Christian Cahlin

Orthotopic liver or multivisceral transplantation as treatment of metastatic neuroendocrine tumors

Liver transplantation can be a therapeutic option for individual patients with neuroendocrine tumors metastatic only to the liver. In this consecutive series of 15 patients (5 multivisceral and 10 orthotopic liver transplantations) with well‐differentiated carcinoids, or endocrine pancreatic tumors, we allowed higher proliferation rate (Ki67 <10%), large tumor burden, and higher age than previous studies. Liver transplantation offered good relief of symptoms, long disease‐free intervals, and potential cure in individual patients. The survival of grafts and patients compared well with transplantation for benign disease. The overall 5‐year survival was 90%. The recurrence‐free survival of both multivisceral and liver transplantation related to the time after transplantation (about 20% at 5 years) despite inclusion of patients with higher risk. In conclusion, the critical prognosticators for long‐term outcome still remain to be defined. The experience with multivisceral transplantation for patients with endocrine tumors of the pancreatic head is still limited. Liver Transpl 13:327–333, 2007.

Effects of the mTOR inhibitor sirolimus in patients with hepatocellular and cholangiocellular cancer

BackgroundHepatocellular cancer (HCC), as well as cholangiocellular cancer (CCC), has an extremely poor prognosis due to the extent of tumor at diagnosis and the underlying liver disease. Sirolimus is used in the transplantation setting as an immunosuppressive agent, but it also possesses antiproliferative and antiangiogenic properties. The objective of the study was to evaluate the effect of sirolimus on HCC and CCC.MethodsIn a prospective single-arm protocol, the tumor response to sirolimus as the primary endpoint was studied in 21 patients with advanced HCC and nine with CCC. Sirolimus was administered once daily by mouth, with the dose adjusted to a serum trough level between 4 and 15 μg/ml. Tumor response was evaluated by computed tomography (CT) or magnetic resonance imaging (MRI), according to the Response Evaluation Criteria in Solid Tumors (RECIST), every third month. Secondary measures were overall survival, time to tumor progression, tumor markers, and side effects.ResultsOf the patients with HCC, one had partial remission (PR) and fi ve patients had stable disease (SD) at 3 months. Of the patients with CCC, three had SD. The median survival for patients with HCC was 6.5 months (range, 0.2–36 months) and that for patients with CCC was 7 months (range, 2.6–35 months).ConclusionTreatment of HCC and CCC with sirolimus can induce temporary PD or SD. This pilot study indicates that sirolimus might be a promising drug for this treatment, but further clinical studies elucidating the biological effects are advocated.

Indications and Results of Liver Transplantation in Patients with Neuroendocrine Tumors

Metastases from neuroendocrine (NE) tumors of the gastrointestinal tract, carcinoids, and endocrine pancreatic tumors (EPTs) can be confined to the liver for long periods and may exhibit slow growth. When considering liver transplantation (LTx) for patients with NE tumors, the expected results with conventional treatment must be weighed against the risk of LTx and immunosuppression. The following indications for LTx may be considered for patients with metastatic NE tumors limited to the liver: (1) tumors not accessible to curative surgery or major tumor reduction; (2) tumors not responding to medical or interventional treatment; and (3) tumors causing life-threatening hormonal symptoms. We excluded patients with poorly differentiated NE carcinoma or well differentiated NE carcinoma with a high proliferation index (Ki 67 > 10%). Over 4 years (1997–2001) we have performed transplants in nine patients (five with EPTs, four with carcinoids) with a mean ± SEM follow-up of 22 ± 5 months (range 4–45 months). Seven patients underwent orthotopic LTx and two multivisceral LTx. Eight patients are alive, six without clinical evidence of disease. Four patients developed recurrent tumors 9 to 36 months after LTx; two were detected at an early stage and underwent resection with curative intent. One patient with multivisceral Tx died after 4 months of posttransplant lymphoproliferative disease without tumor recurrence. In selected series LTx can offer good control of hormonal symptoms, a relatively long disease-free interval, and in individual cases potential cure.

A prospective, randomized, multi-centre trial of systemic adjuvant chemotherapy versus no additional treatment in liver transplantation for hepatocellular carcinoma

The role of adjuvant systemic chemotherapy in liver transplantation (LT) for hepatocellular carcinoma (HCC) is controversial. Here, we report the results of a Nordic prospective, randomized, multi‐centre trial of systemic low‐dose doxorubicin in patients with HCC. Between February 1996 and April 2004, 46 patients were randomized to receive either neoadjuvant doxorubicin in combination with LT (chemo group; n = 19) or LT alone (control group; n = 27). In the chemo group, doxorubicin was administered intravenously, 10 mg/m2 weekly, starting from acceptance onto the waiting list for LT. One intraoperative dose of 15 mg/m2 was given, and postoperatively doxorubicin was given weekly at a dose of 10 mg/m2, depending on the clinical course, up to a cumulative dose of 400 mg/m2. Actuarial, 3‐year overall survival (OS) and disease‐free survival (DFS) in the control group were 70% and 50%, respectively. In the chemo group, both OS and DFS were 63%. Freedom from recurrence at 3 years was 55% in the control group and 74% in the chemo group. None of the differences was statistically significant. Neoadjuvant treatment with systemic low‐dose doxorubicin seems not to improve either survival or freedom from recurrence in patients with HCC undergoing LT.

Liver Transplantation for Treatment of Metastatic Neuroendocrine Tumors

Abstract: Liver transplantation can be considered a therapeutic option for patients with neuroendocrine tumors only metastatic to the liver. Important selection criteria are well‐differentiated tumors and a low proliferation rate (Ki67 <10%). In this series, orthopic liver transplantation offered good relief of symptoms and long disease‐free intervals with initial survival of grafts and patients as in benign disease. The experience with multivisceral transplantation is still limited.

Liver transplantation for metastatic neuroendocrine tumor disease.

METASTASES from neuroendocrine tumors (NET) of the gastrointestinal tract, carcinoids, and endocrine pancreatic tumors (EPT) can be limited to the liver for long periods and may have slow growth. The symptoms are often related to hormone overproduction and debulking surgery, for example, liver resection, is recommended to achieve tumor remission or symptom palliation. If liver resection is not feasable, hepatectomy and orthotopic liver transplantation (OLT) have been proposed. For EPT where the primary tumor is located in the head of the pancrea it may be advantageous to resect the primary tumor and the liver metastases en bloc and perform a multivisceral transplantation (MVTx).

Isolated hepatic perfusion for liver metastases of malignant melanoma.

The objective was to analyze the outcome of three treatment strategies using isolated hyperthermic liver perfusion (IHP) with melphalan for liver metastases of malignant melanoma. It was designed as an exploratory study. The setting was a single-center study in a university hospital. The study was carried out on 27 patients. IHP was used with modifications during three different time periods (IHP I, IHP II and IHP III), in technique and temperature (amount of melphalan: 0.5, 1.0 and 2 mg/kg body weight in the perfusate; 41, 40 and 40°C). Tumor response was estimated according to WHO criteria with computed tomography or MRI. Mortality and morbidity were secondary measures. Six of 11 patients in the IHP I cohort experienced a partial response (PR). In the IHP II cohort, two patients of 11 experienced a complete response and five a PR. In the IHP III cohort, five of five patients experienced a PR. Six postoperative deaths were reported (27%) (three in the IHP I and three in the IHP II series), secondary to liver insufficiency and multiorgan failure. Treatment of liver metastases of malignant melanoma with isolated hyperthermic melphalan perfusion has shown an impressive tumor response rate, which seems to be higher than the response rates reported for other systemic chemotherapy regimens. The maximum tolerated dose for melphalan in the perfusate was surpassed with a 2 mg/kg body weight. By modifying the technique and restricting the allowed tumor burden, the response rate remained high and the mortality was reduced.

Impressive regression of primary liver cancer after treatment with sirolimus

Hepatocellular cancer (HCC) has an extremely poor prognosis due to the extent of the tumour and underlying liver disease. Except for liver transplantation and liver resection there is no proven therapy [1]. Although regarded as a chemoinsensitive tumour, chemoembolisation for selected patients offers a limited survival benefit [2]. For most patients only best supportive care is available. Sirolimus is established as an immunosuppressive agent used in kidney and liver-transplantation. It inhibits mTOR, downstream the Akt pathway, regulating cell-regulatory and nutrient proteins [3]. The activation of Akt seems to be important in HCC and correlates with prognosis [4]. Based on in vitro studies and animal experiments, showing restricted growth of a hepatoma when sirolimus was given, [5] a pilot study was undertaken. The study was approved by the Ehtics Commite of the Faculty of Medicine, University of Gothenburg. The first case included was a 58 year old Caucasian musician. He was admitted for consideration for liver resection or liver transplantation of a large central liver tumor. He had a positive Hepatitis C serology and was a heavy alcohol abuser. BMI was 43kg/m but he had a 10 kg weight loss during the last month. He ran a continuous fever above 38 centigrade. His alpha-fetoprotein at diagnosis was 25 300 mg/l. No histology confirmation of diagnosis was done as CT documented tumours in a cirrhotic liver and this level of alpha-fetoprotein is considered as proof for HCC. His liver function was classified as Child-Pugh A. MRI revealed a central liver tumor, diameter 11 cm and a portal vein thrombosis. He was rejected for surgery and was included in the Sirolimus study. His CT after 3 months was unchanged but an MRI after 6 months showed a remarkable tumor regression, the tumor diameter was reduced to 5 cm. This partial remission was confirmed after 9 months. Alpha-fetoprotein declined to the lowest value 10 900 mg/l after five months (and liver laboratory tests were normalized). After 3 months he returned to his job as a professional dance band musician but he did not discontinue his drinking habits. After nine months there was clinical evidence of tumor progression. The patient succumbed 20 months after the initiation of sirolimus treatment. This case suggests that sirolimus therapy could have a tumor effect in patients with advanced primary hepatocellular cancer. As a remarkable tumor regression was registered in this patient we were obliged at this premature time to inform about it.

Survival after liver transplantation for cholangiocarcinoma has increased during the last decade.

INTRAHEPATIC (IH) or peripheral cholangiocarcinoma (CCC), which arises from the IH bile ducts, is the second most common primary liver cancer after hepatocellular carcinoma. Extrahepatic (EH) CCC arises from the biliary tree outside the liver parenchyma; when it is centrally located in the proximal bile duct it is also known as Klatskin tumor. CCC is often unresectable due to its central location or involvment of portal structure. For these patients liver transplantation (LT) provides an opportunity for radical resection. CCC is, however, a rare indication for LT. The limited number of organs available makes LT for CCC controversial; many centers have reported a dismal prognosis; only few cases of long-term survival after liver transplantation have been reported. The purpose of this retrospective analysis was to study the results of LT for CCC and to determine prognostic variables that could improve the selection of recipients for this procedure.

Surgical treatment for gallbladder cancer – a systematic literature review

Abstract Objective: To evaluate existing evidence regarding surgical treatments for gallbladder cancer in a Health Technology Assessment. A specific aim was to evaluate whether extended surgery regarding liver, lymph nodes, bile duct, and adjacent organs compared with cholecystectomy alone in the adult patient with gallbladder cancer in early and late stages implies improved survival. Methods: In April 2015 and updated in June 2016, a systematic literature search was conducted in PubMed, Embase, and the Cochrane Library. Two authors independently screened titles, abstracts, and full-text articles. The certainty of evidence was evaluated according to GRADE. Main results: Forty-four observational studies (non-randomised, controlled studies) and seven case series were included. Radical resection, including liver and lymph node resection, compared with cholecystectomy alone showed significantly better survival for patients with stages T1b and above. All studies had serious study limitations and the certainty of evidence was very low (GRADE ⊕○○○). A survival benefit seen in patients with stage T1b or higher with lymph node resection, was most evident in stage T2, but the certainty of evidence was low (GRADE ⊕⊕○○). It is uncertain whether routine bile duct resections improve overall survival in patients with gallbladder cancer stage T2–T4 (GRADE ⊕○○○). Conclusion: Data indicate that prognosis can be improved if liver resection and lymph node resection is performed in patients with tumour stage T1b or higher. There is no evidence supporting resection of the bile duct or adjacent organs if it is not necessary in order to achieve radicality.