Liver transplantation and the role of adjuvant therapy for advanced primary liver tumours

Abstract

Liver transplantation (LT) for unresectable locally advanced primary liver tumours (aPLT) is associated with an inferior survival compared to other established indications. As organ shortage in most regions is the major factor limiting the transplant rate, a careful selection of patients accepted for LT is necessary. Thus, the majority of patients with aPLT's will not be considered for LT even though a significant proportion of them may benefit from the procedure. The purpose of this study was to find ways to optimise the selection criteria for LT to a Scandinavian population of patients with hepatocellular carcinoma (HCC) and to explore the effect of adjuvant treatment on hepatic malignancies.

In the first study we performed a retrospective evaluation of our own series of patients (n = 55) with. cirrhosis and HCC that have undergone LT. Two-third of the patients did not meet the standard selection criteria defined as single tumour < 5 em or 5 3 tumours, none sized > 3 em. We found that the number of nodules, the histological grade and the cold ischemia time all were independent risk factors for recurrence. To identify patients with an acceptable prognosis after LT, we hypothetically tested what the outcome would have been if a modification of the standard selection criteria (5 2 tumours with total tumour diameter < 10 em) had been applied for these patients. We found that, although these criteria were less restrictive, the recurrence rate in that group was identical (28%) to the group that met the standard criteria.

The effect of adjuvant systemic chemotherapy after LT is not thoroughly investigated. We have studied the effect of adriamycin with or without cyclosporine A (CsA) on chemically induced rat hepatomas transferred to the spleens of a syngenic rat strain. We found that the tumour morphology was of utmost importance for the outcome. In poorly differentiated tumours, adriamycin exerted growth inhibition as expected, although partly counteracted by CsA. However, when the tumour exhibited less nuclear dysplasia, adriamycin in combination with. CsA paradoxically stimulated tumour growth.

As a next step we conducted a randomised controlled trial with neoadjuvant systemic adriamycin in patients with HCC. Forty-two patients were randomised to receive either low weekly doses of adriamycin or no additional treatment. No significant effect on 3-year over all survival, disease-free survival or freedom from recurrence could be seen. There was a poor tolerability to the drug reflected by the fact that only 11/17 patients in the chemo group received more than half of the prescheduled doses.

Powerful anti-leukaemia effects can be seen after allogeneic haematopoietic stem cell transplantation (HSCT). In order to explore if there is a corresponding effect on residual malignant Ever tumour cells (GVTeffect) after LT in patients with aPLT's, the next part of the study was carried out. First we developed a method for harvest and procurement of bone marrow from cadaveric donors. We found that the optimal source for harvest was the vertebral column and that sufficient amount of stem cells with good viability and functionality for transplantation could he obtained from 10 vertebraes.

Subsequently, one patient with advanced HCC underwent combined liver- and bone marrow transplantation. The bone marrow was harvested together with the fiver from the same cadaveric donor (CD) and there was a major human leukocyte antigen (HLA) mismatch between the donor and recipient. In spite of an initial successful engraftment of the donor marrow, it was not possible to obtain stable mixed chimerism, and the patient died five months after HSCT due to severe immunoincompetence.

The protocol was after this modified so that instead of CD's and myeloablative HSCT, HLA-matched live donors were used for a nonmyeloablative HSCT post LT. Five patients that have undergone this procedure are reported and we found that the concept is feasible with. low transplant-related mortality (TRM). However, 315 patients rejected their stem cell grafts and we suggest that an augmented pre-treatment is necessary. The effect of the concept on survival has yet to be proven.

In conclusion, HCC consisting of less than 3 nodules and with a total diameter < 10 em can be treated with LT alone with an acceptable recurrence rate. Based on experimental data, (neo)adjuvant treatment with adriamycin may be hazardous and does not prolong survival after LT in the clinical setting. In order to achieve a potential GVT-effect, bone marrow can be harvested together with the liver and transplanted as adjuvant treatment in spite of a major HLA-mismatch. However, due to high risk for TRM, an approach with combined LT + HLAmatched HSCT is safer and a refined version of the original protocol is presently used.