Preface - Ous-research.no

Transplantation and Malignancy
In order to get valid effect measures for Ltx for colorectal
cancer the SECA2 study developed. This is a randomized
trial where Ltx is compared to best available oncological
treatment. The study got the approval from the Regional
Ethics Committee, Helse Sor-Ost in December 2010 and it
was initated in January 2011.
The study objectives for SECA2:
••
In a randomized controlled trial to explore whether liver
transplantation in selected patients with liver metastases
from CRC can obtain significant life extension and better
health related quality of life compared to patients receiving
chemotherapy.
••
To explore if patient selection according to nomo-grams
for outcome of colorectal cancer can define a subgroup of
patients with a 5 year survival of at least 50% or even cure
from the disease
Primary endpoint
••
Overall survival after randomization
Secondary endpoints
••
Survival related to Memorial Sloan-Kettering nomograms
for recurrence after liver resection of metastatic CRC.
••
Disease free survival (RECIST criteria and time to lung
lesions of ≥10 mm)
••
Time to start of new treatment (change in strategy)
••
Quality of life (EORTC QLQ-C30), time to decrease in physical
function and global health score
••
Registration of symptoms (NCI-CTCAE version 4.0)
••
Diagnosis of other malignancies
••
Determine nomo-gram scores of patients who survive for
5 years or more
••
Survival in relation to biological markers (plasma TIMP-1
and TPA , circulating tumor cells and micro-metastatic
disease in bone marrow biopsies at time of Ltx, different
micro-arrays of liver biopsies, regulatory T-cells, infiltrating
T-lymphocytes in liver biopsies and KRAS and BRAF
mutations.
••
Correlation between recurrence/metastases and other
biological parameters (proteomics, microarray, micro
Based on pilot data from the SECA-study the assumptions
are; 3-year survival of 70% in the Ltx- and 30% in the chemotherapy
group (allocation ratio 1). To detect differences
in survival, sample size is calculated to n=39 patients in each
study arm, based on a two-sided type I error or 5% and a
power of 80%. Accrual period is 30-36 months. A groupsequential
trial analysis with a triangular test designed for
sequential inspection for every sixth deaths and early termination
as soon as results are conclusive will be performed
Project 1. Characterization of the primary tumor, liver
metastases and temporal T-cell immunity in the SECApatients
1.1 Recent studies have addressed the importance of regulatory
T-cells (T regs) in suppressing T-cell immunity to tumor
associated antigens. There is evidence that T regs may
be a main obstacle of successful tumor immunotherapy and
that patients who exhibit allograft tolerance have increased
levels of T regs. Temporal levels of T regs are measured at
both preoperatively and at fixed intervals postoperatively.
Lymphoid infiltration in tumors will be assessed, as this has
shown to be an independent prognostic factor in CRC.
1.2 Cytokine profiles will be assessed at Ltx and at defined
time points at follow up. The cytokine profiles will be evaluated
in regard to immunosuppressive treatment, to the
cancer disease and in recognition of the liver as an active
immunological organ participating in local and systemic
host defense. Relevant cytokines will be quantified by
Bioplex assays.
1.3 T-cell immunity will be assessed by mRNA from the tumor
cells at time of Ltx (RNA-later). The RNA will be used to
transfect dendritic cells and monocytes in order to measure
T-cells ability to recognize this material post transplant.
1.4 T-cell receptor clonotype mapping will be performed.
CD4+ and CD8+ T cells will be isolated and used for blocking
experiments. Results will be correlated to the clinical
course of the patients.
1.5 Samples of tissue from the metastases as well as normal
liver tissue are being collected and frozen (-70ºC) for later
investigations. The properties of this tissue and the possible
relation to the clinical course of the patients will be
explored. The exact modalities of analysis are not yet fully
established as de-freezing is a nonreversible event that
needs meticulous planning. The analyses will be performed
after all patients have been included in the trial. There are
several possible paths to follow:
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