Preface - Ous-research.no

Transplantation and Malignancy
Leader:
Aksel Foss, Professor, MD, PhD, MHA, FEBS (OUH/UiO)
Scientific staff:
Svein Dueland, MD, PhD (OUH)
Morten Hagness MD, PhD-student (SENRHA)
Einar Martin Aandahl, MD, PhD (OUH)
Tormod Lund, MD, PhD (Sørlandet Hospital, Arendal)
Marit Andersen, MSc, PhD (OUH)
Pål-Dag Line, MD, PhD (OUH)
Kai Hansen, MNu, Coordinator (OUH)
Background
Organ transplantation requires lifelong immunosuppression.
A side effect is increased post-transplant de novo
malignancy. During the last decades, the effectiveness of
standard immunosuppressants in allograft transplantation
has improved and so has the incidence of de novo cancer. A
recent study of 905 recipients of transplanted hearts, lungs,
or both has shown a 7.1 times increase in de novo cancers
compared to the general population. Cancer-related death
following transplantation is increasing and accounts for 13%
of post transplant mortality.
Regulatory T cells (T regs) maintain self-tolerance to autoantigens
and are involved in the pathogenesis of various
clinical conditions such as autoimmune diseases, chronic
viral infections and cancer. T regs appear more frequently
in peripheral blood lymphocytes of cancer patients than
healthy controls and interestingly, it seems that high levels
of T-regs are a prerequisite for allograft tolerance following
transplantation. By manipulation of the interaction between
CD4+ CD25+ T regs and dendritic cells, it may become
possible to influence host offence and defense in cancer
and organ transplantation. In these aspects it is of particular
interest that immunosuppressive drugs used in transplantation
have both an anti-rejection and anti-neoplastic activity.
Rapamycin (Sirolimus, Rapamune®) is an established drug
for prevention allograft rejection by blocking the intracellular
pathway complex mTOR. It also appears that a Sirolimus
based immunosuppression protocol has beneficial effects
on tumor recurrence and survival with an acceptable rate
of rejection and toxicity in liver transplanted HCC patients.
Rapamycin is a potent VEGF antagonist showing significant
anti angiogeneic effects in addition to a direct inhibitory effect
on tumor growth and proliferation. The drug has shown
clinical effect and objective x-ray responses and stabilization
of disease in different types of cancer, such as advanced breast
and renal cancer that has previously progressed on other
treatments. Accordingly, rapamycin is an effective anticancer
drug in addition to its immunosuppressive effects.
This supports the use of the drug for patients transplanted
for cancer and in patients with de novo post transplant
malignancy.
In 2006 we acquired an ethical approval (S-05409 Regional
Ethics Committee, Helse Sor-Ost) for a clinical pilot study
(SECA-study) to investigate liver transplantation (Ltx) as
treatment option for selected patients with non-resectable
liver metastases after colo-rectal carcinoma (CRC), using
the mTOR inhibitor Rapamycin as standard immunosuppression
from postoperative day 1. So far 19 patients have
been enrolled in the study. All of the patients had advanced
metastatic disease solely to the liver not eligible to resection
at the time of Ltx. 14 of the 19 patients (are alive at 2
to 50 months follow-up. The preliminary 2 years survival
is 87.4%The burden of the surgery and convalescence thereafter
is minimal compared to regular chemotherapy (the
patients represent their own controls). Health related quality
of life (HRQOL) of the patients, measured with EORTC
QLQ-C29/30 is excellent As expected, many patients have
experienced recurrence of the disease, mainly to the lungs.
Previous studies have shown that aggressive treatment of
CRC lung metastases with resection and/or radiofrequency
ablation resulted in a 5 year overall survival of 34-58%
(15,16). Thus, some patients included in the SECA study who
develop lung metastases have been resected or treated
with radiofrequency ablation for recurrent disease in lungs,
and are currently disease free.
The pilot data show that Ltx is feasible in selcted patients
with liver metastases from CRC and QOL is excellent after
Ltx. The burden of the surgery and convalescence thereafter
is minimal compared to regular chemotherapy (the patients
represent their own controls).
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