Radioembolization for Neuroendocrine Liver Metastases: Safety, Imaging, and Long-Term Outcomes

Abstract & Commentary

By Samir P. Kanani, MD, Associate Clinical Professor of Neurosurgery and Radiation Oncology, George Washington University, Radiation Oncology, Inova Fairfax Hospital, Falls Church, VA. Dr. Kanani reports no financial relationships relevant to this field of study.

Synopsis: In a retrospective series, 40 patients with liver-dominant metastatic neuroendocrine tumors were treated with 90Y radioembolization between 2003 and 2007 at a single institution. Response to therapy was assessed by World Health Organization (WHO) guidelines for size and European Association for the Study of the Liver disease (EASL) guidelines for necrosis. Time to response and overall survival were calculated using the Kaplan-Meier method. The median dose was 113 Gy. Clinical toxicities included fatigue (63%), nausea/vomiting (40%), abdominal pain (18%), fever (8%), and diarrhea and weight loss (5%); Grade 3 and 4 bilirubin toxicities were experienced by two patients and one patient, respectively. Different responses were noted by WHO (complete response, 1.2%; partial response, 62.7%) and EASL (complete response, 20.5%; partial response, 43.4%). Median time to response was 4 and 4.9 months by lesion and patient, respectively. The 1-, 2-, and 3-year overall survival rates were 72.5%, 62.5%, and 45%, respectively. Eastern Cooperative Oncology Group (ECOG) performance score 0 (P < 0.0001), tumor burden ≤ 25% (P = 0.0019), albumin > 3.5 g/dL (P = 0.017), and bilirubin ≤ 1.2 mg/dL (P = 0.002) prognosticated survival on univariate analysis; only ECOG performance score 0 and bilirubin ≤1.2 mg/dL prognosticated better survival outcome on multivariate analysis (P < 0.0001 and P = 0.02). The authors conclude that Yttrium-90 therapy for hepatic neuroendocrine metastases leads to satisfactory tumor response and patient survival with low toxicity, in line with published national guidelines.

Source: Memon K, et al. Radioembolization for neuroendocrine liver metastases: Safety, imaging, and long-term outcomes. Int J Radiat Biol Phys 2012;83:887-894.

Forty patients with liver-dominant metastatic neuroendocrine tumors (mNETs) were enrolled in this study between 2003 and 2007. This study represents a retrospective review of prospectively collected data. The study inclusion criteria included 1) unresectable mNETs refractory to systemic treatment as determined by oncology and interventional radiology with imaging-confirmed progressive disease, 2) Eastern Cooperative Oncology Group (ECOG) performance score ≤ 2, and 3) adequate hematologic, renal, and liver function (bilirubin ≤ 2.0 mg/dL). Exclusion criteria included: 1) significant extrahepatic disease, 2) evidence of uncorrectable gastrointestinal shunting observed on angiography or technetium-labeled macroaggregated albumin scans, 3) the possibility of estimated lung dose to be > 30 Gy in a single session, and 4) concurrent chemotherapy or radiotherapy. One-third of the patients had minimal extrahepatic disease, 62% had symptoms of carcinoid, and 22% had prior liver directed therapy. In patients taking octreotide, this agent was not stopped for 90Y therapy.

The patients’ treatment consisted of a pretreatment angiogram to determine aberrant shunting of blood from the liver to the lung and also embolization of aberrant vessels. Patients also underwent a nuclear medicine scan consisting of Technetium-labeled macoaggregated albumin to estimate the lung shunt fraction. Patients were then treated with 90Y using a lobar approach with 38/40 patients receiving bilobar therapy. Prophylactic octreotide (200 mg subcutaneous) was administered to all patients immediately before radioembolization.

All patients were evaluated by history, physical examination, laboratory values, and radiologic imaging 4 weeks after treatment and then every 2 to 3 months. The toxicity included fatigue in 25 (63%), abdominal pain in 7 (18%), nausea and vomiting in 16 (40%), fever and chills in 3 (8%), and diarrhea and weight loss in 2 (5%) patients. One patient experienced Grade 4 bilirubin toxicity, and 15 (38%) experienced Grade 3 lymphocyte toxicity. One patient experienced radiation cholecystitis requiring cholecystectomy. Of all lesions, 94% showed at least some decrease in size, whereas 64% of lesions showed > 50% reduction in size. The median time to response (WHO) was 4 months by lesion and 4.9 months by patient. Of 25 patients symptomatic at baseline, 21 (84%) reported subjective improvement after treatment. The median follow-up time was 27 months. The median overall survival time was 34.4 months. The 1-, 2-, and 3-year survival rates for all patients were 72.5%, 62.5%, and 45%, respectively, from 90Y treatment. On multivariate analysis, only ECOG performance score 0 and bilirubin < 1.2 mg/dL independently predicted better survival.

Commentary

Well-differentiated gastroenteropancreatic neuroendocrine tumors generally are considered indolent tumors with a prolonged natural history. However, among patients with liver metastasis the survival can be variable. We all have these patients at our clinics who survive many years without symptoms or progression and others who progress rapidly. Most patients who have liver metastasis are symptomatic from hypersecretion rather than the presence of tumor in their liver. These symptoms are often controlled with octreotide. Systemic options such as streptozocin, dacarbazine, temozolomide, oxaliplatin, capecitabine, bevacizumab, and small molecule TK inhibitors all have been investigated after progression on octreotide and show limited potential. Recent studies evaluating everolimus have demonstrated some promise.1

Yttrium-90 device (TheraSphere, MDS Nordion, Canada) currently is FDA-approved for patients with unresectable hepatocellular carcinoma.2 It consists of 20-30 micrometer-sized nonbiodegradable glass microspheres in which Yttrium is the integral constituent. Yttrium-90 is a pure beta emitter with a half-life of 64.1 hours. The current study demonstrates an encouraging median survival in a group of patients who remain symptomatic after initiating octreotide therapy. The current study compares favorably with other reports in the literature using Y90 radioembolization. In a multi-institutional study with 42 patients treated with Y90, Rhee et al found a median survival of 25 months, with 50% demonstrating radiologic response.3 In another retrospective multi-institutional study, Kennedy et al investigated Y90 microsphere treatment in 148 patients. They reported a median survival time of 70 months, with a radiographic response rate of 60.5%.4 This study, along with a number of previous studies, demonstrates the safety and efficacy of radioembolization in the management of patients with metastatic carcinoid. The procedure should be considered an option in symptomatic patients who progress on octreotide. In my opinion, it is better tolerated than other locoregional therapies, such as chemoembolization or bland embolization, although they have never been compared in a randomized fashion.

References

1. Pavel ME, et al. Everolimus plus octreotide long-acting repeatable for the treatment of advanced neuroendocrine tumours associated with carcinoid syndrome (RADIANT-2): A randomized, placebo-controlled, phase 3 study. Lancet 2011;378:2005-2012.

2. Salem R, et al. Yttrium-90 microspheres: Radiation therapy for unresectable liver cancer. J Vasc Interv Radiol 2002;13(9 Pt 2):S223-S229.

3. Rhee TK, et al. 90Y Radioembolization for metastatic neuroendocrine liver tumors: Preliminary results from a multi-institutional experience. Ann Surg 2008;247:1029-1035.

4. Kennedy AS, et al. Radioembolization for unresectable neuroendocrine hepatic metastases using resin 90Y microspheres: Early results in 148 patients. Am J Clin Oncol 2008;31:271-279.