Neuroendocrine tumors (NET) are a group of relatively slow-growing tumors that arise mostly in the pulmonary and gastrointestinal system.
Considered rare, their incidence has increased 6.3% in the last 25 years, with a prevalence of 35 per 100,000 patients. Because patients with these tumors generally present with vague symptoms, the diagnosis is often delayed by five to seven years. Due to delayed diagnosis, more than 46% of patients present with synchronous liver metastasis and another 25% develop disease during the follow-up period. Even though these tumors are believed to have a more indolent biology, the presence of liver metastasis decreases five-year survival rates from 75–90% to 20–40%. As a result, the treatment of metastatic lesions to the liver has become a major component of the overall treatment planning in these patients.
Despite its significance, the optimal treatment for metastatic lesions to the liver has remained controversial. In referral centers, such patients are commonly treated using a multidisciplinary approach. Surgical resection is preferred if greater than 90% of the disease can be safely removed. However, only 5–15% of patients with liver metastases are surgical candidates, and more than 50% recur after resection. Alternate treatment strategies have emerged — for example, liver-directed therapy including ablation, peptide receptor radionuclide therapy, embolization with (TACE) and without (TAE) chemotherapy or radioembolization (Y-90) to reduce tumor burden or palliate symptoms.
Liver-Directed Therapies
Transarterial bland embolization (TAE) entails using beads introduced via catheter to block tumor microvasculature, which results in ischemic damage and necrosis. The addition of chemotherapy to TAE, called transarterial chemoembolization (TACE), has been suggested to further improve survival outcome in some studies. More recently, radioembolization using Yttrium-90 (Y-90) has emerged as an alternative embolization technique that uses resin or glass microspheres (20-30 μm) loaded with Y-90, a radioisotope that emits pure beta radiation. The main advantages of Y-90 are a short half-life of 64 hours and a low mean penetrance depth of only 2-3 mm. Radiation is contained within the tumor bed, with relative sparing of the normal liver tissue. This leads to tumor damage by both ischemia as well as localized radiation.
Selecting the Right Therapy for Patients
Until recently, data confirming the superiority of one embolization technique over the other were lacking, with poorly defined criteria for patient selection. We sought to determine if the tumor proliferative index (Ki67 score) could be utilized to select patients for one therapy over the other. Collaborating with our oncologists, pathologists and radiologists, we conducted a study on all patients with NET treated at our institute with Y-90 or TAE/TACE between 2001 and 2014. Pathologists blinded to the clinical information performed Ki67 staining on tissue specimens. Among 72 patients (M:39, F:33; median age, 57 years) included in the study, the most common site of tumor origin was small bowel (n=35, 49%), and the most common histology subtype was carcinoid (n=58, 85%). Forty-four patients were treated with Y-90 (61%), and 28 patients received TAE/TACE (39%). Ki67 score was available in 28 patients (64%) treated with Y-90 and 16 patients (57%) in the TAE/TACE group.
We noted no significant difference in overall survival between patients treated with Y-90 and TACE (median, 69 versus 82 months, p=0.47). However, when adjusted for Ki67 score, we found that patients with Ki67 score ≥3% had better overall survival when treated with Y-90, and for patients with Ki67 <3%, survival was better when treated with TACE. Applying this knowledge, we hope to improve patient outcomes through personalized use of these liver-directed therapies.
