Ablative therapies for liver metastases of digestive endocrine tumours

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.     

Ablative therapies for liver metastases of gastroenteropancreatic endocrine tumors

Hepatic metastases are frequent in patients with gastroenteropancreatic (GEP) endocrine tumors. The presence of hepatic metastases affects overall prognosis and quality of life especially in the presence of debilitating functional syndromes. Surgery, although the method of choice for hepatic metastases, is usually impossible due to disease extent. Results of systemic chemotherapy are also disappointing especially in patients with metastases from midgut GEP tumors. These latter patients usually have carcinoid syndrome which can be controlled by somatostatin analogues. Other therapeutic options in the treatment of highly vascular liver metastases from GEP tumors are locoregional strategies by inducing vascular occlusion resulting in ischemia and necrosis of tumoral tissue. Surgical ligation of the hepatic artery or transient hepatic ischemia has been replaced by transcatheter arterial chemoembolization (TACE). TACE has proven effective in controlling symptoms and gives objective tumor response in about half of patients. Other regional destructive methods, used either alone or in combination with surgery, include radiofrequency ablation and cryotherapy. The latter strategies are poorly evaluated to date and are usually adjuncts to surgery and reserved for limited disease.     

Hepatic artery embolization for treatment of endocrine gastrointestinal tumors with liver metastases

We report about six patients with endocrine gastrointestinal tumors and liver metastases (four insulinomas, one carcinoidtumor, one paraganglioma), who were treated with a transluminal embolization of the hepatic artery when cytostatic therapy was ineffective. In two patients a second embolization was necessary after recurrence of clinical symptoms. All patients tolerated the procedure without severe side-effects and improved clinically. Serum insulin levels and HIAA-secretion rapidly decreased. Survival lasted from 3 to 32 months (median 15 months). Five additional patients with metastatic endocrine gastrointestinal tumors, observed during the same time period, were regarded as not suitable for hepatic artery embolization. In selected patients, hepatic artery embolization may become an effective therapy for treatment of metastasing endocrine gastrointestinal tumors when conventional medication with cytostatic drugs has become ineffective.     

Combined liver transplantation plus imatinib for unresectable metastases of gastrointestinal stromal tumours

Therapeutic options for treating unresectable hepatic metastases of leiomyosarcomas were scarce until a few years ago. Recent advances in the study of the biology of intestinal tumours have radically changed our knowledge of their pathogenesis. Many of the tumours previously considered as leiomyosarcomas are now identified as gastrointestinal stromal tumours (GISTs). The introduction of imatinib (an antineoplasic drug that specifically acts on the pathogenesis of these tumours) has shown promising results in patients with advanced GISTs. We present three patients with the initial diagnosis of unresectable hepatic metastases of leiomyosarcomas. They received liver transplants. All three had tumour recurrences after transplantation. Histological re-evaluation identified a stromal origin of the tumours, and the patients were treated with imatinib therapy (400 mg/day). Recurrence occurred in all patients after a mean of 38.3 months, but imatinib treatment achieved control of the tumours. The current survival times with the combination of transplantation and imatinib are 92, 48 and 46 months for the three patients. This series is small and inconclusive, but imatinib treatment showed promising results. The treatment options for patients with unresectable metastases of GISTs must be defined, as in these three patients liver transplantation achieved a disease-free status but all had tumour recurrences before starting the imatinib treatment.     

Chemoembolization of hepatic metastases from intestinal neuroendocrine tumours

Gastrointestinal neuroendocrine tumours, i.e. carcinoids and islet cell tumours, often metastasize diffusely into the liver, rendering complete surgical resection impossible. Unlike other malignancies, prolonged survival may occur even in advanced disease. Chemotherapy of these rare tumours is not only aimed at size reduction (objective response) but also at symptom reduction (biological response). Systemic therapy, using 5-fluorouracil, doxorubicin, cisplatin, cyclophosphamide, somatostatin-analogue, interferon or streptozotocin yielded response rates of up to 69%. Since neuroendocrine tumours are generally hypervascular locoregional chemotherapy and chemoembolization also have been used successfully. However, even though severe complications are rare, some degree of pain and the post-embolization syndrome are almost inevitably present. The expected therapeutic efficacy must be weighed against possible side effects. The best result that can be hoped for in the chemoembolization of intestinal neuroendocrine metastatic disease is, as yet, only palliation.     

Chemoembolization for liver metastases from medullary thyroid carcinoma

BACKGROUND: Medullary thyroid carcinoma (MTC) is a well-differentiated neuroendocrine tumor. Distant metastases are the main cause of cancer-related death. Systemic chemotherapy produces only rare tumor responses. Somatostatin analogs and other available modalities are poorly effective to control symptoms. AIMS: The aim of our study was to evaluate the impact of liver transarterial chemoembolization (TACE) in MTC patients with predominant and progressive liver metastases. PATIENTS AND METHODS: Twelve MTC patients underwent 18 TACE courses (mean, 1.5; range, 1-2). Response evaluation criteria in solid tumors were used to evaluate tumor responses. Symptomatic responses were defined by more than a 25% decrease of symptoms intensity. RESULTS: Partial radiological tumor response was obtained in five patients (42%) with a median duration of 17 months (mean, 19; range, 15-28 months), stabilization in five (42%) with a median duration of 24 months (mean, 24; range, 4-39 months), and progression in the remaining two (16%). The five partial tumor responses were observed in the nine patients with less than 30% liver involvement. Clinical response was observed in two of the five patients with diarrhea. Carcinoembryonic antigen did not appear to be a useful marker in this setting. Significant grade 3-4 toxicity was observed in one patient who had a major tumor necrosis after TACE. CONCLUSION: TACE should be considered for treating MTC patients with progressive and predominant liver metastasis, and preferably at an early stage during the course of metastatic disease.     

A comparison between patients with gastrointestinal stromal tumours diagnosed with isolated liver metastases and liver metastases plus sarcomatosis

Objectives: This study was conducted to compare overall survival (OS) in patients presenting with isolated hepatic metastases with that of patients with synchronous metastatic disease to the liver and sarcomatosis on a background of gastrointestinal stromal tumours (GISTs).Methods: Patients presenting with metastatic GISTs during 1999–2009 were identified. Survival outcomes were compared between groups.Results: Of the 193 patients with GISTs, 43 patients presented with isolated hepatic metastases and 16 presented with synchronous metastases to the liver and sarcomatosis. Thirteen patients with metastases to the liver and sarcomatosis underwent surgery, and 34 patients with metastatic disease solely to the liver underwent hepatic resection. The proportion of patients treated with preoperative tyrosine kinase inhibitor (TKI) therapy was similar in both groups. Similar OS was observed in both groups (isolated liver metastases group: 40.5 months; liver metastases and sarcomatosis group: 28.7 months; P = 0.620).Conclusions: Overall survival in patients with GIST and metastatic disease to the liver and sarcomatosis is similar to that in patients with isolated metastatic liver disease. Although patients with a greater disease burden might be expected to show worse survival, these data do not reflect this assumption.     

Endocrine tumours of the gastrointestinal tract. Biotherapy for metastatic endocrine tumours

Somatostatin analogues have been the mainstay of symptomatic management of patients with neuroendocrine tumours (NETs) for two decades with the main mechanism of action being inhibition of peptide release. Evidence base for interferon use is perhaps less clear. It may contribute to symptom control by abrogating peptide release, and there is some evidence that it has an anti-proliferative action. Combination of somatostatin analogues and interferon provides symptom control, mainly by effecting a reduction in the amount of circulating, physiologically active, peptide hormones. Treatment can also provide disease stabilisation in a proportion of patients. In a minority of patients treatment may lead to partial response.     

Interventional therapies of unresectable liver metastases

Liver metastases are the major cause of mortality in patients with gastrointestinal carcinomas and other malignant tumors, carrying a poor prognosis and presenting considerable management. Surgical resection remains the only curative therapy for liver metastases up to now. However, only a small percentage of patients are suitable for curative resection due to many factors: multi-centric tumors, extrahepatic metastases, early vascular invasion, and coexisting advanced liver cirrhosis. In non-surgical cases, regional interventional therapies have led to a major break through in the treatment of unresectable liver metastases, which include transarterial chemoembolization (TACE), radiofrequency ablation (RFA), laser-induced thermotherapy (LITT), cryosurgical ablation (CSA), microwave coagulation therapy (MCT), percutaneous ethanol injection (PEI), and others. As a result of the technical development of locoregional approaches for unresectable liver metastases during recent decades, the range of combined interventional therapies has been continuously enlarged. The current roles of these treatment options for liver metastases are discussed in this review.     

Endocrine tumours of the gastrointestinal tract. Management of metastatic endocrine tumours

Gastroenteropancreatic tumours are rare. They compromise a heterogenous class of neoplasm. If there is no hypersecretion syndrome, symptoms may be uncharacteristic and thus diagnosis occurs rather late after the first manifestations of the disease. The most important prognostic parameters are histological classification, the localisation of the primary, the tumour size and stage at diagnosis, and the presence or absence of metachronous or synchronous neoplasia. The article will focus on the importance of each of these parameters for the various treatment options in patients with metastatic disease.     

Multipolar radiofrequency ablation of large hepatic metastases of endocrine tumours

Radiofrequency ablation (RFA) is a reliable method of creating thermally induced coagulation necrosis. Local recurrence after RFA of hepatic metastases is directly dependent on tumour size related to the free margin of ablation. To produce larger coagulation volumes a bipolar radiofrequency device was developed that allows the simultaneous activation of three active needles. This technique was used at laparotomy in a patient with liver metastases of an endocrine tumour. Coagulation size up to 12 cm in diameter could be created. The postoperative recovery of the patient was uncomplicated. No local recurrence was seen after 13 months of follow-up with computed tomography scan. The use of simultaneously operated multiple radiofrequency electrodes in a multipolar mode expands the treatment options for patients with large and unresectable intrahepatic metastases.     

Chemoembolization for liver metastases from colorectal carcinoma: risk or a benefit

Results from clinical trials do not allow definitive conclusions about the role of chemoembolization (ChE) in the treatment of colorectal cancer (CRC) liver metastases. The aim of present phase II study was to investigate toxicity and efficacy of ChE for patients, with unresectable colorectal liver metastases after failure of 5-FU based chemotherapy. Secondary endpoint was clinical benefit measurement. Eleven patients were enrolled in first stage (two-stage Simon design), 2 males/9 females, median age 60 (46-71). Performance status was I in 8 patients and II in 3 patients. All patients had radical surgery, 7 of them adjuvant chemotherapy and 4 systemic chemotherapy. The ChE regimen consisted of an injection of iodinated oil Lipiodol with mitomycin C (3 mg/ml). Repeated treatments were performed at 9- to 12-week intervals. We applied 17 ChE (median 1/pts.). Clinical benefit was a composite of measurements of pain, ECOG performance status, weight and tumor fever. Study was stopped after first stage because non of the patients (pts) achieved objective response (RECIST). Stable disease occurred in 5 pts (45%). Median time to progression was 3 months (range 3-9 months). Median survival was 9 months (range 4-16 months). A decrease of the baseline carcinoembryonic antigen level occurred in 0% of the cases. Clinical benefit was recorded in one patient. Common toxicity included a "postembolization syndrome," which consisted of fever, pain in the right upper quadrant, nausea, and vomiting. Grades 3-4 toxicity (NCI-CTC) followed transaminases 6/11, LDH 4/11. In addition, a drop in F V levels was noted in 5 pts, F VII in 9, F IX in 2 and F X in 10 pts. Decrease in At III levels occurred in 6 pts and FDP appeared in one. Thus, The ChE as performed in the present study did not appear to bring any benefit; furthermore, significant liver toxicity compromises the safety of such procedure.     

Gene expression profiles of progressive pancreatic endocrine tumours and their liver metastases reveal potential novel markers and therapeutic targets

The intrinsic nature of tumour behaviour (stable vs progressive) and the presence of liver metastases are key factors in determining the outcome of patients with a pancreatic endocrine tumour (PET). Previous expression profile analyses of PETs were limited to non-homogeneous groups or to primary lesions only. The aim of this study was to investigate the gene expression profiles of a more uniform series of sporadic, non-functioning (NF) PETs with progressive disease and, for the first time, their liver metastases, on the Affymetrix human genome U133A and B GeneChip set. Thirteen NF PET samples (eight primaries and five liver metastases) from ten patients with progressive, metastatic disease, three cell lines (BON, QGP and CM) and four purified islet samples were analysed. The same samples were employed for confirmation of candidate gene expression by means of quantitative RT-PCR, while a further 37 PET and 15 carcinoid samples were analysed by immunohistochemistry. Analysis of genes differentially expressed between islets and primaries and metastases revealed 667 up- and 223 down-regulated genes, most of which have not previously been observed in PETs, and whose gene ontology molecular function has been detailed. Overexpression of bridging integrator 1 (BIN1) and protein Z dependent protease inhibitor (SERPINA10) which may represent useful biomarkers, and of lymphocyte specific protein tyrosine kinase (LCK) and bone marrow stromal cell antigen (BST2) which could be used as therapeutic targets, has been validated. When primary tumours were compared with metastatic lesions, no significantly differentially expressed genes were found, in accord with cluster analysis which revealed a striking similarity between primary and metastatic lesions, with the cell lines clustering separately. We have provided a comprehensive list of differentially expressed genes in a uniform set of aggressive NF PETs. A number of dysregulated genes deserve further in-depth study as potentially promising candidates for new diagnostic and treatment strategies. The analysis of liver metastases revealed a previously unknown high level of similarity with the primary lesions.     

局部消融在肝细胞癌治疗中的应用

手术切除和肝移植被认为是肝细胞癌(HCC)根治性治疗手段,但仅有10%~20%的HCC患者能接受这些治疗。近些年来,射频消融、微波消融、冷冻消融及新近出现的不可逆电穿孔消融等局部治疗方法逐渐成为无法手术患者的替代治疗。除了局部控制肿瘤生长改善预后外,消融技术还有助于肿瘤降级以便二次切除。重点介绍了射频消融及联合其他治疗手段治疗HCC的进展,对射频消融与其他局部消融进行了比较,简述了智能导航技术在辅助消融中的应用,认为随着影像医学的发展以及其他相关领域的进步,未来消融技术在临床应用中将更加广泛。     

Aggressive surgery for liver metastases from gastrointestinal stromal tumors

Background/Purpose. The utility of hepatectomy for patients with metastatic liver tumors from gastrointestinal stromal tumors (GISTs) was evaluated in the present study.Methods. Between 1989 and 2001, ten patients with liver metastases from GIST (four men and six women; age, 34–77 years) underwent hepatectomy at our hospital. All patients underwent complete resection of the primary tumor and hepatectomy with or without microwave coagulation therapy (MCT) for all detectable hepatic tumors.Results. The median survival time after hepatectomy was 39 months (range, 1 to 96 months). There was one postoperative death. One patient is still alive with relapse of hepatic tumors, and the remaining eight patients died of disease (liver in six, peritoneum in one, and bone in one). Relapse of hepatic tumors occurred in seven patients. The disease-free rate after hepatectomy was 22% at 2 years and 11% at 5 years. The survival times of the four patients who received hepatic arterial chemoembolization for recurrent hepatic metastases were 7 months (still alive), 17, 23, and 28 months (average, 19 months).Conclusions. Our data suggest that aggressive surgery (hepatectomy and MCT) for all detectable hepatic tumors and hepatic arterial chemoembolization for recurrent hepatic metastases improve survival.     

Endoscopic resection techniques and ablative therapies for Barrett's neoplasia

Esophageal adenocarcinoma is the most rapidly increas- ing cancer in western countries.High-grade dysplasia (HGD)arising from Barrett’s esophagus(BE)is the most important risk factor for its development,and when it is present the reported incidence is up to 10% per patient-year.Adenocarcinoma in the setting of BE develops through a well known histological sequence,from non-dysplastic Barrett’s to low grade dysplasia and then HGD and cancer.Endoscopic surveillance programs have been established to detect the presence of neo- plasia at a potentially curative stage.Newly developed endoscopic treatments have dramatically changed the therapeutic approach of BE.When neoplasia is confined to the mucosal layer the risk for developing lymph node metastasis is negligible and can be successfully eradi- cated by an endoscopic approach,offering a curative in- tention treatment with minimal invasiveness.Endoscopic therapies include resection techniques,also known as tissue-acquiring modalities,and ablation therapies or non-tissue acquiring modalities.The aim of endoscopic treatment is to eradicate the whole Barrett’s segment,since the risk of developing synchronous and metachro- nous lesions due to the persistence of molecular aberra- tions in the residual epithelium is well established.