De novo malignancies after liver transplantation using tacrolimus-based protocols or cyclosporine-based quadruple immunosuppression with an interleukin-2 receptor antibody or antithymocyte globulin.
BACKGROUND
Although conventional immunosuppression after liver transplantation consists of cyclosporine A (CsA), steroids, and azathioprine, recently introduced protocols entail CsA-based quadruple induction protocols or tacrolimus-based combinations. These protocols aim to reduce the rejection rate and the considerable morbidity related to the side effects of additional immunosuppressive treatment, but have not yet been analyzed regarding their long term de novo neoplastic risk.


METHODS
From September 1988 to May 1994, 500 liver transplantations were performed in 458 patients. The median follow-up was 50 months (range, 0.3-97 months) for all patients. Conventional triple therapy was implemented in 25 patients, CsA-based quadruple induction therapy using an antilymphocyte globulin preparation (ATG) in 190 patients, an interleukin-2 receptor antibody (BT563) in 141 patients, and tacrolimus-based dual or triple immunosuppression in 102 patients. The different protocols were evaluated in four randomized and two nonrandomized prospective trials.


RESULTS
De novo neoplasias were detected in 33 patients (7.2%) and were comprised of lymphomas (n = 7), skin malignancies (n = 8 lesions in 7 patients), intraepithelial neoplasias of the cervix uteri (n = 7), breast carcinoma (n = 3), lung carcinoma (n = 3), and other malignancies (n = 6). The incidence of de novo neoplasias did not differ in the different trial arms. Only a positive T-crossmatch and a low CD4+/CD8+ ratio in patients receiving CsA-based immunosuppression demonstrated a significant correlation with the development of a de novo tumor in a multivariant logistic regression analysis.


CONCLUSIONS
The development of de novo neoplastic diseases after liver transplantation with the use of CsA-based quadruple induction protocols or tacrolimus-based regimens for immunosuppresion was assessed over the long term. Recently introduced immunosuppressive protocols did not alter the posttransplant de novo tumor rate. Patients with a low CD4+/CD8+ ratio during CsA-based therapy or a positive T-crossmatch were identified to be at an increased risk for the development of a de novo malignancy.
Jonas
S
S
Department of Surgery and Transplantation Medicine, Virchow Medical Center, Humboldt University Berlin, Germany.
Rayes
N
N
Neumann
U
U
Neuhaus
R
R
Bechstein
W O
WO
Guckelberger
O
O
Tullius
S G
SG
Serke
S
S
Neuhaus
P
P
D000911:Antibodies, Monoclonal / Q000009:adverse effects*; D000961:Antilymphocyte Serum / Q000009:adverse effects*; D002986:Clinical Trials as Topic; D016572:Cyclosporine / Q000009:adverse effects*; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects*; D016031:Liver Transplantation; D008223:Lymphoma / Q000209:etiology; D016609:Neoplasms, Second Primary / Q000209:etiology*; D011446:Prospective Studies; D016032:Randomized Controlled Trials as Topic; D015375:Receptors, Interleukin-2 / Q000187:drug effects*; D012878:Skin Neoplasms / Q000209:etiology; D016559:Tacrolimus / Q000009:adverse effects*; D002583:Uterine Cervical Neoplasms / Q000209:etiology; D002578:Uterine Cervical Dysplasia / Q000209:etiology
D000911:Antibodies, Monoclonal; D000961:Antilymphocyte Serum; D007166:Immunosuppressive Agents; D015375:Receptors, Interleukin-2; D016572:Cyclosporine; C079843:inolimomab; D016559:Tacrolimus