Cristián Gallardo interviews Per Lindnér ahead of his talk at ESCP’s upcoming Global Reach Webinar: 'Translating Evidence into Practice'.
Per G Lindnér, MD, PhD. Head of Department of Surgery and Transplant Institute, Sahlgrenska University Hospital, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
Dr Lindnér is the main investigator of The Swedish Study of Liver Transplantation for Non-resectable Colorectal Cancer Metastases (SOULMATE) which is an international, randomised controlled, open-label, multicentre study, designed to evaluate if the addition of liver transplantation to conventional treatment of non-resectable/non-abatable colorectal liver metastases increases overall survival compared to best alternative care.
Cristián Gallardo: Firstly, let me say it is a pleasure to interview you prior to ESCP Global Reach webinar on the session: 'Translating Evidence into Practice'. Could you give us some information about your speech?
Per Lindnér: Thank you Cristián. In the first part I'm going to talk about the Norwegian Experience in SECA studies which sets the stage for our study. In the second part, I will mainly describe the SOULMATE study which is an international, randomised controlled, open-label, multicentre study which was designed to evaluate if the addition of liver transplantation (LT), primarily utilising liver grafts from extended criteria donors, to conventional treatment of non-resectable/non-abatable colorectal liver metastases (CLM) increases overall survival compared to best alternative care. The primary outcome measure will assess 5-year overall survival rates.
CG: The results of first experiences of transplanting patients with liver metastasis from colon and rectal cancer in the 1990s failed to demonstrate any survival benefit. However, more contemporary series as the SECA study have shown encouraging results. Do you think that contemporary changes in immunosuppression, systemic chemotherapy and perioperative care, among other factors, have permitted this improvement?
PL: Initial experiences with LT for non-resectable CLM achieved very poor outcomes, with a 5-year overall survival (OS) lower than 20% and with perioperative mortality rates of about 30-40%. However, these initial studies did not have a standardized patient selection nor neoadjuvant or adjuvant therapies. With recent advances in the perioperative care, in surgical and medical oncology fields, the landscape has changed.
I believe the most important factor that has permitted this improvement in survival benefit is the perioperative care. The first experiences of transplanting patients with liver metastasis from colon and rectal cancer in the 1990´s expected a mortality perioperative rate of about 40% and nowadays, because of the better perioperative care, we are expecting a 1-year survival of > 90-95% in transplanted patients. Another important factor is the better selection of patients with colorectal metastasis for trasplantation mainly by using better imaging studies such as PET SCAN that allows to select patients with no extrahepatic disease.
CG: Despite scarce evidence, which patients with colorectal liver metastasis (CRLM) do you believe would benefit most from transplantation? And, which are the inclusion criteria established in SOULMATE study?
PL: After taking into account the first Norwegian Experience in which a group of unselected patients with important metastatic tumor load in terms of size and number of liver metastasis were recruited. In this study we will manage to select patients with smaller and less number of metastasis, who have shown a response to chemotherapy, with stable and no signs of progressive disease and exclude big tumors (>10 cms).
The criteria for inclusion in SOULMATE study will be patients with non-resectable, non-abatable liver metastases from colorectal adenocarcinoma whose primary tumour has been resected with an R0 resection with no signs of extrahepatic metastatic disease or local recurrence according to MRI, CT and PET CT, who have received at least 2 months of chemotherapy with stable and no signs of progressive disease according to RECIST-criteria at the last evaluation before randomization and patients with one year or more from the initial CRC diagnosis to the date of inclusion in the study.
And, on the other hand, we will exclude patients with evidence of extrahepatic disease by PET-CT or CT-thorax/abdomen, with liver metastases larger than 10 cm, with BRAF mutation and microsatellite instability (MSI-H) in the primary tumor, among others.
CG: Competing for a graft against conditions with accepted indications for transplantation (e.g. HCC) in an era of organ shortage contributes to low patient recruitment in prospective protocols. Are there any strategies to handle organ shortage in regions where organ scarcity is a limiting factor?
PL: We know organ shortage for transplantation is a big problem and that the limiting factor for a broader implementation of liver transplantation for colorectal liver metastasis patients remains the scarcity of liver grafts. To overcome this problem, we need to expand the donor pool. A logical solution will be to use extended criteria donors. Several strategies have been developed to handle organ shortage, such as the use of marginal grafts and living donor liver transplantation, which might be potential solutions in regions where organ scarcity is a limiting factor. Marginal livers include grafts from donors more than 70 years old, steatotic grafts, grafts from hepatitis C virus (HCV)-positive donors and split livers. Another group of interest that we believe we could recruit to expand the donor pool is patients with a history of cancer more than 5 years ago. In Sweden we are very restrictive in relation to using donors with history of cancer. However and knowing that the risk of transmission is very low (1%), we believe this is an acceptable risk in patients who already have a metastatic disease so we believe this group of patients will allow to expand our donor pool.
CG: Long-term inmunosupression after liver transplantation confers a known risk of developing de novo malignancies and, consequently, a potential concern is the development of disease progression during this treatment. Is there any strategy to minimise the subsequent risk of distant recurrence during immunosuppression therapy after transplantation?
PL: Long-term immunosuppression is known to confer a risk of developing de novo malignancies after transplantation. Consequently, a potential concern is the development of secondary malignancies in patients subjected to chronic immunosuppression, as well as the risk that some patients might exhibit disease progression, through the growth of subclinical micrometastases. Although the data currently available is derived from a small series of highly selected patients, the SECA investigators evaluated the growth patterns of post transplant pulmonary lesions and found no difference in the growth rate between post transplant (immunosuppressed) and non-immunosuppressed patients with rectal cancer and pulmonary metastases.
In addition to this, certain immunosuppressive agents might also be favoured, such as mTOR inhibitor Everolimus, which has been shown to have some oncological advantage in patients with HCC, in addition to having potential tumour growth inhibition mediated by anti-angiogenesis in an experimental model of metastatic colorectal cancer.
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