Hepatic Metastases Of Neuroendocrine Tumors Research Articles

Dose-response relationship after yttrium-90-radioembolization with glass microspheres in patients with neuroendocrine tumor liver metastases.

In radioembolization, response is achieved through the irradiation and damaging of tumor DNA. For hepatic metastases of neuroendocrine tumors, a dose-response relationship has not been established yet. This study assesses whether increasing tumor-absorbed doses lead to increased response rates. We included all patients who underwent yttrium-90 (90Y) glass microspheres radioembolization in our center if both pre- and post-treatment contrast-enhanced CT and post-injection PET/CT were available. Up to five hepatic tumors and the healthy hepatic tissue were delineated, and absorbed dose was quantified using post-injection PET/CT. Response was measured according to RECIST 1.1 on patient and tumor level. Linear mixed models were used to study the relationship between absorbed dose and response on tumor level. Logistic regression analysis was used on patient level to study dose-response and hepatic dose-toxicity relationships. A total of 128 tumors in 26 patients (31 procedures) were included in the response analysis. While correcting for confounding by tumor volume, a significant effect of response on dose was found (p = 0.0465). Geometric mean of absorbed dose for responding tumors was 170Gy, for stable disease 101Gy, and for progressive disease 67Gy. No significant dose-toxicity relationship could be identified. In patients with neuroendocrine tumor liver metastases, treated with 90Y-radioembolization, a clear dose-response relationship was found. We propose to perform 90Y-radioembolization with an absolute minimum planned tumor-absorbed dose of 150Gy.

Is there indication of liver transplantation in the unresectable metastases of neuroendocrine tumors?

Introduction: Neuroendocrine tumors are rare neoplasms that present bilateral liver metastases at diagnosis. Because of the good initial results obtained, liver transplantation is considered as a potentially curative treatment. The aim is to present our experience in liver transplantation in a series of 22 patients with unresectable bilateral hepatic metastases of neuroendocrine tumors and with previous resection of the primary tumor. Methods: We retrospectively reviewed the medical records of 22 patients (12 men and 10 women), with a mean age of 49,7 years, who underwent liver transplantation due to bilateral neuroendocrine liver metastases with previous resection of the primary tumour during 21 years. The most frequent location of the primary tumor was the pancreas in 13 patients (2 carcinoid, 3 gastrinoma, 1 glucagonoma and 8 non-functioning tumors). The remaining 9 tumors were located in the small bowel (7) and in the lung (2). Results: Only 1 patient died due to technical complications related to the transplant, representing a mortality rate for the entire group of 4,5 %. After a median follow-up of 11 years (range: 1 month-21 years), two patients died due to tumoral recurrence at 15 and 17 months. The survival rate at 3 and 5 years was 86% and 57%, respectively. Conclusions: In our series, the results the liver transplantation in the management of unresectable neuroendocrine liver metastases indicate that careful patient selection is required. The key to obtaining good results is individualization of the indication for this procedure.

Long-Term Toxicity after Transarterial Radioembolization with Yttrium-90 Using Resin Microspheres for Neuroendocrine Tumor Liver Metastases

PurposeTo evaluate long-term effects of yttrium-90 (90Y) transarterial radioembolization (TARE) for unresectable hepatic metastases of neuroendocrine tumors (NETs). Materials and MethodsRetrospective analysis of 93 patients (47 women, 46 men; mean age 59 y) who underwent resin-based 90Y TARE was performed. Variables associated with overall survival were analyzed using univariate and multivariate models. Changes in serologic values and imaging characteristics were assessed with long-term follow-up. ResultsUnilobar TARE was performed in 48 patients, and staged bilobar TARE was performed in 45 patients. In multivariate analysis, ascites (P = .002) and extrahepatic metastases (P = .038) at baseline were associated with poor survival. Among 52 patients who had > 1 year of follow-up, significant increases in alkaline phosphatase, aspartate aminotransferase, and alanine aminotransferase were observed; however, only 4 patients experienced grade 3 serologic toxicities. Imaging signs of cirrhosis-like morphology and portal hypertension were observed in 15 of 52 patients, more frequently in patients treated with bilobar TARE compared with unilobar TARE. Patients treated with bilobar TARE exhibited significantly increased hepatobiliary enzymes and decreased platelet count. Sustained increases in liver enzymes were observed in patients with > 4 years of follow-up. No radioembolization-related liver failure or grade 4 toxicity was observed. Conclusions90Y radioembolization using resin microspheres demonstrated a high safety profile for NET liver metastases, with low-grade, although sustained, long-term liver toxicity evident > 4 years after treatment. Bilobar treatment suggested a trend for treatment-related portal hypertension. Ongoing research will help define parameters for optimizing durable safety and efficacy of radioembolization in this setting.

Fine needle aspiration cytology of hepatic metastases of neuroendocrine tumors: A 20-year retrospective, single institutional study.

Fine needle aspiration (FNA) is considered an excellent technique for documenting metastatic neuroendocrine tumors (NETs). This study aims to evaluate the accuracy of FNA in diagnosing metastatic NETs to the liver and determining the grade and origin of these metastases. Our laboratory information system was searched from 1997 to 2016 to identify all cases of metastatic NETs to the liver that were sampled by FNA. The cytopathology and surgical pathology reports as well as the patients' electronic medical records were reviewed. The cytohistologic type and grade of the metastatic NETs, as well as the site of the patient's primary were recorded. High-grade NETs, including small cell and poorly differentiated neuroendocrine carcinomas, constituted 62% (167/271) of the cases, while low-grade NETs, including well differentiated NET (grade1 and grade 2), pheochromocytomas, paragangliomas, and carcinoid tumors of lung, constituted 38% (104/271) of cases. The most common diagnosis was metastatic small cell carcinoma accounting for 45% (122/271) of cases. The most common primary sites were lung (44%; 119/271) followed by pancreas (19%; 51/271). The FNA diagnosis was confirmed by histopathology in 121 cases that had a concurrent biopsies or resection specimens. FNA is an accurate method for diagnosing metastatic NETs to the liver. There were significantly more high-grade (62%) than low-grade (38%) metastatic NETs to the liver. In our practice, lung (44%) and pancreas (19%) were the most common primary sites of metastatic NETs involving the liver. In 16% of the cases, a primary site could not be established.

Intra-arterial radiopeptide therapy of hepatic metastases of neuroendocrine tumors: a systematic review

Hepatic metastases represent a frequent manifestation of systemic involvement of neuroendocrine tumors and, respectively, neuroendocrine cancers. In the last decade, therapeutic advances could be achieved using radiopeptide receptor-based therapies with 90Y-and 177Lu-radioligands as systemic therapy of this disease. As these conjugates are usually administered intravenously, only few medical centers so far have elucidated the potential benefits of administering these compounds intra-arterially with regard to more specific and effective hepatic treatment of these metastases. It is the aim of this review to provide a concise summary of to date literature on radiopeptide receptor therapy with special focus on intra-arterial administration. We conducted search in PubMed, Google Scholar and Cochrane databases to identify studies using intra-arterial administration (i.a.) of radiopeptide receptor therapies in neuroendocrine tumors. The used therapeutic procedures vary with regard to the used isotopes (e.g., 177Lu/90Y, 111In, 213Bi). Overall, the available evidence points to the fact that i.a. application of, e.g., 177Lu/90Y-DOTATOC causes an objective response rate which varies between 53 and 60% in i.a. application studies, whereas objective response in i.v. application studies published so far with various PRRT ligands cumulates to a maximum of 30%. Intra-arterial radiopeptide receptor therapy using 177Lu or 90Y for hepatic metastases of neuroendocrine tumors is a well-tolerated treatment option in patients suffering from multiple, non-resectable hepatic metastases. Since both loco-regional and systemic effects can be achieved by intra-arterial application of peptide-labeled radioactive isotopes, notably symptom control and treatment response seem to be superior to systemic i.v. protocols. The presented cohorts are nonetheless too small and treatment protocols too heterogenous to allow for an objective comparison.

Transplantation and Surgical Strategies in Patients With Neuroendocrine Liver Metastases: Protocol of Four Systematic Reviews

BackgroundHepatic metastases of neuroendocrine tumors (NETs) are considered a major prognostic factor associated with significantly reduced survival compared to patients without liver metastases. Several surgical and nonsurgical strategies are present to treat resectable and nonresectable liver metastases, some of which have the potential to cure liver mestatases.ObjectiveThe aims of the four systematic reviews presented in the paper are to determine the effectiveness of liver resection versus nonsurgical treatment of patients with NET liver metastases, to investigate the impact of neoadjuvant and adjuvant treatment options on the tumor-free survival, to assess the role of liver transplantation in patients presenting with unresectable bilateral hepatic metastases, and to evaluate the role of primary tumor resection in presence of unresectable liver metastases.MethodsLiterature search was performed on Medical Literature Analysis and Retrieval System Online, Excerpta Medica Database, and the Cochrane Library (Cochrane Database of Systematic Reviews, Database of s of Reviews of Effects, and Cochrane Central Register of Controlled Trials). No language restrictions were applied. Randomized controlled trials, prospective and retrospective comparative cohort studies, and case-control studies will be used for the qualitative and quantitative synthesis of the systematic reviews. Case series will be only included in a separate database for descriptive purposes.ResultsThis study is ongoing and presents a protocol system of four systematic reviews that will assist in determining the effectiveness of liver resection versus nonsurgical treatment of patients with NET liver metastases. This study is also assumed to investigate the impact of neoadjuvant and adjuvant treatment options on the tumor-free survival, the role of liver transplantation, and the relevance of primary tumor resection in presence of unresectable liver metastasis.ConclusionsThe systematic reviews will show the current evidence based on the effectiveness of surgical strategies in patients with NET liver metastases and serve as basis for clinical practice guidelines.Trial RegistrationThe systematic reviews have been prospectively registered with the International Prospective Register of Systematic Reviews: liver resection (CRD42012002652); http://www.crd.york.ac.uk/prospero/display_record.asp?ID=CRD42012002652 (Archived by WebCite at http://www.webcitation.org/6LQUqMnqL,). neoadjuvant and adjuvant treatment strategies (CRD42012002656); http://www.crd.york.ac.uk/prospero/display_record.asp?ID=CRD42012002656 (Archived by WebCite at http://www.webcitation.org/6LQVvEHuf). liver transplantation (CRD42012002655); http://www.crd.york.ac.uk/prospero/display_record.asp?ID=CRD42012002655 (Archived by WebCite at http://www.webcitation.org/6LQW7WFo3,). resection of the locoregional primary NET (CRD42012002654); http://www.crd.york.ac.uk/prospero/display_record.asp?ID=CRD42012002654 (Archived by WebCite at http://www.webcitation.org/6LQWEIuGe).

31p Mr Spectroscopy to Evaluate the Efficacy of Hepatic Artery Embolization in the Treatment of Neuroendocrine Liver Metastases

It is common to treat patients with metastatic disease from gastrointestinal neuroendocrine (NE) tumors with surgical reduction to prolong survival. This can be combined with hepatic arterial embolization (HAE) and medical treatment to reduce hormonal symptoms. Today there are no rapid and reliable methods to evaluate the efficacy of HAE in the treatment of neuroendocrine liver metastasis. To investigate metabolic changes in hepatic metastases of NE tumors following HAE, and to establish if there are any early spectral patterns that might indicate therapeutic efficacy based on in vivo (31)P MRS data. Volume selective (31)P MRS was used to study 11 patients with disseminated NE tumors with regional lymph nodes and bilobar liver metastases. Measurements were performed before and 1 and 3 days after HAE. Non-responders had significantly higher PME/Pi and αNTP/ΣNTP ratios than the responders before HAE (P < 0.05). Three days after HAE, non-responders still had significantly higher αNTP/ΣNTP than the responders did (P < 0.05). We also observed trends for increased PME ratios 3 days after HAE, decreased ATP-levels, and liberated Pi in responders. This (31)P-MRS study showed significant differences in PME/Pi and αNTP/ΣP ratios between responders and non-responders on the day before HAE, which is an interesting finding that may reflect intrinsic properties of the tumor tissue. We also observed trends for cell membrane renewal and increased energy consumption in responders after HAE. These results demonstrate potentials for (31)P-MRS to predict individual responsiveness prior to HAE.

Radioembolization in the Treatment of Neuroendocrine Tumor Metastases to the Liver

Surgical excision remains the preferred treatment for resectable hepatic metastases of neuroendocrine tumors. In cases of more disseminated hepatic disease, transarterial radioembolization with Yttrium-90- (90Y-) labeled microspheres has been demonstrated as a viable option for symptom and locoregional tumor control. On an outpatient basis, radioembolization can be utilized from early line to salvage phases, in various combinations with systemic therapies. Review of available data shows encouraging safety and efficacy profiles for the intraarterial application of 90Y for the treatment of mNETs of the liver. Symptom control and decrease in somatostatin analog use can be achieved, as well as prolonged survival.

Fractionation, dose selection, and response of hepatic metastases of neuroendocrine tumors after 90Y-microsphere brachytherapy

Purpose: We present novel approaches in the use of 90Y-microspheres for unresectable liver metastases from a variety of neuroendocrine tumors. Standard use of microspheres is to apply once, typically to a single lobe, followed a month or so later with treatment of the other lobe. We have used them differently, implanting all the tumors during each treatment, i.e., whole liver. A second and third treatment were given to gain control of large hepatic lesions.

Ki67, E-cadherin, and p53 as prognostic indicators of long-term outcome after liver transplantation for metastatic neuroendocrine tumors.

Patients suffering from hepatic metastases of neuroendocrine tumors (NET) are potential candidates for orthotopic liver transplantation. Because recurrence rates are high and outcome is variable, prognostic indicators are required. The aim of our study was to identify predictors of long-term survival with a focus on the impact of tumor biology. We retrospectively analyzed 19 patients who received an orthotopic liver graft for metastatic NET at the Medizinische Hochschule Hannover. Expression of Ki67, E-cadherin, and p53 was studied immunohistochemically in metastases of neuroendocrine tumors of the explanted livers. Patients were followed up to 146 months after liver transplantation. Six patients died during follow-up. The resulting 1-, 5-, and 10-year survival rates are 89%, 80%, and 50%, respectively. All deaths during long-term follow-up were tumor-associated. Recurrence was diagnosed in 12 patients between 2 weeks and 48 months after liver transplantation. Three patients are without tumor recurrence more than 8 years after liver transplantation. Survival in the 5 patients with low Ki67 and regular E-cadherin staining was significantly better than in the 12 patients with high Ki67 or aberrant E-cadherin expression (7-year survival 100% vs. 0%, respectively, log rank P=0.007). p53 expression did not significantly improve prognostic accuracy. We conclude that analysis of Ki67 and E-cadherin expression may improve the identification of patients with a favorable prognosis after liver transplantation for metastatic neuroendocrine tumors.

Therapeutic Alternatives in Metastatic Neuroendocrine Tumors

In the treatment of neuroendocrine tumors that cannot be resected for cure two goals must be addressed: (1) the control of symptoms related to hormonal hypersecretion and (2) the prolongation of survival by destruction of tumor of the limitation of its growth. Clinical approaches, medical and surgical, have been developed in recent years to meet these goals. Surgical options in the face of metastatic disease include resection of hepatic metastases, cryoablation, and liver transplantation. Medical therapy includes treatment of symptomatic hypersecretory states and systemic chemotherapeutic and immunomodulatory regimes. Hepatic artery chemoembolization has also been used successfully in the treatment of hepatic metastases of neuroendocrine tumors.

Treatment of liver metastases in patients with neuroendocrine tumors.

Hepatic metastases of neuroendocrine tumors demand differentiated therapeutic management due to the unique natural course and hormone secretion of the tumors. The purpose of the prospective nonrandomized study was to review the institutional experience with surgical treatment of hepatic neuroendocrine metastases. From September 1992 until March 1996 29 consecutive patients with neuroendocrine tumors have been evaluated for surgical treatment of liver metastases. Of them, 11 (37.9%) fulfilled criteria for surgical treatment of hepatic secondary tumors. Extensive preoperative workup was carried out. Patients were divided in groups for curative or palliative resection. Liver transplantation was carried out in selected patients with disseminated liver metastases. Of 29 patients 4 (13.7%) underwent curative resection and in 3 patients (10.3%) palliative resection was performed. The patients who underwent curative resection are all biochemically and clinically tumor free at a mean postoperative follow-up of 22.3 months. Two patients who underwent palliative resection are alive at 40 and 29 months, respectively. From 12 patients evaluated for liver transplantation 4 were considered as suitable candidates. Liver resection can be recommended in patients with hepatic metastases of neuroendocrine tumors in terms of potential survival prolongation and palliation. Liver transplantation is generally acceptable treatment in highly selected group of these patients. Long-term results have to be awaited before definitive proof of the beneficial effect of surgical treatment.

Differentiation between multiple liver hemangiomas and liver metastases of gastrinomas: value of enhanced MRI.

Hepatic metastases of neuroendocrine tumors are known to mimic hemangiomas on nonenhanced SE MR sequences. The usefulness of MR examination with gadolinium injection to identify lesions was prospectively evaluated. Nine patients with multiple liver metastases of gastrinomas were compared with six patients showing multiple liver hemangiomas. Patients underwent unenhanced T2-weighted SE, T1-weighted SE, and FLASH sequences, followed by enhanced sequential FLASH sequences and a 5 min delayed T1-weighted SE sequence. On T2-weighted SE sequence, all hemangiomas displayed the same typical morphology as a sharply defined, homogeneous, high signal intensity lesion, but this pattern was also observed for some or all of the lesions in seven of nine patients with gastrinoma metastases. Dynamic FLASH sequences were accurate for lesions larger than 2 cm, hemangiomas displaying a nodular peripheral enhancement with centripetal filling in, and metastases displaying either an initial homogeneous or a regular peripheral enhancement. Precise assessment of lesions smaller than 2 cm remained equivocal. Delayed T1-weighted. SE sequence (performed at least 5 min after Gd-chelate injection) was the most accurate technique to identify metastases by showing hypo- or isointensity signal, whereas all hemangiomas were hyperintense. Postcontrast delayed T1-weighted sequence is the primary technique to differentiate equivocal cases of hemangiomas from metastases of gastrinoma.