment planning angiography 1–2 weeks before radioembolization treatment according to previously published guidelines (12). During planning angiography, the tumor feeding vessels and anatomic variants were identified, and technetium-99m-labeled macroaggregated albumin was injected into the hepatic arteries to determine the magnitude of hepatopulmonary shunting. The average lung shunt was 7.2% ± 3.3% (range, 3.2%–12.7%). Radioembolization was performed using ⁹⁰Y-labeled glass microspheres (TheraSphere; BTG International Ltd, London, United Kingdom). In patients with bilobar disease, the left and right lobes were treated separately, approximately 5–7 weeks apart. Repeat radioembolization treatment to the same lobe or segment was not performed. The delivered hepatic dose was calculated based on the treated liver volume, the administered activity, and the lung shunt fraction. The average delivered dose was 137.6 Gy ± 27.6.

Clinical Outcome Measures

Overall survival was calculated from the date of the RCC diagnosis, from the date of the diagnosis of liver metastasis, and from the date of liver-directed therapy to last encounter/follow-up or death. Hepatic progression–free survival was calculated from date of radioembolization therapy until death, last follow-up, or date of first liver progression.

Clinical and laboratory toxicities were assessed at follow-up visits at 1 month, 3 months, and every 3–6 months after radioembolization treatment. Clinical toxicity was defined as subjective reporting by the patient of pain, fatigue, gastrointestinal symptoms (anorexia, nausea, vomiting), or other. Toxicities were defined according to the Common Terminology Criteria for Adverse Events Version 4.03 scoring system. Tumor response was evaluated using modified Response Evaluation Criteria in Solid Tumors (mRECIST) (13). At follow-up visits at 1 month, 3 months, and every 3–6 months after treatment, 17 patients underwent baseline and follow-up contrast-enhanced cross-sectional imaging (computed tomography [CT] or magnetic resonance imaging). RECIST (14) was used to evaluate tumor response in 1 patient who did not receive an intravenous contrast agent for imaging.

Statistical Analysis

Statistical analysis was performed with IBM SPSS Statistics for Windows version 22 (IBM Corporation, Armonk, New York). Data are presented as mean ± SD. The probabilities of survival and hepatic progression–free survival were calculated by the Kaplan-Meier method. The Model for End-Stage Liver Disease scores were compared with Student t test.

RESULTS

The median follow-up period from radioembolization treatment was 17.8 months (range, 3–54.4 months). As of March 2016, 7 patients are alive and 11 patients have died. The median overall survival from RCC diagnosis was 64 months (95% confidence interval [CI], 0–144.1 months) (Fig 1). The median overall survival from diagnosis of liver metastasis was 29 months (95% CI, 7.2–50.8 months) (Fig 2). The median overall survival from radioembolization treatment was 22.8 months (95% CI, 13.2–32.3 months) (Fig 3). The hepatic progression–free survival did not reach the median (Fig 4).

Figure 1.

Overall survival from diagnosis of RCC of 18 patients who underwent ⁹⁰Y radioembolization treatment. Kaplan-Meier method revealed that the median overall survival from RCC diagnosis was 64 months (95% CI, 0–144.1 months).

Figure 2.

Overall survival from diagnosis of RCC liver metastasis of 18 patients who underwent ⁹⁰Y radioembolization treatment. Kaplan-Meier method revealed that the median overall survival from diagnosis of liver metastasis was 29 months (95% CI, 7.2–50.8 months).

Figure 3.

Overall survival from hepatic ⁹⁰Y radioembolization treatment of 18 patients with metastatic RCC. Kaplan-Meier method revealed that the median overall survival from diagnosis of liver metastasis was 22.8 months (95% CI, 13.2–32.3 months).

Figure 4.

Hepatic progression–free survival from hepatic ⁹⁰Y radioembolization treatment of 18 patients with metastatic RCC. Hepatic progression–free survival did not reach the median.

The reported clinical toxicity after radioembolization treatment was mild; 8 patients were asymptomatic, and 10 patients experienced fatigue. Two patients also had decreased appetite, and 1 patient experienced mild right upper quadrant pain. Mild, grade 1 and 2 biochemical toxicities were detected in < 50% of patients at the 3-month follow-up examination after the radioembolization. The most common biochemical toxicity was mildly elevated alkaline phosphatase (grade 1 and 2 toxicities) in 8 patients at the 3-month follow-up. The alkaline phosphatase level stayed mildly elevated in 7 patients at the 6-month follow-up and normalized in 1 patient. The Model for End-Stage Liver Disease score was not significantly different at the 3-month follow-up compared with the score before radioembolization (9.6 ± 5.1 vs10.2 ± 4.7, P = .74).

Baseline and follow-up contrast-enhanced cross-sectional imaging were available for 17 patients. The best radiographic responses of these 17 patients were evaluated by mRECIST criteria, which showed complete response in 16 patients and partial response in 1 patient. Analyzing the last available imaging of these 17 patients by mRECIST demonstrated complete response in 14 patients, partial response in 1 patient, and progression of disease in 2 patients (Fig 5). The images of a patient who underwent noncontrast CT showed stable disease as best response and stable disease on the last available imaging evaluated by RECIST.

Figure 5.

Contrast-enhanced arterial phase CT images of a 69-year-old man with metastatic RCC who underwent hepatic radioembolization. Image obtained before the procedure demonstrates multiple hyperenhancing tumors in both lobes of the liver. Images obtained 3, 6, and 30 months after hepatic radioembolization demonstrate no enhancement in the metastatic lesions, which is consistent with complete response by mRECIST criteria.

DISCUSSION

The presence of liver metastasis in patients with RCC indicates a very poor prognosis with a median overall survival of 7.6 months (3). At the present time, there is no specific recommended treatment for RCC liver metastases (2). Conventional treatments, such as chemotherapy, radiation, or cytokine therapy, have almost no influence on the progression of metastatic RCC (15). New therapeutic agents that block specific growth pathways have been developed and approved to treat metastatic RCC (16). Two of the approved drugs, temsirolimus and everolimus, block the mammalian target of rapamycin, a serine/threonine protein kinase that regulates cell growth, division, and survival (17). Other agents approved for RCC treatment, including pazopanib, sunitinib, sorafenib, and bevacizumab, target vascular endothelial growth factor–mediated pathways (16). These therapies targeted at the mammalian target of rapamycin and vascular endothelial growth factor demonstrated superior results over traditional cytokine therapy in patients with metastatic RCC with reported median overall survival ranges of 14.8–29.3 months, but these treatments are still lacking long-term survival benefit and carry risks of side effects (18–21).

In a selected group of patients, the resection of RCC liver metastases led to excellent survival benefit with a median survival of 142 months (7). Ruys et al (8) reported an overall survival of 33 months after hepatic RCC metastasectomy. These results are superior to the historical median survivals of 7.4 months and 7.6 months in patients with metastatic RCC to the liver and are consistent with the concept that controlling the liver disease is a key for long-term survival, although these are independent single-arm series, not direct comparisons (3,22). However, multifocality of the liver lesions, poor hepatic functional reserve, and presence of extrahepatic metastases exclude 95% of patients from surgery (8). Resection of hepatic metastases is also associated with a 2.3% postoperative mortality (6) and 21.5% major complication rate (23), and 50% of patients have recurrence of disease within 1 year after resection (24).

Transarterial liver-directed therapies are an alternative to hepatic metastasectomy that could be used even when the liver metastases are too numerous or unresectable because of their location and have a relatively low morbidity and mortality rate (9). Nabil et al (25) reported a series of 22 patients who underwent transarterial chemoembolization using mitomycin or mitomycin plus gemcitabine with ethiodized oil and degradable starch microspheres. The patients achieved a median survival of only 6.6 months from the start of transarterial chemoembolization treatment. Mild postembolization syndrome occurred in 10 patients (45%), and there were no major complications (25). Abdelmaksoud et al (11) used transarterial radio-embolization treatment with ⁹⁰Y-labeled resin microspheres in patients with metastatic RCC and reported a median survival of 12 months from the start of the treatment with no major complications. This study was limited to 6 patients. The best imaging response was evaluated by mRECIST, and 3 patients showed complete responses, and 1 patient showed a partial response. Two patients had rapid progression of disease and died within 2 months of treatment (11).

The current series includes 18 patients with liver-dominant metastatic RCC who were treated with radioembolization using ⁹⁰Y-labeled glass microspheres. These results show median survivals of 29 months from diagnosis of liver metastasis and 22.8 months from the start of radioembolization treatment, which appear significantly better than previously reported with liver-directed therapies (11,25). Radioembolization resulted in long-term complete response of RCC liver metastases in 82% of patients (14 of 17 patients; 1 patient did not have contrast-enhanced imaging), as there was no sign of recurrent liver metastasis up to the last follow-up imaging. Radioembolization treatment was well tolerated by the patients; only mild, grade 1 and 2, clinical and biochemical toxicities were observed, and there were no major complications.

These data are superior to data of any previously published treatment options except metastasectomy (7,8), but those data are achieved in a highly selected group of patients who were deemed to be surgical candidates, whereas transarterial radioembolization was used in a less selective manner including patients who were not surgical candidates. In addition, mortality and morbidity rates after radioembolization are lower compared with metastasectomy (6,23).

The main limitations of this study are its retrospective nature and low number of patients. In addition, this was a single-institution experience, and patient selection was at the preference of the clinical oncologists, which may have skewed the results.

In conclusion, these results suggest that radioembolization is safe and effective. Radioembolization treatment led to improved hepatic disease control and overall survival in patients with liver-dominant metastatic RCC.

ABBREVIATIONS

CI

confidence interval

mRECIST

modified Response Evaluation Criteria in Solid Tumors

RCC

renal cell carcinoma

⁹⁰Y

yttrium-90