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Neuroendocrine Hepatic Metastases: Does Aggressive Management Improve Survival?
Abstract
The aim of this study was to determine whether aggressive management of neuroendocrine hepatic metastases improves survival.
Survival in patients with carcinoid and pancreatic neuroendocrine tumors is significantly better than adenocarcinomas arising from the same organs. However, survival and quality of life are diminished in patients with neuroendocrine hepatic metastases. In recent years, aggressive treatment of hepatic neuroendocrine tumors has been shown to relieve symptoms. Minimal data are available, however, to document improved survival with this approach.
The records of patients with carcinoid (n = 84) and pancreatic neuroendocrine tumors (n = 69) managed at our institution from January 1990 through July 2004 were reviewed. Eighty-four patients had malignant tumors, and hepatic metastases were present in 60 of these patients. Of these 60 patients, 23 received no aggressive treatment of their liver metastases, 19 were treated with hepatic resection and/or ablation, and 18 were managed with transarterial chemoembolization (TACE) frequently (n = 11) in addition to resection and/or ablation. These groups did not differ with respect to age, gender, tumor type, or extent of liver involvement.
Median and 5-year survival were 20 months and 25% for the Nonaggressive group, >96 months and 72% for the Resection/Ablation group, and 50 months and 50% for the TACE group. The survival for the Resection/Ablation and the TACE groups was significantly better (P < 0.05) when compared with the Nonaggressive group. Patients with more than 50% liver involvement had a poor outcome (P < 0.001).
These data suggest that aggressive management of neuroendocrine hepatic metastases does improve survival, that chemoembolization increases the patient population eligible for this strategy, and that patients with more than 50% liver involvement may not benefit from an aggressive approach.
... It is estimated that almost 80%-90% of these tumors are inoperable at the time of presentation [1]. However, several studies have demonstrated that resection of hepatic metastasis from NETs improves both quality of life and prolongs 5-year survival [2,3]. These studies demonstrated that aggressive management of hepatic neuroendocrine metastases with adjunct modalities such as transarterial embolization, chemoembolization, and thermal ablation significantly prolong long-term survival and improve patient outcomes [2,4]. ...
... However, several studies have demonstrated that resection of hepatic metastasis from NETs improves both quality of life and prolongs 5-year survival [2,3]. These studies demonstrated that aggressive management of hepatic neuroendocrine metastases with adjunct modalities such as transarterial embolization, chemoembolization, and thermal ablation significantly prolong long-term survival and improve patient outcomes [2,4]. Despite these findings there is hesitancy among surgeons to utilize radiofrequency ablation due to fear of bleeding, abdominal infections, and biliary tree injury [5,6]. ...
... Treatment algorithms for hepatic NETs metastases have changed over time. Non-operative management with chemotherapy, external beam radiation, and octreotide has been shown to be significantly inferior to surgical management [2]. Touzios et al [2] demonstrated that patients who did not undergo surgery had a median survival of 20 months while patients who underwent resection with or without ablation had a median survival of greater than 96 months. ...
BACKGROUND
Resection of hepatic metastasis from neuroendocrine tumors (NETs) improves quality of life and prolongs 5-year survival. Ablation can be utilized with surgery to achieve complete resection. Although several studies report long-term outcomes for patients undergoing ablation, none have explored perioperative effects of ablation in patients with metastatic NETs.
AIM
To determine if intra-operative ablation during hepatectomy increases risk of adverse outcomes such as surgical site infections (SSIs), bleeding, and bile leak.
METHODS
A retrospective analysis of the hepatectomy National Surgical Quality Improvement Program database from 2015-2019 was performed to determine the odds of SSIs, bile leaks, or bleeding in patients undergoing intraoperative ablation when compared to hepatectomy alone.
RESULTS
Of the 966 patients included in the study, 298 (30.9%) underwent ablation during hepatectomy. There were 78 (11.7%) patients with SSIs in the hepatectomy alone group and 39 (13.1%) patients with a SSIs in the hepatectomy with ablation group. Bile leak occurred in 41 (6.2%) and 14 (4.8%) patients in the two groups, respectively; bleeding occurred in 117 (17.5%) and 33 (11.1%), respectively. After controlling for confounding variables, ablation did not increase risk of SSI (P = 0.63), bile leak (P = 0.34) or bleeding (P = 0.07) when compared to patients undergoing resection alone on multivariate analysis.
CONCLUSION
Intraoperative ablation with hepatic resection for NETs is safe in the perioperative period without significant increased risk of infection, bleeding, or bile leak. Surgeons should utilize this modality when appropriate to achieve optimal disease control and outcomes.
... The long-term prognosis of patients with G1/G2 GEP-NET liver metastases without extrahepatic metastases is consistently reported to be improved by hepatectomy with curative intent. [10][11][12][175][176][177][178][179][180][181][182][183][184][185][186] A systematic review and meta-analysis were performed to evaluate the effectiveness of hepatectomy for liver metastases from GEP-NET. ...
... In the previous reports of hepatectomy for liver metastases from GEP-NET, the 5-and 10-year OS rates reached 71% (31%-100%) and 42% (0%-100%), respectively. [10][11][12][175][176][177][178][179][180][181][182][183][184][185][186] In contrast to these encouraging results, the 3-, 5-, and 10year rates of RFS were 32% (24%-69%), 29% (6%-66%), and 1% (0%-11%), respectively. [10][11][12][175][176][177][178][179][180][181][182][183][184][185][186] Although hepatectomy for liver metastases from GEP-NET has consistently been reported to be effective, the evidence level was low due to small patient numbers and probable bias in patient selection. ...
... [10][11][12][175][176][177][178][179][180][181][182][183][184][185][186] In contrast to these encouraging results, the 3-, 5-, and 10year rates of RFS were 32% (24%-69%), 29% (6%-66%), and 1% (0%-11%), respectively. [10][11][12][175][176][177][178][179][180][181][182][183][184][185][186] Although hepatectomy for liver metastases from GEP-NET has consistently been reported to be effective, the evidence level was low due to small patient numbers and probable bias in patient selection. We accepted 11 cohort studies for a meta-analysis comparing outcomes between those receiving hepatectomy and those treated without hepatectomy; we evaluated the rates of 5-year OS, relief of symptoms, and postoperative complications. ...
Background
Hepatectomy is standard treatment for colorectal liver metastases; however, it is unclear whether liver metastases from other primary cancers should be resected or not. The Japanese Society of Hepato‐Biliary‐Pancreatic Surgery therefore created clinical practice guidelines for the management of metastatic liver tumors.
Methods
Eight primary diseases were selected based on the number of hepatectomies performed for each malignancy per year. Clinical questions were structured in the population, intervention, comparison, and outcomes (PICO) format. Systematic reviews were performed, and the strength of recommendations and the level of quality of evidence for each clinical question were discussed and determined. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used to assess evidence and make recommendations.
Results
The eight primary sites were grouped into five categories based on suggested indications for hepatectomy and consensus of the guidelines committee. Fourteen clinical questions were devised, covering five topics: (1) diagnosis, (2) operative treatment, (3) ablation therapy, (4) the eight primary diseases, and (5) systemic therapies. The grade of recommendation was strong for one clinical question and weak for the other 13 clinical questions. The quality of the evidence was moderate for two questions, low for 10, and very low for two.
A flowchart was made to summarize the outcomes of the guidelines for the indications of hepatectomy and systemic therapy.
Conclusions
These guidelines were developed to provide useful information based on evidence in the published literature for the clinical management of liver metastases, and they could be helpful for conducting future clinical trials to provide higher‐quality evidence.
... It should not be attempted unless at least 90% of the lesions can be safely removed. In a study of 170 patients, hepatic resection improved symptoms in over 90% of cases Touzios et al. 2005;Chamberlain et al. 2000;Sarmiento and Que 2003). Reported survival rates for this approach have been greater than 60% at 5 years, which is double that of patients with untreated liver metastases (Touzios et al. 2005;Chamberlain et al. 2000). ...
... In a study of 170 patients, hepatic resection improved symptoms in over 90% of cases Touzios et al. 2005;Chamberlain et al. 2000;Sarmiento and Que 2003). Reported survival rates for this approach have been greater than 60% at 5 years, which is double that of patients with untreated liver metastases (Touzios et al. 2005;Chamberlain et al. 2000). ...
... [1][2][3] Metastasis, particularly to the liver, is associated with poorer survival. 4,5 The management of metastatic PNET is frequently multimodal and may include somatostatin-analog therapy, liverdirected therapies, cytoreductive-surgery, chemotherapy, and peptide-receptor radionucleotide therapy. 4 Surgery has been advocated when >90%, or more recently >70% of visible tumor can be removed safely. ...
... Such studies are limited, however, by selection bias and study groups are difficult to match in the absence of accurate quantification of pre-and post-treatment disease burden. [3][4][5][6] Indeed, imaging or serum biomarkers with a strong predictive capacity for disease burden, survival or response to therapy remain elusive. ...
Background:
Studies supporting surgical management of metastatic pancreatic neuroendocrine tumor (PNET) are limited by selection bias. Chromogranin A (CgA) has been used as a biomarker for PNET and may reflect disease burden or biology. This study aimed to correlate CgA level with overall survival and to use it to match patients selected for different treatment approaches in an analysis of the impact of surgical management.
Methods:
1478 patients diagnosed with PNET in the National Cancer Database (2004-2014) were retrospectively identified, and logistic regression analyses were used to evaluate associations between the presence of metastatic disease and CgA level. After matching patients by CgA level and other factors predictive of surgical management, Kaplan-Meier survival analysis was performed.
Results:
Median CgA level was significantly higher in metastatic versus localized PNET(169 ng/mL versus 66 ng/mL, p < 0.001). On multivariate logistic regression, CgA level was predictive of metastatic disease(OR 1.002, p < 0.001) and survival in metastatic and non-metastatic patients. After matching for CgA level, surgery was associated with improved overall survival.
Discussion:
CgA level is predictive of the presence of distant metastatic disease and overall survival in PNET. When matched by CgA and other predictors of treatment approach, patients with metastatic PNET undergoing surgery have improved survival.
... Interestingly, Prospective research shows that serial serum Carcinoembryonic antigen (CEA) testing is the most reliable screening method for identifying colorectal liver metastases. 17 Lung cancer was the second most frequent primary tumor for patients with hepatic metastasis followed by breast cancer, this sequence is similar to the result of other studies 6 and different from another study 18 . This could be related to the difference of the incidence of these cancers in these counties. ...
... The tumor burden is another key factor: a liver involvement of more than 50% is associated with poor prognosis both after liver resection and after transplantation [26,27]. In a series from Le Treut et al., hepatomegaly, defined as an explanted liver volume of more than 20% greater than the standard liver volume, was an independent predictor of poor prognosis [17]. ...
Opinion statement
Transplant oncology is a new field of medicine referred to the use of solid organ transplantation, particularly the liver, to improve prognosis and quality of life in cancer patients. In unresectable, liver-only metastases from neuroendocrine tumors (NETs) of the digestive tract, liver transplantation represents a competitive chance of cure. Due to the limited resource of donated organs, accurate patients’ selection is crucial in order to maximize transplant benefit. Several tumor- and patient-related factors should be considered. Among them, primary tumors with a low grade of differentiation (G1-G2 or Ki67 < 10%), located in a region drained by the portal system and removed before transplantation with at least 3–6 months period of disease stability observed before transplant listing, can be considered for transplantation. In case of NET located in the pancreas, extended lymphadenectomy should complement curative pancreatic resection. A number of other features are described in this review of liver transplantation for NET metastases. Comprehensive approach including various forms of non-surgical treatment and detailed planning and timing of total hepatectomy are discussed. Open issues remain on possible expansion of current criteria while maintaining the same long-term benefit demonstrated with the Milan NET criteria with respect to other non-transplant options, with particular reference to liver resection, peptide receptor radionuclide therapy, and locoregional and systemic treatments.
... In our series, in the same surgical session, 87% of M1 patients received an associated liver surgery and/or ablation, with surgical morbidity and hospital stay similar to patients undergoing a pancreatic resection only. The resection and/or ablation of liver metastases may improve 5-year OS from 25% to 72% compared to nonoperated patients [47]; from the analysis of more than 2000 pNENs of the SEER database, Franko et al. reported the greatest survival benefit for patients who underwent resection of both primary pNEN and liver metastases (p < 0.001) [24]. Therefore, our study confirmed previously reported data of an association between survival and surgical treatment among selected patients with both localized and metastatic disease. ...
Background:
Pancreatic neuroendocrine neoplasms (pNENs) are often detected as large primary lesions, even with distant metastases, and their prognosis may be difficult to predict.
Methods:
In this retrospective study, we retrieved data of patients treated for a large pNEN in our Surgical Unit (1979-2017) to evaluate the possible prognostic role of clinic-pathological features and surgery. Cox-proportional hazard regression models were used to find possible associations among some variables (clinical features, surgery, and histology) and survival at univariate and multivariate analyses.
Results:
Among 333 pNENs, we identified 64 patients (19%) with a lesion > 4 cm. Patients' median age was 61 years, median tumor size was 6.0 cm, and 35 (55%) patients had distant metastases at diagnosis. There were 50 (78%) nonfunctioning pNENs, and 31 tumors localized in the body/tail region of the pancreas. Overall, 36 patients underwent a standard pancreatic resection (with 13 associated liver resection/ablation). Regarding histology, 67% of pNENs were N1, and 34% were grade 2. After a median follow-up of 48 months (up to 33 years), 42 patients died of disease. Median survival after surgery was 79 months, and six patients experienced recurrence (median DFS 94 months). At multivariate analysis, distant metastases were associated with a worse outcome, while having undergone radical tumor resection was a protective factor.
Conclusions:
In our experience, about 20% of pNENs have a size > 4 cm, 78% are nonfunctioning, and 55% show distant metastases at diagnosis. Nevertheless, a long-term survival of more than five years may be achieved after surgery.
... Although the biological behavior and treatment of pNEC are very different from PDAC and often associated with a better prognosis, it has a significant risk of distant metastasis, even higher than PDAC. It has been mentioned in the literature that pNEC is often accompanied by metastasis, presenting with synchronous metastases in up to 65% of patients (37), aggressive treatment (surgery, radio-frequency ablation, etc.) will prolong the survival of patients with pNEC even in the presence of liver metastases (38,39). Regarding the impact of PDAC location on A B D C FIGURE 6 The calibration curves of the nomogram for the 6 (A), 12 (B), and 18 months (C) in the validation set. ...
Objective
Cancer of the pancreas is a life-threatening condition and has a high distant metastasis (DM) rate of over 50% at diagnosis. Therefore, this study aimed to determine whether patterns of distant metastases correlated with prognosis in pancreatic ductal adenocarcinoma (PDAC) with metastatic spread, and build a novel nomogram capable of predicting the 6, 12, 18-month survival rate with high accuracy.
Methods
We analyzed data from the Surveillance, Epidemiology, and End Results (SEER) database for cases of PDAC with DM. Kaplan-Meier analysis, log-rank tests and Cox-regression proportional hazards model were used to assess the impact of site and number of DM on the cancer-specific survival (CSS) and over survival (OS). A total of 2709 patients with DM were randomly assigned to the training group and validation group in a 7:3 ratio. A nomogram was constructed by the dependent risk factors which were determined by multivariate Cox-regression analysis. An assessment of the discrimination and ability of the prediction model was made by measuring AUC, C-index, calibration curve and decision curve analysis (DCA). In addition, we collected 98 patients with distant metastases at the time of initial diagnosis from Ningbo University Affiliated LiHuili Hospital to verify the efficacy of the prediction model.
Results
There was a highest incidence of liver metastases from pancreatic cancer (2387,74.36%), followed by lung (625,19.47%), bone (190,5.92%), and brain (8,0.25%). The prognosis of liver metastases differed from that of lung metastases, and the presence of multiple organ metastases was associated with poorer prognosis. According to univariate and multivariate Cox-regression analyses, seven factors (i.e., diagnosis age, tumor location, grade of tumor differentiation, T-stage, receipt of surgery, receipt of chemotherapy status, presence of multiple organ metastases) were included in our nomogram model. In internal and external validation, the ROC curves, C-index, calibration curves and DCA were calculated, which confirmed that this nomogram can precisely predict prognosis of PDAC with DM.
Conclusion
Metastatic PDAC patients with liver metastases tended to have a worse prognosis than those with lung metastases. The number of DM had significant effect on the overall survival rate of metastatic PDAC. This study had a high prediction accuracy, which was helpful clinicians to analyze the prognosis of PDAC with DM and implement individualized diagnosis and treatment.
... Resection with curative intent is the gold standard for LMs of neuroendocrine neoplasia, with a 5-year survival rate of 60%-80%, low mortality (0%-5%) and morbidity (30%) (46). Patients whose LMs were not resected have a very poor prognosis with a 5-year survival rate of only 30% (47). The conditions for resection with curative intent are limited and are present in only 10%-25% of patients (46). ...
Liver metastases (LM) occur in up to 90% either simultaneously with the diagnosis of the primary tumor or at a later time-point. While resection of colorectal LM and resection or transplantation of neuroendocrine LM is part of a standard therapy with a 5-year patient survival of up to 80%, resection of non-colorectal and non-neuroendocrine LM is still discussed controversially. The reason for it is the significantly lower survival benefit of all different tumor entities depending on the biological aggressiveness of the tumor. Randomized controlled trials are lacking. However, reviews of case series with ≥100 liver resections are available. They show a 5-year patient survival of up to 42% compared to only <5% in patients without treatment. Risk factors for poor survival include the type of primary tumor, a short interval between resection of the primary tumor and liver resection, extrahepatic manifestation of the tumor, number and size of the LM, and extent of liver resection. Overall, it has recently been shown that a good patient selection, the technical advances in surgical therapy and the use of a risk score to predict the prognosis lead to a significantly better outcome so that it is no longer justified not to offer liver resection to patients with non-colorectal, non- endocrine LM. Since modern therapy of LM is multimodal, the optimal therapeutic approach is decided individually by a multidisciplinary team consisting of visceral surgeons, oncologists, interventional radiologists and radiologists as part of a tumor board.
... [1] Neuroendocrine tumors are uncommon, slow-growing neoplasms with incidence of 1-2 in 100,000 patients. [2][3][4] Carcinoid tumors were described first in 1882. In 1930, it was classified and designated as bronchial adenoma. ...
Introduction:
Carcinoid tumors are malignant neoplasms of neuroendocrine cells. This study tended to evaluate the demographic and rare clinical characteristics of patients with thoracic carcinoid tumor during 2006-2016 at Razi and Aria Hospitals in Rasht.
Materials and methods:
The present study was performed on records of 43 patients with lung carcinoid tumors referred to Razi and Aria Hospitals of Rasht during 2006-2016. Information on age, gender, rare clinical symptoms, smoking history, diagnosis tools, treatment, and outcome were analyzed.
Results:
Of 43 patients treated with definitive diagnosis of carcinoid tumor pathology, 31 patients had typic carcinoid tumor and 12 patients with atypic carcinoma (mean age 43.14 ± 15.16 years). The most common clinical symptom was cough and hemoptysis. Two cases presented with cushing syndrome, The most common diagnostic method in this study was simultaneous use of both CT scans and bronchoscopy. In 95.3% of cases, the tumor was pulmonary and in 4.7% of cases, it was extrapulmonary. Right lower lobe was the most common site of tumors and most of the surgeries used were lobectomy.
Conclusion:
This study showed that the most common clinical sign of thoracic carcinoid is cough and the tumor is pulmonary in 95.3% of cases. Right lower lobe was the most common site of tumors and most of the surgeries used were lobectomy. outcome was good.
... GEP-NET'lerin tedavisinde önce primer tümör rezeke edilip sonra metastatik tümöre yönelik geniş olarak carrahi rezeksiyon veya tümör küçültme operasyonu yapılmadır. Çünkü cerrahi tedaviler hastaların hormonal semptomlarından kurtulmasına, hayatta kalma süresinin uzatmasına ve tümöre nedeniyle olacak olan ek hastalıkların önlenmesinde yardımcı olur (39,51). Günümüzde GEP-NET karaciğer metastaz tedavisinde karaciğer rezeksiyonu en başarılı tedavi yöntemi olup ameliyat sonrası mortalite % 5 'in altında olduğu bildirilmiştir (52). ...
GASTROENTEROPANKREATİK
NÖROENDOKRİN
TÜMÖRLERİN KARACİĞER
METASTAZLARINDA
CERRAHİ YAKLAŞIMLAR
... The incidence of neuroendocrine tumors has been increasing in recent years [1]. Neuroendocrine tumors are uncommon, slow-growing neoplasms with incidence of 1-2 in 100,000 patients [2][3][4]. Carcinoid tumors were described first in 1882. In 1930, it was classified and designated as bronchial adenoma [5]. ...
Introduction: Carcinoid tumors are malignant neoplasms of low-malignant neuroendocrine cells. This study tended to evaluate the demographic and rare clinical characteristics of patients with thoracic carcinoid tumor during 2006-2016 at Razi and Aria Hospitals in Rasht. Materials and Methods: The present study was performed on records of 43 patients with lung carcinoid tumors referred to Razi and Aria Hospitals of Rasht during 2006-2019. Information on age, gender, rare clinical symptoms, smoking history, diagnosis tools, treatment and outcome were analyzed. Results: Of the 43 patients treated with definitive diagnosis of carcinoid tumor pathology, 31 patients had typic carcinoid tumor and 12 patients had atypic carcinoma (mean age 43.14±15.16 years). The most common clinical symptom was cough and hemoptysis. Two cases presented with Cushing’s syndrome. The most common diagnostic method in this study was simultaneous use of both CT scan and bronchoscopy. In 95.3% of cases, the tumor manifested as pulmonary and in 4.7% of cases it was extrapulmonary. Right lower lobe was the most common site of tumor involvement and lobectomy was the most frequent surgical procedure performed. Conclusion: based upon our study the most common clinical sign of thoracic carcinoid was cough and the tumor was pulmonary in 95.3% of cases. Right lower lobe was the most common site of involvement and the most frequent surgical procedure performed was lobectomy. The outcome was good.
... In NET patients with liver disease only or with liverdominant metastases, loco-regional approaches such as ablative techniques or intra-arterial therapies can be proposed in place of upfront surgery with a cytoreductive aim, leading to lesion resectability and a 5-year survival rate of 50%. [34][35][36] In particular, it is well known that NET hepatic metastases are characterized by a high rate of vascularization, as opposed to many other liver primary or secondary malignancies. Vascularization of NETs LM depends mostly on the hepatic artery, whereas normal liver parenchyma has a unique dual blood supply from both the proper hepatic artery (20-40%) and the portal vein (60-80%). ...
In neuroendocrine tumors (NETs), liver metastases (LM) represent the most crucial prognostic factor, irrespective of the primary tumor site. At diagnosis, about 65-95% of gastroenteropancreatic neuroendocrine tumors (GEP-NETs) show hepatic metastasis. Management strategies of LM are heterogeneous and range from systemic therapy to liver-directed procedures. The type of systemic therapy used is dependent on the grade and proliferation of the tumor and includes somatostatin analogues, interferon, m-Tor and tyrosine kinase inhibitors, and chemotherapy. Angiographic liver-directed techniques, such as transarterial embolization/chemoembolization and selective internal radiation therapy, offer excellent palliation for patients with liver-predominant disease. In highly selected cases, liver transplantation and peptide receptor radionuclide therapy are considered. The relatively low disease incidence and the diversity of presentation have led to a lack of well-conducted randomized controlled trials comparing the efficacy of different treatment options. Experience indicates that surgery is the only treatment that offers potential for cure. For unresectable lesions, the absence of data from rigorous trials limits the validity of many publications that detail management. In this review we will discuss the existing approaches for hepatic metastases from GEP-NETs.
... However, resection of pancreatic tumors in the presence of unresectable LM should be selectively considered in patients with symptomatic non-functioning p-NETs [122,123] and in low-risk patients with life-threatening symptoms [124]. Regarding p-NETs, in a systematic review including one prospective study and two retrospective studies, a greater 5-year survival rate was observed in patients who had their primary tumor resected [125][126][127][128]. ...
Simple Summary
As we are facing an increasing incidence of pancreatic neuroendocrine tumors (pNETs), it appears necessary to better classify this disease—and in 2017 the WHO classification introduced a new category of well differentiated grade 3 tumors. pNETs treatment requires some specific background and recent reviews on the multimodal management of this disease are missing. Indeed, those modalities constantly evolve and this review, focusing on Grade 1 and Grade 2 pNETs, aims to clarify both oncological and surgical treatment options from localized tumors to multi metastatic disease. Every aspect of the strategy are discussed in this review from the oncologist and the surgeon’s point of view and with a special focus on a minimally invasive approach.
Abstract
Pancreatic neuroendocrine tumors (p-NETs) are rare tumors with a recent growing incidence. In the 2017 WHO classification, p-NETs are classified into well-differentiated (i.e., p-NETs grade 1 to 3) and poorly differentiated neuroendocrine carcinomas (i.e., p-NECs). P-NETs G1 and G2 are often non-functioning tumors, of which the prognosis depends on the metastatic status. In the localized setting, p-NETs should be surgically managed, as no benefit for adjuvant chemotherapy has been demonstrated. Parenchymal sparing resection, including both duodenum and pancreas, are safe procedures in selected patients with reduced endocrine and exocrine long-term dysfunction. When the p-NET is benign or borderline malignant, this surgical option is associated with low rates of severe postoperative morbidity and in-hospital mortality. This narrative review offers comments, tips, and tricks from reviewing the available literature on these different options in order to clarify their indications. We also sum up the overall current data on p-NETs G1 and G2 management.
... RFA can also be effectively combined with surgical resection in an effort to preserve the highest possible percentage of hepatic parenchyma. Studies assessing outcomes from patients undergoing resection and concomitant ablation of NELM have documented equally good long-term outcomes [83][84][85]. Reported complications after RFA include portal vein thrombosis, hemoperitoneum, viscus perforation, bile leak, liver abscess, pneumothorax and pleural effusions [78,82]. Furthermore, RFA mandates a high level of operator experience in the use of conventional ultrasoundand CT-navigation in order to achieve precise 3D alignment of probes and subsequently create adequately overlapping ablation areas. ...
Neuroendocrine neoplasms (NEN) are frequently characterized by a high propensity for metastasis to the liver, which appears to be a dominant site of distant-stage disease, affecting quality of life and overall survival. Liver surgery with the intention to cure is the treatment of choice for resectable neuroendocrine liver metastases (NELM), aiming to potentially prolong survival and ameliorate hormonal symptoms refractory to medical control. Surgical resection is indicated for patients with NELM from well-differentiated NEN, while its feasibility and complexity are largely dictated by the degree of liver involvement. As a result of advances in surgical techniques over the past decades, complex 1- and 2-stage, or repeat liver resections are performed safely and effectively by experienced surgeons. Furthermore, liver transplantation for the treatment of NELM should be anchored in a multimodal and multidisciplinary therapeutic strategy and restricted only to highly selected individual cases. A broad spectrum of interventional radiology treatments for NELM have recently been available, with expanding indications that are more applicable, as they are less limited by patient- and tumor-related parameters, being therefore important adjuncts or alternatives to surgery. Overall, liver-targeted treatment modalities may precede the administration of systemic molecular targeted agents and chemotherapy for patients with liver-dominant metastatic disease; these appear to be a crucial component of multimodal management of patients with NEN. In the present review, we discuss surgical and non-surgical liver-targeted treatment approaches for NELM, each complementing the other, with a view to assisting physicians in optimizing multimodal NEN patient care.
... RFA can also be effectively combined with surgical resection in an effort to preserve the highest possible percentage of hepatic parenchyma. Studies assessing outcomes from patients undergoing resection and concomitant ablation of NELM have documented equally good long-term outcomes [83][84][85]. Reported complications after RFA include portal vein thrombosis, hemoperitoneum, viscus perforation, bile leak, liver abscess, pneumothorax and pleural effusions [78,82]. Furthermore, RFA mandates a high level of operator experience in the use of conventional ultrasoundand CT-navigation in order to achieve precise 3D alignment of probes and subsequently create adequately overlapping ablation areas. ...
Neuroendocrine neoplasms (NEN) are frequently characterized by a high propensity for metastasis to the liver, which appears to be a dominant site of distant-stage disease, affecting quality of life and overall survival. Liver surgery with the intention to cure is the treatment of choice for resectable neuroendocrine liver metastases (NELM), aiming to potentially prolong survival and ameliorate hormonal symptoms refractory to medical control. Surgical resection is indicated for patients with NELM from well-differentiated NEN, while its feasibility and complexity are largely dictated by the degree of liver involvement. As a result of advances in surgical techniques over the past decades, complex 1- and 2-stage, or repeat liver resections are performed safely and effectively by experienced surgeons. Furthermore, liver transplantation for the treatment of NELM should be anchored in a multimodal and multidisciplinary therapeutic strategy and restricted only to highly selected individual cases. A broad spectrum of interventional radiology treatments for NELM have recently been available, with expanding indications that are more applicable, as they are less limited by patient- and tumor-related parameters, being therefore important adjuncts or alternatives to surgery. Overall, liver-targeted treatment modalities may precede the administration of systemic molecular targeted agents and chemotherapy for patients with liver-dominant metastatic disease; these appear to be a crucial component of multimodal management of patients with NEN. In the present review, we discuss surgical and non-surgical liver-targeted treatment approaches for NELM, each complementing the other, with a view to assisting physicians in optimizing multimodal NEN patient care.
... Although cancer patients with metastatic diseases are generally unsuitable for surgical resection in the field of oncology, partial hepatectomy is often performed in pNENs patients with liver metastases, depending upon the number, size and location of the lesions, the extent of the primary tumor and the patient's performance status [41]. The rationale is provided by studies showing longer survival after resection of liver metastases, and the clinical effectiveness of liver resection can be partly explained by intrinsic slow progression of well-differentiated pNENs [42,43]. When liver lesions are not resectable, radiofrequency ablation and transarterial chemoembolization are frequently employed as palliative approaches [44]. ...
Pancreatic neuroendocrine neoplasms (pNENs) are rare tumors accounting for only 1-2% of all pancreatic tumors. pNENs are pathologically heterogeneous and are categorized into three groups (neuroendocrine tumor: NET G1, NET G2 and neuroendocrine carcinoma: NEC) on the basis of Ki-67 proliferation index and mitotic count according to the 2010 WHO classification of gastroenteropancreatic NENs. NEC in this classification includes both histologically well-differentiated and poorly differentiated subtypes, and modification of the WHO 2010 classification is under discussion based on genetic and clinical data. Genomic analysis has revealed NETs G1/G2 have genetic alterations in chromatin remodeling genes such as MEN1, DAXX and ATRX, whereas NECs have an inactivation of TP53 and RB1, and these data suggest that different treatment approaches would be required for NET G1/G2 and NEC. While there are promising molecular targeted drugs, such as everolimus or sunitinib, for advanced NET G1/G2, treatment stratification based on appropriate predictive and prognostic biomarkers is becoming an important issue. The clinical outcome of NEC is still dismal, and a more detailed understanding of the genetic backround together with preclinical studies to develop new agents, including those already under investigation for SCLC, will be needed to improve the prognosis.
... Moreover, since cytoreduction surgery for NETs with metastatic lesions can control hormonal hypersecretion and alleviate symptoms, cytoreduction surgery is recommended.21 However, the surgical resection of multiple organs for NETs associated with metastatic lesions is highly invasive, and a careful assessment of the indications for surgery and the risks and benefits of surgical resection is required.For patients with liver metastases, the 5-year survival rate after hepatectomy has been reported to range from 61% to 81%, and rates of improvement of associated signs and symptoms, including hormonal symptoms, has been reported to range from 90% to 100%.[47][48][49][50][51] Cytoreduction surgery is often recommended if at least 90% of the liver tumors can be resected.[52][53][54][55] ...
Neuroendocrine tumors (NETs) are rare neoplasms, with an estimated annual incidence of 6.9/100 000. They arise from cells of the diffuse endocrine system, which are mainly dispersed throughout the gastrointestinal (GI), pancreatic, and respiratory tracts. The incidence of GI‐NETs has recently begun to show a steady increase. According to the Surveillance, Epidemiology, and End Results database, 53% of patients with NETs present with localized disease, 20% with locoregional disease, and 27% with distant metastases at the time of diagnosis. Surgery is the mainstay for the treatment of locoregional GI‐NETs. Endoscopic resection is an option for well‐differentiated early GI‐NETs, which are thought to very rarely metastasize to lymph nodes. A lesion that is technically difficult to resect via endoscopy is an indication for local resection (partial resection without lymph node dissection). GI‐NETs with possible lymph node metastasis is an indication for enterectomy with lymph node dissection. For NETs with metastatic lesions, cytoreduction surgery can control hormonal hypersecretion and alleviate symptoms; therefore, cytoreduction surgery is recommended. The indications for surgery vary and are based on the organ where the NET arose; therefore, an understanding of the patient's clinical state and individualized treatment that is based on the characteristics of the patient's GI‐NET is needed. This review summarizes surgical treatments of GI‐NETs in each organ.
... For pNETs and pNECs, the most likely site for metastasis is the liver, although metastases to other sites have also been reported [54] . Similar to patients with colorectal cancer with resectable liver metastases, pNETs patients with only liver metastases can still undergo partial liver resection [55,56] . Patients with pNETs G3, which is more malignant and more likely to have liver metastases than G1/2, may also benefit from surgical resection of primary lesions and liver metastases [57] . ...
In 2017 the World Health Organization revised the criteria for classification of pancreatic neuroendocrine neoplasms (pNENs) after a consensus conference at the International Agency for Research on Cancer. The major change in the new classification was to subclassify the original G3 group into well-differentiated pancreatic neuroendocrine tumors G3 (pNETs G3) and poorly differentiated pancreatic neuroendocrine carcinomas (pNECs), which have been gradually proven to be completely different in biological behavior and clinical manifestations in recent years. In 2019 this major change subsequently extended to NENs involving the entire digestive tract. The updated version of the pNENs grading system marks a growing awareness of these heterogeneous tumors. This review discusses the clinicopathological, genetic and therapeutic features of poorly differentiated pNECs and compare them to those of well-differentiated pNETs G3. For pNETs G3 and pNECs (due to their lower incidence), there are still many problems to be investigated. Previous studies under the new grading classification also need to be reinterpreted. This review summarizes the relevant literature from the perspective of the differences between pNETs G3 and pNECs in order to deepen understanding of these diseases and discuss future research directions.
... The presence of LM significantly affects the clinical decision-making and patients' prognosis. Unlike brain metastasis towards which treatment response is generally poor, the prognosis for patients with solely LM may be significantly improved after timely and sufficient treatments, especially for carefully selected patients with colorectal cancer (CRC), neuroendocrine cancer and gastric cancer [6][7][8]. Thus, early identification of LM is essential to improve patients' survival. Despite the profound impact that LM has on patients' prognosis, an epidemiological study on the incidence of LM based on a large sample size that might provide generalizable estimation is lacking. ...
Metastasis is a major cause of cancer-related death and liver metastasis (LM) is a distinct type for its relatively good prognosis after timely treatment for selected patients. However, a generalizable estimation of incidence and prognosis of LM is lacking. Cancer patients with known LM status in the Surveillance, Epidemiology and End Results database were enrolled in the present study. The incidence and prognosis of LM were calculated by primary cancer type and clinicopathological factors. Among 1,630,725 cases, 105,329 (6.46%) cases present LM at diagnosis, with a median survival of 4 months. LM presents at diagnosis in 39.96% of pancreatic cancer, 16.00% of colorectal cancer (CRC) and 12.68% of lung cancer. Of all LM cases, 25.58% originated from lung cancer, with 24.76% from CRC and 17.55% from pancreatic cancer. LM originated from small intestine cancer shows the best prognosis (median survival: 30 months), followed by testis cancer (25 months) and breast cancer (15 months). Subgroup analyses demonstrated disparities in incidence and prognosis of LM, with higher incidence and poorer prognosis in the older population, African American, male, and patients with inferior socioeconomic status. The current study provides a generalizable data resource for the epidemiology of LM, which may help tailor screening protocol, design clinical trials and estimate disease burden.
... [7][8][9][10][11] PNET related death is most often the result of metastasis to the liver. 12 Complete surgical resection remains the only curative treatment for PNETs, 13 and resection of both primary and metastatic tumors has been associated with improved OS. [14][15][16] Though surgical resection is the mainstay of treatment, because of their relatively indolent nature, current treatment guidelines support expectant management of small, non-functional PNETs. [17][18][19][20] In fact, several treatment algorithms advocate observation with serial imaging of patients with non-functional PNETs B 2 cm in size. ...
Background
Pancreatic neuroendocrine tumors (PNETs) are often indolent; however, identifying patients at risk for rapidly progressing variants is critical, particularly for those with small tumors who may be candidates for expectant management. Specific growth rate (SGR) has been predictive of survival in other malignancies but has not been examined in PNETs.MethodsA retrospective cohort study of adult patients who underwent PNET resection from 2000 to 2016 was performed utilizing the multi-institutional United States Neuroendocrine Study Group database. Patients with ≥ 2 preoperative cross-sectional imaging studies at least 30 days apart were included in our analysis (N = 288). Patients were grouped as “high SGR” or “low SGR.” Demographic and clinical factors were compared between the groups. Kaplan–Meier and log-rank analysis were used for survival analysis. Cox proportional hazard analysis was used to assess the impact of various clinical factors on overall survival (OS).ResultsHigh SGR was associated with higher T stage at resection, shorter doubling time, and elevated HbA1c (all P ≤ 0.01). Patients with high SGR had significantly decreased 5-year OS (63 vs 80%, P = 0.01) and disease-specific survival (72 vs 91%, P = 0.03) compared to those with low SGR. In patients with small (≤ 2 cm) tumors (N = 106), high SGR predicted lower 5-year OS (79 vs 96%, P = 0.01). On multivariate analysis, high SGR was independently associated with worse OS (hazard ratio 2.67, 95% confidence interval 1.05–6.84, P = 0.04).Conclusion
High SGR is associated with worse survival in PNET patients. Evaluating PNET SGR may enhance clinical decision-making, particularly when weighing expectant management versus surgery in patients with small tumors.
... Die Resektion mit kurativem Ansatz ist der Goldstandard in der Therapie von Lebermetastasen bei NET mit einem 5-Jahres-Überleben von 60-80 % und einer niedrigen Mortalität (0-5 %) und Morbidität (30 %) [10][11][12]. Im Gegensatz dazu zeigten sich bei Patienten, deren Lebermetastasen nicht reseziert wurden, sehr schlechte Ergebnisse mit einem 5-Jahres-Überleben von nur 30 % [13,14]. Die Voraussetzungen, unter denen eine Resektion mit kurativem Ansatz möglich ist, sind allerdings sehr strikt und treten nur bei 10-25 % der Patienten auf [15]. ...
Neuroendocrine tumors (NETs) are a heterogenous group of tumors. Most commonly they occur in the
intestine and pancreas, but they are also found in the lung and elsewhere. Synchonous liver metastases are
detected in 65–95% of cases independent of the primary tumor, its extent, differentiation and proliferation.
Liver metastasis can be approached with an curative intention with both liver resection or transplantation
provided that the patient is otherwise free of NET. Both therapies achieve excellent results with a 5-year-survival
rate of 60–80% and 97%, respectively; however, selection criteria allow surgical treatment in only
between 1–25% of patients. For palliation, both tumor ablation and transarterial chemoembolization are
effective for local tumor control. Additional somatostatin-analoga are first-line systemic antiproliferative
treatment-options for palliative patients.Up to date prospective randomized trials (RCT) are pending. Thus, todays treatment regimens are based on
retrospective data limited due to the high heterogenity of NET. Therefore, patients with NET must be treated in
highly specialized centers for best clinical outcome.
... Liver resection has an acceptable morbidity (approximately 30%) and a low mortality rate (less than 5%). On the other hand, when liver metastases are not resected, the survival rate is about 30% [82,83] . However, considering the retrospective nature of the studies, bias in patient selection (such as less advanced disease and better performance status) may have affected the surgical outcomes. ...
Zollinger-Ellison syndrome (ZES) is characterized by gastric acid hypersecretion causing severe recurrent acid-related peptic disease. Excessive secretion of gastrin can now be effectively controlled with powerful proton pump inhibitors, but surgical management to control gastrinoma itself remains controversial. Based on a thorough literature review, we design a surgical algorithm for ZES and list some significant consensus findings and recommendations: (1) For sporadic ZES, surgery should be routinely undertaken as early as possible not only for patients with a precisely localized diagnosis but also for those with negative imaging findings. The surgical approach for sporadic ZES depends on the lesion location (including the duodenum, pancreas, lymph nodes, hepatobiliary tract, stomach, and some extremely rare sites such as the ovaries, heart, omentum, and jejunum). Intraoperative liver exploration and lymphadenectomy should be routinely performed; (2) For multiple endocrine neoplasia type 1-related ZES (MEN1/ZES), surgery should not be performed routinely except for lesions > 2 cm. An attempt to perform radical resection (pancreaticoduodenectomy followed by lymphadenectomy) can be made. The ameliorating effect of parathyroid surgery should be considered, and parathyroidectomy should be performed first before any abdominal surgery for ZES; and (3) For hepatic metastatic disease, hepatic resection should be routinely performed. Currently, liver transplantation is still considered an investigational therapeutic approach for ZES. Well-designed prospective studies are desperately needed to further verify and modify the current considerations.
... The untreated patients with unresectable neuroendocrine liver metastases have a 5-year survival rate of 25-38%. [27] In patients with metastatic neuroendocrine tumors who are unlikely to be cured by surgery or unable to tolerate an invasive form of treatment, RFA has been shown to ameliorate the symptoms (95%), significantly or completely control the symptoms (80%), and partially or significantly decrease the circulating hormone levels (65%) [28,29]. LRFA seems appealing for these patients because the recurrence rate after resection is >80% at 5 years. ...
... According to ENETS guidelines, an aggressive approach toward liver metastases is recommended whenever a radical resection (>90% of tumor removal) is possible, in the absence of extraabdominal disease, and in the presence of a low Ki-67 (G1-G2 at cytology) and somatostatin receptors (to deliver radiolabeled therapies after cytoreductive surgery). Even in selected cases, the rate of tumor recurrence is high, up to 76% [52,53]. But, the 5-year survival of patients treated with hepatic resection may be as long as 60% [54]. ...
Purpose of review:
Pancreatic neuroendocrine tumors (pNETs) are a rare, heterogeneous group of pancreatic neoplasms with a wide range of malignant potential. They may manifest as noninfiltrative, slow-growing tumors, locally invasive masses, or even swiftly metastasizing cancers.
Recent findings:
In recent years, because of the increasing amount of scientific literature available for pNETs, the classification, prognostic stratification criteria, and available consensus guidelines for diagnosis and therapy have been revised and updated.
Summary:
The vast majority of new pNET diagnoses consist of incidentally discovered lesions on cross-sectional imaging. The biologic behavior of pNETs is defined by the grade and stage of the tumor. Surgery is the only curative treatment and it, therefore, represents the first therapeutic choice for any localized pNET; however, recent evidence suggests that patients with small (<2 cm), nonfunctioning G1 tumors can be safely observed.An aggressive surgical approach towards liver metastases is recommended in selected cases, as well as liver-directed therapies for disease control. In the presence of unresectable progressive disease, somatostatin analogs, targeted therapies such as everolimus, peptide receptor radionuclide therapy, and systemic chemotherapy are all useful tools for prolonging survival.
... Touzios ve ark. ise karaciğerdeki tümör oranının %50'nin üzerinde olduğu durumda rezeksiyonun sağkalım avantajı sağlamadığını vurgulamışlardır (13). Hepatik rezeksiyon nadiren küratif bir tedavi yaklaşımı olup, R0 rezeksiyona rağmen hastaların %90'dan fazlasında nüks hastalık gelişmektedir (14,15). ...
... Primary tumor resection could also enhance the response to further treatments, such a peptide receptor radionuclide therapy (PRRT), and improve progression free survival (31). The survival benefits of the surgical resection of metastases are still controversial (32)(33)(34)(35)(36). In our study, there was no impact on survival of surgical resection of metastasis, for all NETS, as well as in P-NETs and I-NETs subgroups. ...
Background:
Intestinal and pancreatic neuroendocrine tumors (IP-NETs) are rare tumors with heterogeneous outcomes. The aim of our study was to determine the clinical, therapeutic and pathological factors which impact the overall survival (OS) in IP-NETs.
Methods:
All the patients diagnosed with IP-NETs at the Nantes University Hospital between October 1994 and October 2013 were retrospectively analysed. Patients with MEN-1 (Type 1 Multiple Endocrine Neoplasia) or Von Hippel-Lindau syndrome were excluded. Additionally, a prospective analysis of tumor grade (mitotic index and Ki67 index) was performed on tumor samples. OS was evaluated by Kaplan-Meier method and prognostic factors by log-rank test and Cox model.
Results:
The study included 151 patients. Median age was 60 (range, 14-81). Primary tumor was pancreatic in 86 patients (56.95%) and intestinal in 65 patients (43.05%). Tumors were metastatic (synchronous or metachronous) in 72 patients (47.7%). The median OS was 157 months. For all IP-NETs, age >65 years (P<0.0001), Ki67 >5% (P=0.03), synchronous metastases (P=0.016), primary tumor size >25 mm (P=0.03) and emergency surgery (P=0.007) were independent poor prognostic factors.
Conclusions:
In this large series of patients with IP-NET, age >65 years, Ki67 >5%, primary tumor size >25 mm, synchronous metastases and emergency surgery for acute complications have been identified as independent poor prognostic factors.
... Therefore, we hypothesized that significantly different values for PET image-derived heterogeneity may be observed between the different histological profiles and molecular subgroups of BC, assuming that heterogeneous parameters such as tumour phenotype, nuclear pleomorphism, and steroid receptor and HER2 status, together with the Ki-67 index, have different underlying pathophysiological properties. Parallel to the development of techniques to identify favourable tumour biology and the ability to select patients who are expected to have a more protracted disease course or tumours that are responsive to systemic therapies, more patients will be considered for metastasectomy or cytoreductive surgical techniques (15,16). PET imaging, with further refinements in technical performance, might prove to be a very useful tool for functional and biological localization of malignant lesions, with all the recognized limitations (17). ...
Background/Aim: Positron emission tomography/ computed tomography (PET/CT) with ¹⁸F-fluorodeoxyglucose (18F-FDG) has recently been used to investigate lymph node (LN) metastases and several predictive features in patients with breast cancer (BC). The aim of this study was to assess the value of this non-invasive imaging procedure for axillary staging. Patients and Methods: Fifty patients with early primary unilateral, locally advanced, or recurrent invasive operable BC were enrolled. All patients underwent preoperative 18F-FDG PET/CT, and the results were compared with the histopathology of dissected axillary LNs and their biological and immunohistochemical characteristics. The diagnostic performance of 18F-FDG PET/CT in detecting LN metastases from primary or recurrent BC was analyzed. The mean values of the initial PET/CT parameters, including the primary tumour (SUV T) and ipsilateral axillary LNs (SUV LN), were compared with the clinicopathological features of patients to determine their usefulness for predicting clinical interactions. Results: The sensitivity, specificity, overall accuracy, positive predictive value, and negative predictive value of 18F-FDG PET/CT for axillary LN staging were 87%, 90%, 88%, 93%, and 82%, respectively. Bivariate analyses showed strong interactions of nuclear grade (p=0.05), progesterone receptor expression (p=0.001), Ki-67 index (0.027), and local relapse with the SUV T. A high SUV LN value was significantly correlated with a higher nuclear grade score (p=0.05), oestrogen receptor negativity (p=0.001), progesterone receptor negativity (p=0.014), a high Ki-67 index (>20%; p=0.048), LN metastasis (p<0.001), a basal tumour (p=0.04), and locoregional recurrence (p<0.001). Conclusion: PET/CT is a reproducible, non-invasive imaging modality that is useful for evaluating a primary BC mass and its relationship with metastatic axillary LNs, thereby predicting tumour behaviour and guiding clinical practice. © 2018 International Institute of Anticancer Research. All rights reserved.
The continuous research in locoregional curative therapies, designed to reduce the number of oncologic patients undergoing palliative treatments, is getting more and more results. One of the most interesting among these is the combination of percutaneous and intra-arterial treatments for primary and secondary liver neoplasms.
Interventional oncology has emerged as an important specialty within cancer care, providing targeted therapy and palliative benefits without the side effects of chemotherapy, surgery and radiation. Covering the principles of current and emerging interventional oncology techniques and detailed diagnosis, staging and treatment algorithms, this book outlines the ways in which these image-guided therapies can inform cancer management strategies. Access to the most current information is vital in this rapidly growing and evolving area of practice. This new edition reflects the most recent clinical data on interventional oncology procedures. Chapters on image guidance and targeting, tumor ablation, embolotherapy, and response assessment have been updated to reflect major technological advances, and new material on microwave ablation and irreversible electroporation has been added. This invaluable resource for interventional radiologists provides essential education and guidance on the full range of minimally invasive image-guided procedures and their integration into comprehensive cancer care.
Pancreatic cancer is now the second most prevalent gastrointestinal neoplasm after colorectal cancer. Pancreatic neuroendocrine tumors (PNETs) are rare neoplasms that originate from the islet cells of the pancreas. While they only account for approximately 7% of all pancreatic tumors, their incidence has been increasing over the past decade. Pancreatic neuroendocrine tumors are often classified according to functional status and tumor grade. Functional neuroendocrine tumors are those associated with a well-defined or classic syndrome and comprise 10–40% of PNETs. Functional tumors produce high levels of bioactive compounds or hormones including insulin, gastrin, glucagon, vasoactive intestinal peptide (VIP), or somatostatin. Nonfunctional tumors may overexpress various peptides, including neurotensin or calcitonin, yet patients remain largely asymptomatic until the tumor itself causes symptoms through mass effect from local expansion or metastatic disease. Symptoms associated with neuroendocrine tumors, including those produced by hormones, lead patients to pursue diagnoses early and have better survival. The surgical management of PNET varies widely, depending on the size and the location of the disease, as well as the presence of symptoms and the extent of the metastatic disease. A multidisciplinary team best manages PNET patients.
The presence of neuroendocrine liver metastases is one of the poorest prognostic factors in patients with pancreatic neuroendocrine neoplasms, and surgical resection of neuroendocrine liver metastases is the only curable treatment. A 38-year-old man had a pancreatic neuroendocrine neoplasm with synchronous multiple liver metastases, and two surgeries and continuous everolimus and octreotide achieved R0 resection. However, multiple neuroendocrine liver metastases developed twice after more than 5 years of recurrence-free survival. Aggressive repeat hepatectomy was performed and he has survived for more than 10 years after the initial surgery. This report highlights that patients with pancreatic neuroendocrine neoplasms have a potential risk of recurrence even after 5 years of recurrence-free survival. In addition, combined aggressive hepatectomy and continuous medication can contribute dramatically to long-term survival even for late-stage recurrence of liver metastases.
Neuroendocrine liver metastases (NELM) are very heterogeneous with respect to the clinical presentation and the prognosis. The treatment of NELMs requires a multidisciplinary approach and patients with NELM should be referred to a specialized center. When possible, the resection of NELMs provides the best long-term results. The general selection criteria for liver resection include an acceptable general physical condition for a large liver operation, tumors with a favorable differentiation grade 1 or 2, a lack of extrahepatic lesions, a sufficient residual liver volume and the possibility to resect at least 70% of the metastases. Supplementary treatment, including simultaneous liver ablation, are generally safe and can increase the number of patients who can be considered for surgery. For patients with resectable NELM, the resection of the primary tumor is recommended either in a 2-stage or combined procedure. In selected patients with nonresectable NELM a liver transplantation can be carried out, which can be associated with excellent long-term results.
Neuroendocrine tumors (NETs) are neoplasms that arise from cells of the endocrine (hormonal) and nervous systems. Many are benign, while some are malignant. They most commonly occur in the intestine, where they are often called carcinoid tumors, but they are also found in the pancreas, lung and the rest of the body. Although there are many kinds of NETs, they are treated as a group of tissue because the cells of these neoplasms share common features, such as looking similar, having special secretory granules, and often producing biogenic amines and polypeptide hormones.
In der Vergangenheit wurden Resektionen oder Transplantationen wegen non-kolorektaler Lebermetastasen durch die Abwägung von geringem Überlebensvorteil und Komplikationsrate eher zurückhaltend indiziert. Mittlerweile zählt die Leberchirurgie jedoch zu den komplikationsarmen Standardverfahren in der Tumortherapie, die unter Einbettung in multimodale Therapiekonzepte zu einer deutlichen Steigerung des Patientenüberlebens führen.
Publication History
Publication Date:
04 October 2021 (online)
© 2020. Thieme. All rights reserved.
Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany
Neuroendocrine tumors (NETs) are a relatively rare and heterogeneous group, comprising about 2% of all malignancies with almost 2/3 of NETs being nonfunctional tumors. The incidence increases with age. Most non-appendix, non-pancreas NETs are seen in age over 60 years. Diagnosis of NET is often challenging and requires careful clinical history along with laboratory tests and an array of imaging procedures. While functioning NETs could present with symptoms related to hormone hypersecretion, non-functioning NETs often present incidentally or due to mass effect. Surgical resection remains the treatment of choice even with metastatic disease. The newer diagnostic and treatment modalities offer potential treatment and prolong disease-free survival for patients with improvement in quality of life.
Surgical exeresis of neuroendocrine tumors is the only treatment scheme able to “cure” the neuroendocrine (NET) patient. Accordingly, all NET patients, regardless of disease extent, should be considered for surgery. However, curative surgery in malignant NETs is possible in probably less than 30% of the cases, depending on tumor histotype, site, and spread. Unfortunately, despite radical surgery, recurrence can occur in 75% of the patients within a time frame up to 15 years. Furthermore, the management of neuroendocrine liver secondaries is a genuine dilemma since their presence worsens patients’ survival because practically there is not a precise consensus about the optimal treatment strategy for the neuroendocrine liver metastases. A substantial ergography was achieved by Ser Yee Lee et al., who conducted a systematic search in the PubMed database from 1995 to 2010 and a second one from 2010 to 2014, identified from the Surveillance Epidemiology and End Results database. In the first database, 22 case series were studied with a total of 793 patients undergoing neuroendocrine liver metastases surgery. The overall survival ranged from 46 to 86% at 5 years and 35 to 79% at 10 years, the median survival from 52 to 123 months, whereas, after cytoreductive surgery, the mean duration of symptom reduction was between 16 and 26 months with a 5-year progression rate of 59–76%. In the second database, a total of 47/191 (24.6%) patients with pancreatic neuroendocrine tumor with liver metastases underwent surgical resection, and the rest 144 (75.4%) did not. The results showed that surgical resection of primary tumor was associated with cancer-specific survival (p = 0.028) and overall survival (p = 0.025) benefit, whereas patients not receiving surgery were associated with poor survival. An aggressive surgical approach, including a combination with additional liver-targeted procedures, is recommended because it will result in a longer-term survival, significant longer-term palliation, and a better quality of life. A multidisciplinary approach should be established as a platform for decision-making. This chapter mirrors in detail the status of surgery in the NET patient generally as well as in the NET liver secondaries particularly, based on the experience obtained in our institution and the international reviewed ergography.
Surgical resection is the foundation for treatment of small bowel neuroendocrine tumors (SBNETs). Guidelines for surgical management of SBNETs rely on retrospective data, which suggest that primary tumor resection and cytoreduction improve symptoms, prevent future complications, and lengthen survival. In advanced NETs, improvement in progression-free survival has been reported in large, randomized, controlled trials of various medical treatments, including somatostatin analogues, targeted therapy, and peptide receptor radionuclide therapy. This review discusses important studies influencing the management of SBNETs and the limitations of current evidence regarding surgical interventions for SBNETs.
Patients with neuroendocrine tumor liver metastases (NETLMs) may develop carcinoid syndrome, carcinoid heart disease, or other symptoms from overproduction of hormones. Hepatic resection and cytoreduction is the most direct treatment of NETLMs in eligible patients, and cytoreduction improves symptoms, may reduce the sequelae of carcinoid syndrome, and extends survival. Parenchymal-sparing procedures, such as ablation and enucleation, should be considered during cytoreduction to maximize treatment of multifocal tumors while preserving healthy liver tissue. For patients with large hepatic tumor burdens, high-grade disease, or comorbidities precluding surgery, liver-directed and systemic therapies can be used to palliate symptoms and improve progression-free survival.
Background
Neuroendocrine tumor (NET) metastases are a major cause of morbidity and mortality. The role of liver transplantation to treat unresectable metastases from NET is controversial.Methods
We evaluated outcomes of all patients undergoing “isolated” liver transplantation (LT) for metastatic NETs in the USA, from October 1988 through June 2018 using the UNOS dataset.ResultsDuring the study period, 160,360 LTs were performed. Two hundred six adult patients underwent “isolated” LT for metastatic NETs. The mean (SD) age was 48.2 (11.7) years, ranging from 19 to 75 years; 117 (56.8%) patients were male. Overall 1-, 3-, 5-, and 10-year patient survival rates were 89.1%, 75.3%, 64.9%, and 46.1%, respectively. Tumor recurrence was seen in 70 of 206 patients who underwent LT (34%). The median time to recurrence was 28 months (range, 1 to 192 months) and median wait time for LT was 112 days. Tumor recurrence was significantly higher in transplanted patients waiting less than 6 months compared with those waiting more than 6 months (74.3% vs. 25.7%). Patients’ age ≤ 45 years had significantly better survival compared with those > 45 years (p = 0.03). Younger patients with carcinoid tumors had better survival but this trend was not observed in the non-carcinoid group. On multivariable analysis, recipient age, donor age, cold ischemic time MELD score, and tumor recurrence were significant predictors of poor patient survival.Conclusions
Waiting time longer than 6 months is associated to lower rates of tumor recurrence. Younger patients ≤ 45 years had significantly improved survival after LT for NET metastases.
Background
The optimal timing of treatment of liver metastases from low-grade neuroendocrine tumors (LG-NELM) varies significantly due to numerous treatment modalities and the literature supporting various treatment(s). This study sought to create and validate a literature-based treatment algorithm for LG-NELM.
Methods
A treatment algorithm to maximize overall survival (OS) was designed using peer-reviewed articles evaluating treatment of LG-NELM. This algorithm was retrospectively applied to patients treated for LG-NELM at our institution. Deviation was determined based on whether or not a patient received treatment consistent with that recommended by the algorithm. Patients who did and did not deviate from the algorithm were compared with respect to OS and number of treatments.
Results
Applying our algorithm to a 149-patient cohort, 57 (38%) deviated from recommended treatment. Deviation occurred in the form of alternative (28, 49%) versus additional procedures (29, 51%). Algorithm deviators underwent significantly more procedures than non-deviators (median 1 vs. 2, p < 0.001). Cox model indicated no difference in OS associated with algorithm deviation (HR 1.19, p = 0.58) when controlling for age and tumor characteristics.
Conclusion
This literature-based algorithm helps standardize treatment protocols in patients with LG-NELM and can reduce cost and risk by minimizing unnecessary procedures. Prospective implementation and validation is required.
Gastrointestinal neuroendocrine tumors are rare neoplasms. Currently, incidence of gastric neuroendocrine tumors (gNETs) is being significantly increased. There are 3 groups of gNETs: types I, II and III. Each type has important features regarding clinical picture, prognosis and treatment strategy. Type I is the most common (70-80%) and associated with chronic atrophic gastritis including autoimmune gastritis and Helicobacter associated atrophic gastritis. Type II (5-6%) is associated with multiple endocrine neoplasia type I and Zollinger-Ellison syndrome (MEN I - ZES). Both types are characterized by hypergastrinemia and small tumor dimension. These neoplasms are multiple and mostly benign. On the contrary, NETs type III (10-15%) is not associated with hypergastrinemia and represented by single large neoplasms. Tumors are malignant as a rule. Therefore, surgical resection and chemotherapy are preferred for these tumors. Endoscopic surgery followed by observation is acceptable for almost all NETS type I and II. At the same time, this approach is advisable only for small and highly differentiated neoplasms type III.
Background:
Resection of liver metastasis in small bowel neuroendocrine tumors (SBNET) may improve survival, however, factors influencing prognosis are unclear. We evaluated how the extent of resection influences outcomes.
Methods:
Patients with SBNET with liver metastasis from 1990 to 2013 who underwent resection of the primary tumor were identified. Outcomes among patients undergoing complete resection (CR), partial resection (PR), or no resection (NR) of liver metastases with resection of the primary tumor only were compared.
Results:
One hundred eleven patients met the criteria. The median number of liver lesions was seven and median lesions resected was one. Fifty (45%) patients had NR, 41 (36.9%) underwent CR, and 20 (18.1%) underwent PR. The 5-year overall survival (OS) was 79.4% for NR, 84.7% for PR, and 100% for CR, demonstrating a trend that CR was best, followed by PR then NR (P = .02). 10-year OS showed no significant differences (72.7% NR; 84.7% PR; 82.5% CR; P = .10). Greater than 10 liver lesions (hazard ratio [HR] 3.6; P = 0.04) or receiving chemotherapy (HR 3.7; P = .03) were negative predictors of survival.
Conclusion:
The extent of resection of liver disease in SBNET influenced survival at 5 years but not at 10 years. In addition, more than 10 liver lesions and chemotherapy were predictors of mortality.
Background
Since neuroendocrine tumors have an indolent behavior, studies looking at oncologic outcomes should report a long-term follow-up. Over the years, we have been treating selected patients with neuroendocrine liver metastases (NELM) with laparoscopic ablation (LA) and reported favorable local tumor control. The aim of this study is to see whether this local efficacy translates into long-term oncologic outcomes.
Methods
This was an IRB-approved study of patients who underwent LA for NELM at a single center. Overall and progression-free survivals were analyzed using Kaplan–Meier and Cox proportional hazards model.
Results
Study included 58 women and 71 men with a median age of 58 (IQR 47–67) years. Tumor type included carcinoid (n = 92), pancreatic islet cell (n = 28), and medullary thyroid cancer (n = 9). There was a median of 6 (IQR 3–8) tumors, measuring 1.6 (IQR 1.1–2.4) cm. At a median follow-up of 73 (IQR 34–135) months, local liver recurrence per patient, new liver recurrence, and new extrahepatic recurrence rates were 22, 68, and 33%, respectively. Local tumor recurrence per lesion was 5% (n = 42/770). Median overall survival was 125 months, with 5-year, and 10-year overall survivals being, 76%, and 59%, respectively; and median disease-free survival was 13 months, with 5-year, and 10-year progression-free survivals being 26%, and 6%, respectively. On Cox proportional hazards model, overall survival was independently predicted by tumor size, grade, and resection status of primary.
Conclusion
To our knowledge, this is the largest single-center experience with the longest follow-up regarding the utilization of LA for NELM. Our results demonstrate that in selected patients, LA achieves a 95% local tumor control and 59% 10-year overall survival.
The purpose of this study was to assess the value and timing of orthotopic liver transplantation (OLT) in the treatment of metastatic neuroendocrine tumors (NET).
Liver metastasis from NET seems less invasive than other secondary tumors. This observation suggests that OLT may be indicated when other therapies become ineffective. However, the potential benefit of this highly aggressive procedure is difficult to assess due to the scarcity and heterogeneity of NET.
A retrospective multicentric study was carried out, including all cases of OLT for NET performed in France between 1989 and 1994. There were 15 cases of metastatic carcinoid tumor and 16 cases of islet cell carcinomas. Hormone-related symptoms were present in 16 cases (55%). Only 5 patients (16%) had no previous surgical or medical therapy before OLT. Median delay from diagnosis of liver metastasis and OLT was 19 months (range, 2 to 120).
The primary tumor was removed at the time of OLT in 11 cases, by upper abdominal exenteration in 7 cases and the Whipple resection in 3. Actuarial survival rate after OLT was 59% at 1 year, 47% at 3 years, and 36% at 5 years. Survival rates were significantly higher for metastatic carcinoid tumors (69% at 5 years) than for noncarcinoid apudomas (8% at 4 years), because of higher tumor- and non-tumor-related mortality rates for the latter.
OLT can achieve control of hormonal symptoms and prolong survival in selected patients with liver metastasis of carcinoid tumors. It does not seem indicated for other NET.
Endocrine tumours of the pancreas, even in case of liver involvement, are generally characterized by a slower evolution and a better prognosis, if compared with ductal carcinoma. This fact gives reason to a radical surgical approach, whenever possible, and to the research of any effective adjuvant treatment. For this purpose, hepatic transarterial chemoembolization (TACE) has been proposed in recent years for the treatment of metastatic endocrine tumours. Out of 80 patients suffering from endocrine tumours of the pancreas, observed between January 1985 and December 1996, 28 (35%) presented liver metastases at the time of diagnosis. Twelve of these patients were submitted to palliative resection of pancreatic tumour and one or more cycles of TACE. Overall survival was 50% (6/12); median survival was 35.4 months (range 4-75). These results suggest that chemoembolization, combined with surgical resection of primary malignancy, appears to be able to control the disease for a certain time and to increase the survival rate.
Hepatic metastases are frequently encountered in patients with digestive endocrine tumors and their presence plays an important role in quality of life and overall prognosis. Surgery is the treatment method of choice for hepatic metastases but this is frequently impossible due to the extent of disease. Systemic chemotherapy is offered to patients with diffuse and/or progressive liver metastases but results are disappointing especially in patients with metastases of midgut origin. In the latter patients with carcinoid syndrome, somatostatin analogs are frequently initially effective but their efficacy wanes due to disease progression and development of tachyphylaxis. Other therapeutic options in the treatment of hepatic metastases are locoregional strategies where vascular occlusion induces ischemia in these highly vascular tumors using either surgical or radiological techniques. Available methods include surgical ligation of the hepatic artery, transient hepatic ischemia or sequential hepatic arterialization. Trans-catheter arterial chemoembolization has proven effective in terms of long palliation and objective tumor responses. Other treatments aimed at regional destruction either alone or in combination with surgery include radiofrequency ablation and cryotherapy. The latter are usually important adjuncts to surgery and are usually reserved for limited disease.
Background and Objectives
While liver resection for metastatic disease from colorectal cancer extends survival in selected patients, the efficacy of hepatectomy for metastases from other malignancies has not been defined.
Methods
Between 1988 and 1998, 20 hepatic resections were performed in 18 patients (2 underwent a double resection due to recurrence) as treatment of noncolorectal metastases. One‐, 2‐, and 5‐year overall and disease‐related actuarial survival rates were calculated.
Results
No intraoperative or early postoperative deaths were reported. Seven minor (30%) and 1 major (5%) postoperative complications occurred; mean blood loss was 401 ± 324 ml. In 25% of patients, intra‐ or postoperative blood transfusion was needed. The mean postoperative hospital stay was 13.2 days (range 9–23).
The overall actuarial survival rate was 54% at 1 year, 42% at 2 years, and 21% at 5 years (mean 38 ± 11 months). Survival is related to the primary tumor nature.
Conclusions
Hepatic resection for metastases from noncolorectal carcinoma is safe and feasible, with a relatively low incidence of intra‐ or postoperative complications and a short hospital stay. Although it achieves good results in terms of survival in patients suffering from neuroendocrine metastases, it could also have a cytoreductive effect for other tumors. J. Surg. Oncol. 2000;74:24–29. © 2000 Wiley‐Liss, Inc.
While the prognosis for patients with untreated liver metastases from neuroendocrine primaries is rather good, they often suffer disabling symptoms due to syndromes of hormonal excess. Thirteen patients with metastatic neuroendocrine tumours were treated by hepatic cryotherapy; seven patients were symptomatic and five of these had elevated levels of hormonal tumour markers. Twelve patients are alive and mostly asymptomatic with a median follow up of 13.5 months; one patient died after 45 months of bronchopneumonia without evidence of tumour recurrence. All patients with elevated preoperative tumour markers have had a significant fall in markers postoperatively. Two patients were returned to the operating theatre for coagulopathy‐associated bleeding: one patient each developed acute renal failure and pulmonary embolism, but there was no mortality. This study shows that hepatic cryotherapy offers a useful treatment option for this group of patients, alleviates symptoms and may have an impact on survival. Semin. Surg. Oncol. 14:175–183, 1998. © 1998 Wiley‐Liss, Inc.
EST 5275 is a phase II and III study of fluorouracil plus streptozocin (5-FU plus STZ) or doxorubicin in patients with measurable progressive carcinoid tumor. Among one hundred seventy-two cases with no prior chemotherapy and no heart disease, the response rate was 22% for 5-FU plus STZ and 21% for doxorubicin, while the median response duration and median survival were 31 weeks and 64 weeks for the combination and 26 weeks and 48 weeks for doxorubicin. Thirty-three patients who failed 5-FU plus STZ crossed over to doxorubicin and achieved an 18% response. Of the thirty-five patients who failed on doxorubicin, 29% responded to 5-FU plus STZ. Hematologic toxicity was similar for both treatments; however, the 5-FU plus STZ patients experienced more vomiting but acceptable renal toxicity. Both chemotherapy regimens have antitumor activity in carcinoid tumors.
While the prognosis for patients with untreated liver metastases from neuroendocrine prima ries is rather good, they often suffer disabling symptoms due to syndromes of hormonal excess. Thirteen patients with metastatic neuroendocrine tumours were treated by hepatic cryotherapy; seven patients were symptomatic and five of these had elevated levels of hormonal tumour markers. Twelve patients are alive and mostly asymptomatic with a median follow up of 13.5 months; one patient died after 45 months of bronchopneumonia without evidence of tumour recurrence. All patients with elevated preoperative tumour markers have had a significant fall in markers postoperatively. Two patients were returned to the operating theatre for coagulopathy associated bleeding: one patient each developed acute renal failure and pulmonary embolism, but there was no mortality. This study shows that hepatic cryotherapy offers a useful treatment option for this group of patients, alleviates symptoms and may have an impact on survival. (C) 1998 Wiley-Liss, Inc.
Objective: The purpose of this study was to assess the value and timing of orthotopic liver transplantation (OLT) in the treatment of metastatic neuroendocrine tumors (NET). Summary Background Data: Liver metastasis from NET seems less invasive than other secondary tumors. This observation suggests that OLT may be indicated when other therapies become ineffective. However, the potential benefit of this highly aggressive procedure is difficult to assess due to the scarcity and heterogeneity of NET. Methods: A retrospective multicentric study was carried out, including all cases of OLT for NET performed in France between 1989 and 1994. There were 15 cases of metastatic carcinoid tumor and 16 cases of islet cell carcinomas. Hormone-related symptoms were present in 16 cases (55%). Only 5 patients (16%) had no previous surgical or medical therapy before OLT. Median delay from diagnosis of liver metastasis and OLT was 19 months (range, 2 to 120). Results: The primary tumor was removed at the time of OLT in 11 cases, by upper abdominal exenteration in 7 cases and the Whipple resection in 3. Actuarial survival rate after OLT was 59% at 1 year, 47% at 3 years, and 36% at 5 years. Survival rates were significantly higher for metastatic carcinoid tumors (69% at 5 years) than for noncarcinoid apudomas (8% at 4 years), because of higher tumor- and non-tumor-related mortality rates for the latter. Conclusion: OLT can achieve control of hormonal symptoms and prolong survival in selected patients with liver metastasis of carcinoid tumors. It does not seem indicated for other NET.
Background. Neuroendocrine tumors of the gastrointestinal tract (carcinoids, pancreatic endocrine tumors) have low malignant potential but can decrease survival rates if they spread to the liver (LNET). Methods. The records of 16 patients with LNET primarily from gastrointestinal carcinoids treated surgically were retrospectively reviewed. Results. There were 12 women and 4 men. Median age was 56 years (range 25 to 75). Thirteen (81%) had a carcinoid tumor and 5 had gastrinoma. Two patients with multiple endocrine neoplasia type I had both a gastric carcinoid and a jejunal gastrinoma. Eight patients (50%) had the carcinoid syndrome. Each patient had all identifiable LNET either resected or ablated. Ten patients had liver wedge resections, 1 right trisegmentectomy, 5 left hepatic lobectomies, and 2 radiofrequency ablations. Thirteen (81%) patients had concomitant bowel resections. Two patients had concomitant total gastrectomies to remove stomach primaries. The final patient had an extraintestinal pelvic primary or a liver primary. There were no operative deaths, and all 8 (100%) patients with the carcinoid syndrome had amelioration of symptoms. The 5-year actuarial survival rate was 82% with a median follow-up of 32 months. Conclusions. This study demonstrates that liver and concomitant extrahepatic surgery can be performed safely in patients with liver metastases because of carcinoids or pancreatic endocrine tumors. It results in excellent long-term survival and amelioration of symptoms. Surgery should be the first-line therapy for patients with LNET.
Hepatic metastases are frequently encountered in patients with digestive endocrine tumors and their presence plays an important role in quality of life and overall prognosis. Surgery is the treatment method of choice for hepatic metastases but this is frequently impossible due to the extent of disease. Systemic chemotherapy is offered to patients with diffuse and/or progressive liver metastases but results are disappointing especially in patients with metastases of midgut origin. In the latter patients with carcinoid syndrome, somatostatin analogs are frequently initially effective but their efficacy wanes due to disease progression and development of tachyphylaxis. Other therapeutic options in the treatment of hepatic metastases are locoregional strategies where vascular occlusion induces ischemia in these highly vascular tumors using either surgical or radiological techniques. Available methods include surgical ligation of the hepatic artery, transient hepatic ischemia or sequential hepatic arterialization. Trans-catheter arterial chemoembolization has proven effective in terms of long palliation and objective tumor responses. Other treatments aimed at regional destruction either alone or in combination with surgery include radiofrequency ablation and cryotherapy. The latter are usually important adjuncts to surgery and are usually reserved for limited disease. Endocrine-Related Cancer (2003) 10 463–468
Background:
In most instances, advanced neuroendocrine tumors follow an indolent course. Hepatic metastases are common, and although they can cause significant pain, incapacitating endocrinopathy, and even death, they are usually asymptomatic. The appropriate timing and efficacy of interventions, such as hepatic artery embolization (HAE) and operation, remain controversial.
Study design:
The records of 85 selected patients referred for treatment of hepatic neuroendocrine tumor metastases between 1992 and 1998 were reviewed from a prospective database. A multidisciplinary group of surgeons, radiologists, and oncologists managed all patients. Overall survival among this cohort is reported and prognostic variables, which may be predictive of survival, are analyzed.
Results:
There were 37 men and 48 women, with a median age of 52 years. There were 41 carcinoid tumors, 26 nonfunctional islet cell tumors, and 18 functional islet cell tumors. Thirty-eight patients had extrahepatic metastases, and in 84% of patients, the liver metastases were bilobar. Eighteen patients were treated with medical therapy or best supportive care, 33 patients underwent HAE, and 34 patients underwent hepatic resection. Both the HAE-related mortality and the 30-day operative mortality rates were 6%. By univariate analysis, earlier resection of the primary tumor, curative intent of treatment, and initial surgical treatment were associated with prolonged survival (p < 0.05). On multivariate analysis, only curative intent to treat remained significant (p < 0.04). Patients with bilobar or more than 75% liver involvement by tumor were least likely to benefit from surgical resection. One-, 3-, and 5-year survival rates for the entire group were 83%, 61%, and 53%, respectively. The 1-, 3-, and 5-year survivals for patients treated with medical therapy, HAE, and operation were 76%, 39%, and not available; 94%, 83%, and 50%; and 94%, 83%, and 76%, respectively.
Conclusions:
Hepatic metastases from neuroendocrine tumors are best managed with a multidisciplinary approach. Both HAE and surgical resection provide excellent palliation of hormonal and pain symptoms. In select patients, surgical resection of hepatic metastases may prolong survival, but is rarely curative.
Recent studies have demonstrated the relationship between clinical outcomes of complex surgical procedures and provider volume.
Hepatic resection is one such high-risk surgical procedure. The aim of this analysis was to determine whether mortality and
cost of performing hepatic resection are related to surgical volume while also examining outcomes by extent of resection and
diagnosis, variables seen with this procedure. Maryland discharge data were used to study surgical volume, length of stay,
charges, and mortality for 606 liver resections performed at all acute-care hospitals between January 1990 and June 1996.
One high-volume provider accounted for 43.6% of discharges, averaging 40.6 cases per year. In comparison, the remainder of
resections were performed at 35 other hospitals, averaging 1.5 cases per year. Data were stratified into these high- and low-volume
groups, and adjusted outcomes were compared. The mortality rate for all procedures in the low-volume group was 7.9% compared
to 1.5% for the high-volume provider (P <0.01, relative risk = 5.2). No overall differences were observed between low- and high-volume providers in total hospital
charges. When analyzing by procedure type and diagnosis, lower mortality was seen in the high-volume center for both minor
and major resections, as well as resections for metastatic disease. It was concluded that hepatic resection can be performed
more safely and at comparable cost at high-volume referral centers.
Neuroendocrine liver metastases are rare, yet they represent an entity that has attracted much attention lately. The protracted course of neuroendocrine tumors and the hormone origin of their typical incapacitating symptoms constitute a logical basis for well founded and bespoke treatment. Demonstration of the liver secondaries is best done by ultrasonography (US) and contrast-enhanced computed tomography (CT), which on the whole have replaced the invasive angiography techniques. By use of histochemical and molecular biologic methods the exact nature of the tumor can be typified in tissue samples obtained percutaneously, laparoscopically, or surgically. Localization of nonpalpable metastases of the liver is best done by intraoperative US. Surgical removal of liver metastases is curative in some cases and is usually effective in relieving the symptoms. Also, palliative debulking or cytoreductive surgery is often worthwhile as it offers a chance of prolonged survival and symptom relief. Similar benefits are achieved by ischemic therapy preferably by temporary dearterialization, which in our department is done on an outpatient basis using a specially designed (externally controlled) occluder applied during a single laparotomy that includes debulking when appropriate as well as cholecystectomy. Hormonal therapy with somatostatin analogs may be used as a single treatment or in combination with ischemic therapy. It has an ensured symptom-reducing effect, whereas its influence on tumor growth is unsettled. Lately similar effects have been ascribed to human leukocyte interferon. In conclusion the specific characteristics of neuroendocrine tumors and the available treatment arsenal favor an active treatment approach in patients who have developed liver metastases.
This review summarizes regional strategies for management of neuroendocrine liver metastases (NLM), including hepatic resection, ablation, liver transplantation, and hepatic arterial embolization/chemoembolization. Despite early disease recurrence and/or progression, resection of NLM with or without combined ablation provides long-term survival and symptom improvement. When complete resection of gross liver disease is not feasible, resection as a tumor debulking strategy should be considered in patients with extreme hormonal symptoms refractory to other treatments or with tumors in locations that would affect short-term quality of life. Hepatic arterial embolization with or without local instillation of chemotherapy may induce disease response, symptomatic improvement, and prolonged survival in patients with unresectable NLM. Early disease recurrence, high postoperative mortality, the absence of extensive experience, and lack of universal indications for organ allocation preclude orthotopic liver transplantation as an option for most patients with unresectable NLM.
Forty-four patients irradiated for metastatic or unresectable carcinoid tumors at Memorial Sloan-Kettering Cancer Center from 1950 to 1986 were studied. The response to radiation was analyzed at four sites: epidural space (11 pts), brain (8 pts), bone (8 pts), and abdominal (17 pts). Although survival was generally poor, substantial palliation was achieved in most cases. No patient with brain metastases had progression of intracranial disease after radiation therapy (median dose: 3300 cGy); all died of progression of systemic metastases (median survival: 4 months). Infield control following radiation therapy for epidural and osseous metastases was achieved in 77% and 78% of sites, respectively, with median doses of 3000 cGy and 4000 cGy. Median survival for epidural and bone metastases was 11 and 13 months, respectively. In-field control was obtained in 62% of patients with intraabdominal disease (median dose: 2700 cGy). Among the subset of seven patients who were irradiated at ten sites of unresectable abdominal (non-hepatic) disease, the median survival was 23 months with 80% achieving a complete or partial response and 50% maintaining permanent in-field control. No dose-response relationship was demonstrated. Radiation therapy can achieve local control and symptomatic palliation in most patients with metastatic carcinoid tumors. Our current recommendation would be to treat non-hepatic sites with 4500-5000 cGy in 4-5 weeks. More rapid fractionation schemes could be used for patients with limited life expectancies.
Unlike its lethal exocrine counterpart, islet cell carcinoma of the pancreas is an indolent neuroendocrine neoplasm. The majority of these tumors are hormonally active. When functioning, a number of clinical syndromes (for example, hyperinsulinism, Zollinger-Ellison and Cushing's syndromes) may be evident. Fifty-eight patients surgically treated between 1965 and 1984 were retrospectively analyzed. The purpose of this study was to determine the distribution of functioning versus nonfunctioning tumors and the response to type of therapy. Mean postoperative follow-up was 7.4 years. Survival and prognostic indices were calculated by the Kaplan-Meier method and compared with log-rank tests. Of the group, 54% had functioning and 46% nonfunctioning tumors. Gastrinomas were the most common functioning tumors encountered (19%). Of interest was the finding that nonfunctioning tumors increased steadily during the last 15 years of the study (25% to 65%). Curative resections were performed in 15 (26%) and noncurative procedures in 43 patients (74%), with an overall operative mortality rate of 3%. Symptomatic improvement was achieved in 90% (curative) and 51% (noncurative). Survival at 3 years was 87% and 66% for the curative and noncurative groups, respectively (p less than 0.1), with an overall 5-year survival of 42%. The absence of hepatic metastases was a major predictor of survival at 3 years (82% vs 56%, p less than 0.05). Survival was statistically better at 3 years in those patients with gastrinomas compared with patients with nonfunctioning tumors (91% vs 58%, p less than 0.05). Although surgical cure is rare, significant long-term palliation may be achieved in a large percentage of patients with an aggressive surgical approach, occasional total gastrectomy, combination chemotherapy, H2 blockade, when indicated, and, most recently, with the new long-acting analogue of somatostatin.
A prospective Phase II trial of combination chemotherapy in patients with metastatic carcinoid tumors was conducted by the Southwest Oncology Group. The therapy included 5-fluorouracil, Adriamycin, cyclophosphamide, and streptozotocin (FAC-S) or the same combination without Adriamycin (FC-S) in patients with heart disease. Seventy-four patients were entered and two were ineligible. Sixty-nine of the 72 were histologically reviewed. Six patients were declared ineligible after this review. Fifty-six patients received FAC-S, and nine received FC-S (one patient was inevaluable). The response rates were 31% and 22%, respectively. The median survival of all patients was 10.8 months. The analyses of various clinical and histologic parameters indicated that responses were more common in patients with gastrintestinal carcinoids; there was also a tendency toward shorter survival in patients with tumors that had a higher mitotic rate or the atypical and/or undifferentiated histologic pattern. The FAC-S combination can produce objective responses in patients with metastatic carcinoid tumors, but these are generally partial and brief. It was also concluded that currently available chemotherapy is inadequate.
EST 5275 is a phase II and III study of fluorouracil plus streptozocin (5-FU plus STZ) or doxorubicin in patients with measurable progressive carcinoid tumor. Among one hundred seventy-two cases with no prior chemotherapy and no heart disease, the response rate was 22% for 5-FU plus STZ and 21% for doxorubicin, while the median response duration and median survival were 31 weeks and 64 weeks for the combination and 26 weeks and 48 weeks for doxorubicin. Thirty-three patients who failed 5-FU plus STZ crossed over to doxorubicin and achieved an 18% response. Of the thirty-five patients who failed on doxorubicin, 29% responded to 5-FU plus STZ. Hematologic toxicity was similar for both treatments; however, the 5-FU plus STZ patients experienced more vomiting but acceptable renal toxicity. Both chemotherapy regimens have antitumor activity in carcinoid tumors.
To compare the effect of octreotide with f placebo on symptoms, tumour marker and quality of life in patients with gastrointestinal neuroendocrine tumours and liver metastases.
A blinded, placebo-controlled, cross-over study was performed. The number of flushing epidodes and diarrhoea episodes were registered for 1 week prior to the study and for the 8-week duration of the study. Quality of life and 24-h urinary 5-hydroxyindoleacetic acid (5-HIAA) excretion were measured before the start, and at 4 and 8 weeks. Quality of life was registered with the Psychosocial Adjustment to Illness Scale (PAIS) and 5-HIAA measured by high-performance chromatography with electrochemical detection. 5-HIAA values exceeding 45 mumol 24 h-1 were considered to be elevated.
The study was performed in a tertiary referral centre.
Twelve patients were approached; eleven patients were included, with a mean age of 56.5 (range 30-72) years. The primary tumour originated from the small intestine in nine and from the pancreas in two patients. The main symptoms were diarrhoea, flushing and nausea. The 24-h excretion of 5-HIAA was increased in all patients.
Patients were treated for 4 weeks with octreotide (100 micrograms) subcutaneously, twice daily, and for 4 weeks on placebo (octreotide vehicle) in random starting order.
The main outcome measures were the number of episodes of the main clinical symptom(s) and 24-h 5-HIAA excretion.
Octreotide lowered diarrhoea and flushing frequency significantly compared to placebo. 5-HIAA excretion was reduced during treatment with the active drug. Two domains of the PAIS were significantly improved, indicating that the reduction of tumour marker and symptoms were clinically important.
The clinical effect of octreotide on symptoms in patients with neuroendocrine tumours was demonstrated in a controlled, prospective trial.
Metastatic neuroendocrine malignancies frequently cause incapacitating endocrinopathies, and metastases predominant in the liver. Hepatic resection of metastases from such tumors is attractive because the natural history of neuroendocrine tumors is protracted, clinical severity of the endocrinopathy correlates with tumor volume, and local and intrahepatic growth characteristics often allow complete resection.
To define the role of hepatic resection for metastatic neuroendocrine tumors, the records of 74 patients who underwent hepatic resection for such tumors between 1984 and 1992 were reviewed. Neuroendocrine tumors were classified by site of origin and clinical endocrinopathy. Survival, and type and duration of symptomatic response, were assessed as the major outcomes of this study.
There were 50 carcinoid, 23 islet-cell, and 1 atypical neuroendocrine tumors. Resections included 36 hemihepatectomies or extended hepatectomies and 38 nonanatomic resections. Thirty-eight primary tumors were resected concomitantly. Perioperative mortality was 2.7% and morbidity was 24%. Four-year survival was 73%. Overall postoperative symptomatic response rate was 90% with a mean duration of response of 19.3 months.
Hepatic resection for metastatic neuroendocrine malignancies is safe, provides effective palliation, and probably prolongs survival.
Liver metastases from neuroendocrine tumors often present with disabling symptoms due to syndromes of hormonal excess. A locally destructive technique such as hepatic cryotherapy not only alleviates symptoms but may improve survival in this group of patients.
Six patients with metastatic neuroendocrine tumors were treated with hepatic cryotherapy. Four patients were symptomatic and three of these had elevated tumor markers from ectopic hormone production.
All patients are alive and asymptomatic, with a median follow-up of 24 months (range, 6 months to 6 years). All have had a complete radiologic response. All with elevated preoperative markers have had a greater than 89% decrease in tumor markers. Coagulopathy occurred in two patients necessitating additional surgery, but there was no other morbidity attributable to the cryotherapy.
To the authors' knowledge, this study demonstrates for the first time that hepatic cryotherapy offers supportive treatment for patients with neuroendocrine tumors metastatic to the liver. Cryotherapy alleviates symptoms and may improve survival.
We reviewed our experience with 34 patients with metastatic endocrine tumors (METs) who were treated by different modalities. Eight patients were treated by chemotherapy or chemoembolization because of stable disease or surgical contraindications. Seventeen patients underwent curative or cytoreductive surgical resection. Nine patients received grafts based on the following criteria: no extrahepatic spread on imaging workup and nonresectable symptomatic metastatic disease. Of the eight medically treated patients, the five patients with initial stable clinical condition are alive 32 to 56 months after referral. Of the 17 patients treated by liver resection, 13 are alive 6 to 108 months after surgery, and 7 are disease-free. After curative resection, the 5-year actuarial survival and disease-free survival rates were 62% and 52%, respectively. Of the nine grafted patients, three patients grafted for carcinoid tumor are alive at 15, 24, and 62 months, one of whom has a late recurrence. Our results indicate that therapeutic indications for METs should be based on age, clinical symptoms, histologic type, and tumor extension: Patients with stable MET may benefit from surgical restraint; liver resection in patients with aggressive MET may provide good long-term palliation and possibly cure one-third of the patients; liver transplantation should be restricted to young patients with nonresectable carcinoid MET but remains a high-risk operation because of previous surgery and chemoembolization.
While the prognosis for patients with untreated liver metastases from neuroendocrine primaries is rather good, they often suffer disabling symptoms due to syndromes of hormonal excess. Thirteen patients with metastatic neuroendocrine tumours were treated by hepatic cryotherapy; seven patients were symptomatic and five of these had elevated levels of hormonal tumour markers. Twelve patients are alive and mostly asymptomatic with a median follow up of 13.5 months; one patient died after 45 months of bronchopneumonia without evidence of tumour recurrence. All patients with elevated preoperative tumour markers have had a significant fall in markers postoperatively. Two patients were returned to the operating theatre for coagulopathy-associated bleeding: one patient each developed acute renal failure and pulmonary embolism, but there was no mortality. This study shows that hepatic cryotherapy offers a useful treatment option for this group of patients, alleviates symptoms and may have an impact on survival.
Neuroendocrine tumors commonly metastasize to the liver. Although surgical resection is considered a treatment option for patients with localized metastases confined to the liver, the longterm survival benefit of liver resection has not been clearly demonstrated. We examined the survival of patients undergoing liver resection for this disease.
Between 1984 and 1995, we evaluated 38 patients with liver-only metastases from neuroendocrine tumors, including 21 carcinoid, 13 islet cell, and 4 atypical neuroendocrine neoplasms. Data from a combined prospective and retrospective database and a tumor registry were analyzed. Of these patients, 15 underwent complete resection of all known disease. The remaining 23 patients, who also had disease confined to the liver, had comparable tumor burden but were believed to be unresectable. The longterm survival rates of these two groups were compared.
Patients who underwent liver resection did not differ from those who were unresectable with regard to age, pathology, primary tumor site, serum alkaline phosphatase levels, or percentage of the liver involved. All resections were complete, leaving no residual disease, and consisted of lobectomy (n = 3), segmentectomy (n = 1), and wedge resections (n = 11). There were no operative deaths. Patients who underwent hepatic resection had a significantly longer survival than unresected patients. Although median survival had not been reached in resected patients, the median survival in the unresectable group was 27 months. Patients who underwent liver resection had a higher 5-year actuarial survival (73% versus 29%).
Hepatic resection in selected patients with isolated liver metastases from neuroendocrine tumors may prolong survival. This conclusion was reached by comparing our resected group with an unresectable group with similar tumor burden.
Hepatic resection for colorectal metastases has been established as the best option for patients with 4 or less lesions meeting specified criteria. Recently, the use of intraoperative ultrasound has increased the detection of previously occult liver lesions, and cryotherapy has allowed the treatment of liver lesions in inaccessible areas with less destruction of normal liver in the case of multiple lesions. 14e prospectively performed hepatic resection or cryotherapy to test the hypothesis that more than 4 liver metastases could be safely and successfully treated with improved long-term survival.
From August 1993 to January 1999, 137 patients with liver metastases from colorectal cancer were treated with hepatic resection or cryotherapy at the Medical College of Wisconsin. Preoperative and postoperative computed tomography scans, intraoperative assessments of lesion number and curability, number of blood transfusions administered, length of stay, complications experienced, and overall survival rates were reviewed.
One hundred thirty-seven patients were explored. Treatment consisted of resection alone in 34, cryotherapy alone in 20, both treatments in 52, and no treatment was possible in 31 patients. "Curability" was defined as complete resection or cryotherapy of all identifiable tumor at the conclusion of the operation. A Cox proportional hazards model demonstrated that survival was determined by the destruction of all identifiable metastases (P < . 001) and was not statistically influenced by age, gender type of therapy, or the number of metastases treated.
Surgical treatment of colorectal liver metastases remains the best option for patients with this disease. A key factor in overall survival is the destruction or resection of all identifiable disease and not the number of tumors per se. Using cryotherapy as an addition to the surgical arsenal, patients previously deemed unresectable because of the number of lesions have a chance for long-term survival. This study demonstrates improved long-term survival for "cured" patients with more than 4 metastatic lesions, thereby extending the indications for resection/ablation.
Neuroendocrine tumors are usually slow growing and carry a prolonged prognosis. The presence of liver metastases significantly impairs long-term survival. The clinical experience with 28 patients admitted since 1981 for liver metastases from neuroendocrine tumors was retrospectively reviewed to analyze the clinical and surgical management and to evaluate their outcome.
Surgery was indicated in 25 (89.2%) patients. Three had metachronous metastases. A correct diagnosis of these liver metastases was achieved before laparotomy in 15 (68.1%) of the remaining 22. The primary tumor site, unknown in 14/22 patients, was located during surgery only in 8 (57.1%).
Due to tumoral spread, surgery was limited to exploration in 3 cases. Liver resections were performed in 19/22 patients (3 for palliation): 11/19 (57.9%) were major hepatectomies and in 8/19 (42.1%) cases they were accomplished by procedures for removing the primary tumor. Overall, curative procedures were carried out in 16/28 (57.1%). Resections were performed in 6 cases without the knowledge of the primary site. There was no operative mortality. Overall recurrence rate was 50.0%. Four-year actuarial survival was 92.6% after resection and 18.5% for patients that did not receive surgery (P < 0.001).
Our experience confirms that the small number of patients makes the management of liver metastases from neuroendocrine tumors difficult to plan. In consideration of the satisfactory results achieved with an aggressive policy of resection, we advise referral of these patients to specialized liver units where major hepatic procedures, even if extended, can be safely performed.
While liver resection for metastatic disease from colorectal cancer extends survival in selected patients, the efficacy of hepatectomy for metastases from other malignancies has not been defined.
Between 1988 and 1998, 20 hepatic resections were performed in 18 patients (2 underwent a double resection due to recurrence) as treatment of noncolorectal metastases. One-, 2-, and 5-year overall and disease-related actuarial survival rates were calculated.
No intraoperative or early postoperative deaths were reported. Seven minor (30%) and 1 major (5%) postoperative complications occurred; mean blood loss was 401 +/- 324 ml. In 25% of patients, intra- or postoperative blood transfusion was needed. The mean postoperative hospital stay was 13. 2 days (range 9-23). The overall actuarial survival rate was 54% at 1 year, 42% at 2 years, and 21% at 5 years (mean 38 +/- 11 months). Survival is related to the primary tumor nature.
Hepatic resection for metastases from noncolorectal carcinoma is safe and feasible, with a relatively low incidence of intra- or postoperative complications and a short hospital stay. Although it achieves good results in terms of survival in patients suffering from neuroendocrine metastases, it could also have a cytoreductive effect for other tumors.
This randomized, controlled trial assessed the efficacy of transarterial Lipiodol (Lipiodol Ultrafluide, Laboratoire Guerbet, Aulnay-Sous-Bois, France) chemoembolization in patients with unresectable hepatocellular carcinoma. From March 1996 to October 1997, 80 out of 279 Asian patients with newly diagnosed unresectable hepatocellular carcinoma fulfilled the entry criteria and randomly were assigned to treatment with chemoembolization using a variable dose of an emulsion of cisplatin in Lipiodol and gelatin-sponge particles injected through the hepatic artery (chemoembolization group, 40 patients) or symptomatic treatment (control group, 40 patients). One patient assigned to the control group secondarily was excluded because of unrecognized systemic metastasis. Chemoembolization was repeated every 2 to 3 months unless there was evidence of contraindications or progressive disease. Survival was the main end point. The chemoembolization group received a total of 192 courses of chemoembolization with a median of 4.5 (range, 1-15) courses per patient. Chemoembolization resulted in a marked tumor response, and the actuarial survival was significantly better in the chemoembolization group (1 year, 57%; 2 years, 31%; 3 years, 26%) than in the control group (1 year, 32%; 2 years, 11%; 3 years, 3%; P =.002). When adjustments for baseline variables that were prognostic on univariate analysis were made with a multivariate Cox model, the survival benefit of chemoembolization remained significant (relative risk of death, 0.49; 95% CI, 0.29-0.81; P =.006). Although death from liver failure was more frequent in patients who received chemoembolization, the liver functions of the survivors were not significantly different. In conclusion, in Asian patients with unresectable hepatocellular carcinoma, transarterial Lipiodol chemoembolization significantly improves survival and is an effective form of treatment.
There is no standard treatment for unresectable hepatocellular carcinoma. Arterial embolisation is widely used, but evidence of survival benefits is lacking.
We did a randomised controlled trial in patients with unresectable hepatocellular carcinoma not suitable for curative treatment, of Child-Pugh class A or B and Okuda stage I or II, to assess the survival benefits of regularly repeated arterial embolisation (gelatin sponge) or chemoembolisation (gelatin sponge plus doxorubicin) compared with conservative treatment. 903 patients were assessed, and 112 (12%) patients were finally included in the study. The primary endpoint was survival. Analyses were by intention to treat.
The trial was stopped when the ninth sequential inspection showed that chemoembolisation had survival benefits compared with conservative treatment (hazard ratio of death 0.47 [95% CI 0.25-0.91], p=0.025). 25 of 37 patients assigned embolisation, 21 of 40 assigned chemoembolisation, and 25 of 35 assigned conservative treatment died. Survival probabilities at 1 year and 2 years were 75% and 50% for embolisation; 82% and 63% for chemoembolisation, and 63% and 27% for control (chemoembolisation vs control p=0.009). Chemoembolisation induced objective responses sustained for at least 6 months in 35% (14)of cases, and was associated with a significantly lower rate of portal-vein invasion than conservative treatment. Treatment allocation was the only variable independently related to survival (odds ratio 0.45 [95% CI 0.25-0.81], p=0.02).
Chemoembolisation improved survival of stringently selected patients with unresectable hepatocellular carcinoma.
Our objective was to report the outcome in patients with liver metastasis from endocrine tumors who underwent transarterial chemoembolization (TACE) as first-line non-surgical treatment. From January 1990 to December 2000, 14 patients with progressive unresectable liver metastases from digestive neuroendocrine tumor were treated with TACE (mean of 3.6 sessions) before any non-surgical treatment (somatostatin analogue, chemotherapy or interferon). Liver involvement was less than 50% in 11 patients. Size of the largest lesion ranged from 1.5 to 10 cm. Ten patients presented with carcinoid symptoms. The TACE was performed with Doxorubicin emulsified in Lipiodol and gelatin sponge particles. Symptomatic response upon flushes and/or diarrhea was complete in 7 of 10 cases and partial in 2 of 10 cases. An objective morphologic response was noted in 12 of 14 cases. The 5- and 10-year survival rate from diagnosis was 83 and 56%, respectively. Six patients were alive at the end of the study after 27-100 months from first TACE and 38-142 months from diagnosis. Three of them were successfully palliated for 55, 69, and 100 months with only TACE as treatment. Long-term palliation is possible in unresectable liver metastases from digestive neuroendocrine tumors with a few sessions of TACE as first-line and eventually exclusive treatment.
Hepatic metastases from neuroendocrine tumors have a protracted natural history and are associated with endocrinopathies. Resection is indicated for symptom control. Previous reports have suggested improvement in survival for patients undergoing debulking procedures.
The records of all consecutive patients undergoing resection of hepatic metastases from neuroendocrine tumors between 1977 and 1998 were reviewed. Tumors were classified according to histology, endocrine activity, and primary location. Patients lost to followup before 1 year were excluded. Followups were based on outpatient evaluations and were updated by correspondence. The Kaplan-Meier method was used to generate survival and recurrence curves, and the log-rank test was used for comparison.
A total of 170 patients fulfilled the inclusion criteria, of whom 73 were men. Mean age (+/-SD) was 57 (+/-11.5) years. Carcinoid (n = 120) and nonfunctioning islet cell tumors (n = 18) predominated; the ileum (n = 85) and the pancreas (n = 52) were the most common primary sites. Major hepatectomy (one or more lobes) was performed in 91 patients (54%). The postoperative complication rate was 14%, and two patients died (1.2%). Operation controlled symptoms in 104 of 108 patients, but the recurrence rate at 5 years was 59%. Operation decreased 5-hydroxyindoleacetic acid levels considerably, and no patient experienced carcinoid heart disease postoperatively. Recurrence rate was 84% at 5 years. Overall survival was 61% and 35% at 5 and 10 years, respectively, with no difference between carcinoid and islet cell tumors.
Hepatic resection for metastatic neuroendocrine tumors is safe and achieves symptom control in most patients. Debulking extends survival, although recurrence is expected. Hepatic resection is justified by its effects on survival and quality of life.
Primary hepatic carcinoid tumors (PHCTs) are extremely rare, and fewer than 50 cases have been reported in the English-language literature. We report a patient with a PHCT and review the cases in the literature.
Our patient presented with symptoms and underwent liver resection for PHCT and regional lymph node metastasis. He underwent two more liver resections over the following 7 years for recurrent PHCT. Cases reported in the English-language literature were reviewed and survival analysis was performed with the Kaplan-Meier method. The survival impacts of age, gender, tumor foci, extrahepatic metastasis, unilobar versus bilobar disease, and type of preoperative treatment were determined by means of log-rank test.
Our patient has been free of symptoms for 14 years of follow-up and free of disease for 8 years of follow-up. Forty-eight cases of PHCT were found in the literature, and 92% of these patients underwent resection. Actuarial 5- and 10-year survival for all patients was 78% and 59%, respectively, whereas for resected patients, 10-year survival was 68%. The administration of preoperative chemotherapy, radiation therapy, or chemoembolization did not impact survival, nor did age, gender, presence of extrahepatic metastasis, number of tumors, or distribution of the tumor within the liver.
Resection is the treatment of choice for PHCT and has provided favorable outcomes. Resection for PHCT can be performed in most patients and offers long-term survival.
Neuroendocrine tumors of the gastrointestinal tract (carcinoids, pancreatic endocrine tumors) have low malignant potential but can decrease survival rates if they spread to the liver (LNET).
The records of 16 patients with LNET primarily from gastrointestinal carcinoids treated surgically were retrospectively reviewed.
There were 12 women and 4 men. Median age was 56 years (range 25 to 75). Thirteen (81%) had a carcinoid tumor and 5 had gastrinoma. Two patients with multiple endocrine neoplasia type 1 had both a gastric carcinoid and a jejunal gastrinoma. Eight patients (50%) had the carcinoid syndrome. Each patient had all identifiable LNET either resected or ablated. Ten patients had liver wedge resections, 1 right trisegmentectomy, 5 left hepatic lobectomies, and 2 radiofrequency ablations. Thirteen (81%) patients had concomitant bowel resections. Two patients had concomitant total gastrectomies to remove stomach primaries. The final patient had an extraintestinal pelvic primary or a liver primary. There were no operative deaths, and all 8 (100%) patients with the carcinoid syndrome had amelioration of symptoms. The 5-year actuarial survival rate was 82% with a median follow-up of 32 months.
This study demonstrates that liver and concomitant extrahepatic surgery can be performed safely in patients with liver metastases because of carcinoids or pancreatic endocrine tumors. It results in excellent long-term survival and amelioration of symptoms. Surgery should be the first-line therapy for patients with LNET.
Gastrointestinal carcinoid tumors are rare neuroendocrine tumors arising from the embryologic primitive gut. Depending on the location in the gastrointestinal tract, these tumors may secrete a variety of hormonally active substances. However, many of these tumors are found incidentally, or the diagnosis is made postoperatively. Also, there is a significant incidence of multicentric carcinoid tumors and synchronous noncarcinoid malignancies in these patients. Treatment is usually based on the size of the tumor. Surgical resection remains the cornerstone of therapy. For advanced metastatic disease, somatostatin analog therapy and surgical debulking provide the best symptomatic relief and may improve survival. Recent studies have demonstrated a benefit from radiolabeled somatostatin analogs for carcinoid tumor localization. In contrast, radiolabeled somatostatin analogs have shown little therapeutic benefit. Future directions include somatostatin receptor profiling of carcinoid tumors, with somatostatin analog therapy targeting the specific receptors.
A phase II trial of combination therapy in patients with metastatic carcinoid tumor
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Should hepatic resections be performed at high-volume referral centers? Touzios et al Annals of Surgery @BULLET Volume 241 Result of liver resection as treatment for metastases from noncolorectal cancer
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