Survival and Quality of Life after Isolated Hepatic Perfusion with Melphalan as a Treatment for Uveal Melanoma Liver Metastases - Final Results from the Phase III Randomized Controlled Trial SCANDIUM.

OBJECTIVE: To investigate overall survival (OS) and health-related quality of life (HRQOL) of first-line isolated hepatic perfusion (IHP) compared to best alternative care (BAC) for patients with uveal melanoma liver metastases. SUMMARY BACKGROUND DATA: Approximately half of patients with uveal melanoma develop metastatic disease, most commonly in the liver and systemic treatment options are limited. Isolated hepatic perfusion (IHP) is a locoregional therapy with high response rates but with unclear effect on overall survival (OS). METHODS: In this phase III randomized controlled multicenter trial (the SCANDIUM trial) patients with previously untreated isolated uveal melanoma liver metastases were included between 2013-2021, with at least 24 months of follow-up. The planned accrual was 90 patients randomized 1:1 to receive a one-time treatment with IHP or BAC. Crossover to IHP was not allowed. The primary endpoint was the 24-month OS rate, with the hypothesis of a treatment effect leading to a 50% OS rate in the IHP group compared to 20% in the control group. HRQOL was measured by the EuroQol 5-domains 3-levels (EQ-5D-3L) questionnaire over 12 months. RESULTS: The intention-to-treat (ITT) population included 87 patients randomized to the IHP group (43 patients; 41 [89%] received IHP) or the control group (44 patients). The control group received chemotherapy (49%), immunotherapy (39%), or localized interventions (9%). In the ITT population, the median PFS was 7.4 months in the IHP group compared with 3.3 months in the control group, with a hazard ratio of 0.21 (95% CI, 0.12-0.36). The 24-month OS rate was 46.5% in the IHP group versus 29.5% in the control group (P=0.12). The median OS was 21.7 months versus 17.6 months, with a hazard ratio of 0.64 (95% CI, 0.37-1.10). EQ-5D-3L showed a sustained high health status for the IHP group over 12 months, compared to a deteriorating trend in the control group. CONCLUSIONS: For patients with liver metastases from uveal melanoma, IHP offers high response rates translating to a benefit in PFS including a trend of better HRQOL compared to the control group. However, the primary endpoint of OS at 24 months was not met.

Isolated Hepatic Perfusion With Melphalan for Patients With Isolated Uveal Melanoma Liver Metastases: A Multicenter, Randomized, Open-Label, Phase III Trial (the SCANDIUM Trial).

PURPOSE: About half of patients with metastatic uveal melanoma present with isolated liver metastasis, in whom the median survival is 6-12 months. The few systemic treatment options available only moderately prolong survival. Isolated hepatic perfusion (IHP) with melphalan is a regional treatment option, but prospective efficacy and safety data are lacking. METHODS: In this multicenter, randomized, open-label, phase III trial, patients with previously untreated isolated liver metastases from uveal melanoma were randomly assigned to receive a one-time treatment with IHP with melphalan or best alternative care (control group). The primary end point was overall survival at 24 months. Here, we report the secondary outcomes of response according to RECIST 1.1 criteria, progression-free survival (PFS), hepatic PFS (hPFS), and safety. RESULTS: Ninety-three patients were randomly assigned, and 87 patients were assigned to either IHP (n = 43) or a control group receiving the investigator's choice of treatment (n = 44). In the control group, 49% received chemotherapy, 39% immune checkpoint inhibitors, and 9% locoregional treatment other than IHP. In an intention-to-treat analysis, the overall response rates (ORRs) were 40% versus 4.5% in the IHP and control groups, respectively (P < .0001). The median PFS was 7.4 months versus 3.3 months (P < .0001), with a hazard ratio of 0.21 (95% CI, 0.12 to 0.36), and the median hPFS was 9.1 months versus 3.3 months (P < .0001), both favoring the IHP arm. There were 11 treatment-related serious adverse events in the IHP group compared with seven in the control group. There was one treatment-related death in the IHP group. CONCLUSION: IHP treatment resulted in superior ORR, hPFS, and PFS compared with best alternative care in previously untreated patients with isolated liver metastases from primary uveal melanoma.

A prospective clinical trial on sorafenib treatment of hepatocellular carcinoma before liver transplantation.

BACKGROUND: Patients with hepatocellular carcinoma waiting for liver transplantation are commonly treated with locoregional treatments, such as TACE and ablation, to prevent tumor progression and dropout and to improve long-term outcome after transplantation. We wanted to prospectively assess feasibility of systemic antitumor treatment with sorafenib as neoadjuvant treatment for hepatocellular carcinoma while waiting for liver transplantation, evaluating tolerability, toxicity and posttransplant morbidity. We also wanted to evaluate perfusion CT parameters to assess tumor properties and response early after start of sorafenib treatment in patients with early hepatocellular carcinoma. METHODS: Twelve patients assigned for liver transplantation due to hepatocellular carcinoma, within the UCSF and who fulfilled other criteria, were included January 2012-August 2014. After baseline evaluation, sorafenib treatment was started. Treatment was evaluated by perfusion CT at 1, 4 and 12 weeks and thereafter every 8 weeks. Toxicity and quality of life was assessed at 1 and 4 weeks and every 4 weeks thereafter during treatment. Treatment was stopped when patients were prioritized on the transplantation waiting list or when intolerable side effects or tumor progress warranted other treatments. Posttransplant morbidity after 90 days was registered according to Clavien-Dindo. RESULTS: Baseline perfusion CT parameters in the tumors predicted the outcome according to RECIST/mRECIST at three months, but no change in CTp parameters was detected as a result of sorafenib. Sorafenib as neoadjuvant treatment was associated with intolerability and dose reductions. Therefore the prerequisites for evaluation of the sorafenib effect on both CT parameters and tumor response were impaired. CONCLUSIONS: This study failed to show changes in CTp parameters during sorafenib treatment. Despite the curative treatment intention, tolerability of neoadjuvant sorafenib treatment before liver transplantation was inadequate in this study. TRIAL REGISTRATION: EudraCT number: 2010-024306-36 (date 2011-04-07).

Surgical treatment for gallbladder cancer - a systematic literature review.

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.

Isolated hepatic perfusion as a treatment for liver metastases of uveal melanoma.

Isolated hepatic perfusion (IHP) is a procedure where the liver is surgically isolated and perfused with a high concentration of the chemotherapeutic agent melphalan. Briefly, the procedure starts with the setup of a percutaneous veno-venous bypass from the femoral vein to the external jugular vein. Via a laparotomy, catheters are then inserted into the proper hepatic artery and the caval vein. The portal vein and the caval vein, both supra- and infrahepatically, are then clamped. The arterial and venous catheters are connected to a heart lung machine and the liver is perfused with melphalan (1 mg/kg body weight) for 60 min. This way it is possible to locally perfuse the liver with a high dose of a chemotherapeutic agent, without leakage to the systemic circulation. In previous studies including patients with isolated liver metastases of uveal melanoma, an overall response rate of 33-100% and a median survival between 9 and 13 months, have been reported. The aim of this protocol is to give a clear description of how to perform the procedure and to discuss IHP as a treatment option for liver metastases of uveal melanoma.

Isolated hepatic perfusion as a treatment for uveal melanoma liver metastases (the SCANDIUM trial): study protocol for a randomized controlled trial.

BACKGROUND: Uveal melanoma is the most common primary intraocular malignancy in adults. Despite successful control of the primary tumor, metastatic disease will ultimately develop in approximately 50% of patients, with the liver being the most common site for metastases. The median survival for patients with liver metastases is between 6 and 12 months, and no treatment has in randomized trials ever been shown to prolong survival. A previous phase II trial using isolated hepatic perfusion (IHP) has suggested a 14-month increase in overall survival compared with a historic control group consisting of the longest surviving patients in Sweden during the same time period (26 versus 12 months). METHODS/DESIGN: This is the protocol for a multicenter phase III trial randomizing patients with isolated liver metastases of uveal melanoma to IHP or best alternative care (BAC). Inclusion criteria include liver metastases (verified by biopsy) and no evidence of extra-hepatic tumor manifestations by positron emission tomography-computed tomography (PET-CT). The primary endpoint is overall survival at 24 months, with secondary endpoints including response rate, progression-free survival, and quality of life. The planned sample size is 78 patients throughout five years. DISCUSSION: Patients with isolated liver metastases of uveal melanoma origin have a short expected survival and no standard treatment option exists. This is the first randomized clinical trial to evaluate IHP as a treatment option with overall survival being the primary endpoint. TRIAL REGISTRATION: ClinicalTrials.gov registration number: NCT01785316 (registered 1 February 2013). EudraCT registration number: 2013-000564-29.

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

BACKGROUND: Hepatocellular 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. METHODS: In 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 mug/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. RESULTS: Of 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). CONCLUSION: Treatment 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.

Growth associated proteins in tumor cells and stroma related to disease progression of colon cancer accounting for tumor tissue PGE2 content.

Connections among specific proteins (Bax, Bcl-2, bFGF, COX-1, COX-2, E-cad, p15, p53, PCNA, TGFbeta3, TUNEL, vWF) in control of cell proliferation, apoptosis, cell adhesion, tumor vascularity and PGE2 content were evaluated in colon cancer as related to disease progression and survival. Tumor tissue and adjacent normal colon mucosa were obtained at curative resection in 22 patients. PGE2 concentrations were assessed in tumor tissue and tumor derived blood, splanchnic blood, peripheral venous blood and urine. Host inflammation was determined (CRP, ESR) in relationship to tumor differentiation and stage. Patients survived as expected according to Dukes A-D staging. Growth-related proteins correlated between tumor cells and stroma as well as between protein factors within tumor cells and tumor stroma. COX-2 predicted tumor tissue content of PGE2 (p<0.002), without reflection in tumor derived blood. Systemic inflammation was predicted by p15, TGFbeta3 and Bcl-2 in tumor tissue (p<0.001). p15 and vWF predicted reduced survival in ungrouped patients (p<0.02), while p15, PCNA, TGFbeta3 and vWF predicted reduced survival (p<0.0001) when patient grouping accounted for high tumor content of PGE2. Our results connect systemic inflammation and survival to COX-2 staining and increased PGE2 in colon cancer. Thus, it seems important to understand proximal signals behind upregulation of COX-2 and subsequent PGE2 production in certain tumor cells in colon cancer.

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 degrees 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.

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.

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/m(2) weekly, starting from acceptance onto the waiting list for LT. One intraoperative dose of 15 mg/m(2) was given, and postoperatively doxorubicin was given weekly at a dose of 10 mg/m(2), depending on the clinical course, up to a cumulative dose of 400 mg/m(2). 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.

The effects of non-selective, preferential-selective and selective COX-inhibitors on the growth of experimental and human tumors in mice related to prostanoid receptors.

Earlier observations on cyclo-oxygenase inhibitors (NSAIDs) restricting tumor growth were re-evaluated by comparing the effects of non-selective, preferential selective and selective derivatives of COX-inhibitors on tumor growth in mouse models with either prostaglandin-sensitive (MCG-101, human tumors) and -insensitive transplants (K1735-M2). Tumor growth, with and without provision of a classical cyclo-oxygenase inhibitor (indomethacin), was related to tumor content of COX-1/COX-2 protein as well as to EP1-EP4 and prostacyclin receptor expression. Mouse serum amyloid protein (SAP) was measured as an indicator of systemic inflammation, which relates to pro-inflammatory cytokines. Indomethacin inhibited tumor growth and prolonged the survival of mice bearing MCG-101 tumors, which display a high production of PGE2, while K1735-M2 tumors with insignificant amounts of PGE2 did not respond to indomethacin at all. However, the effects of various NSAIDs on tumor growth were highly variable in combination with the fact that most preferential selective and selective COX-2 inhibitors attenuated poorly systemic inflammation evaluated by plasma concentrations of mouse SAP. The ability of NSAIDs to attenuate tumor growth was not related to the tumor content of COX-2 protein as expected. Multivariate analysis suggests that significant COX-inhibition of tumor growth may be related to tumor expression of subtype EP2, EP3 (p<0.005) and perhaps EP4 (p<0.09) in complex interplay. The extent of tumor growth inhibition by COX-inhibitors is not simply related to drug specificity on COX-1 or COX-2 pathways. Such effects may instead be related to tumor expression of prostanoid receptors in tumor tissue.

Liver transplantation for treatment of metastatic neuroendocrine tumors.

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.

[Treatment of patients with liver metastases from colorectal cancer. More patients can benefit from the treatment!]. / Behandling av levermetastaser från kolorektal cancer. Fler kan ha nytta av behandling!

Liver resection for liver metastases goes with 30-40% five years survival. It is estimated that 10% of patients with liver metastases can be subjected to liver resection. In the Västra Götaland region, this number is not achieved. In the present material of 147 patients, the postoperative mortality was 2.7%. Five years survival was 33%. Preoperative chemotherapy and preoperative porta embolisation have extended the indication for liver resection. Reresection after recurrence limited to the liver should be considered in selected cases. Ablative measures are under development and should be evaluated in clinical trials. New chemotherapeutic drugs (oxaliplatin, irinotecan) with improved recurrence rate but with limited gain in survival might have an impact as adjuvant therapy. A surgeon with liver surgery competence should see patients with a presumably resectable cancer.

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.