Complete Remission of Postransplant Lung Metastases from Hepatocellular Carcinoma under Therapy with Sirolimus and Mycophenolate Mofetil

A 37-year-old Caucasian female with hepatocellular carcinoma (pT3 pN0 M0) received a postmortal liver allograft in November 1998 with initial immunosuppression with cyclosporine, azathioprine, and prednisolone. In August 2001, histologically confirmed multiple bilateral pulmonary metastases were diagnosed and completely resected. The immunosuppressive therapy was maintained with cyclosporine. In January 2003, computed tomography showed three recurrent bilateral pulmonary metastases (Fig. 1a). As former studies have shown an antiproliferative effect of the inhibition of the mammalian target of rapamycin (mTOR), we decided to shift the immunosuppressive therapy from cyclosporine to sirolimus and mycophenolate mofetil (MMF) (1,2,4).FIGURE 1. (a) Computed tomography of the lung before conversion of the immunosuppression. The arrows mark the metastases located in the left laterobasal sinus phrenico-costailis, in the right dorsal upper lobe as well as on the left side of the lung approximately on a level with the hilus. (b) Computed tomography of the chest 6 months after conversion of the immunosuppressive therapy from cyclosporine to sirolimus and MMF. The metastases were not detectable anymore. (c) Computed tomography of the chest 18 months after conversion of the immunosuppressive therapy from cyclosporine to sirolimus and MMF. The metastases were still not detectable anymore.We started on February 17, 2003 with 8 mg sirolimus p.d. and maintained the dosage on 4 mg p.d. since April 7, 2003. Under that, the corresponding serum levels were between 9.0 μg/L and 13.1 μg/L. MMF was started with 250 mg b.i.d. Due to insufficient serum levels we increased the MMF dose rate to 500 mg b.i.d. in May 2003. Already 4 months after conversion, there were no pulmonary metastases detectable by computed tomography anymore (Fig. 1b). A subsequent positron emission tomography combined with a computed tomography also revealed no pulmonary metastases. In the meantime the patient is free of a pulmonary metastases recurrent for 18 months after conversion of the immunosuppressive therapy (Fig. 1c). To our knowledge, this is the first report on a complete remission of posttransplant lung metastases from HCC after conversion of the immunosuppressive therapy from cyclosporine to sirolimus and MMF. Several studies showed that the macrolide sirolimus is highly effective in constraining metastatic tumor progression (3,4). Luan et al. developed a human renal cell cancer (RCC) pulmonary metastases model. In this model sirolimus reduced but cyclosporine increased the number of pulmonary metastases. Interestingly, sirolimus not only reduced the number of metastases but also reduced the size of tumor nodules achieved by cell cycle arrest and targeted reduction of the tumor promoting cytokines TGF-β1 and VEGF-A (3). Consistent with these findings, Guba et al. showed that sirolimus inhibits metastatic tumor growth and angiogenesis in an experimental model of metastatic colorectal cancer (4). Interestingly, these effects occurred with doses of sirolimus roughly equivalent to those used in organ transplantation. Therefore, the antiproliferative and antiangiogenetic effect of sirolimus could be involved in the remission of pulmonary metastases as reported in this case report. Another possible mechanism of tumor inhibition could be the induction of apoptosis by sirolimus (1,2). Furthermore there is evidence that MMF is not associated with increased risk of posttransplant malignancy. Robson et al. recently presented results of a prospective, observational cohort study where there was a statistically significant reduction in risk of developing any malignancy in MMF patients compared with controls (5). Therefore MMF could increase the efficacy of sirolimus in the remission of pulmonary metastases. Immunosuppression with sirolimus and MMF may reduce the risk of recurrence in high-risk transplant recipients and we recommend it in patients after HCC. Mohammed Elsharkawi Ludger Staib Doris Henne-Bruns Jens Mayer Department of General, Visceral and Transplantation Surgery, University Hospital Ulm, Ulm, Germany