Antitumor Efficacy of Mammalian Target of Rapamycin Inhibitor Therapy in Liver Transplant Recipients With Oncological Disease: A Case-Control Study

Antitumor Efficacy of Mammalian Target of Rapamycin Inhibitor Therapy in Liver Transplant Recipients With Oncological Disease: A Case-Control Study J.M. Álamo, C. Bernal, L.M. Marín, G. Suárez, J. Serrano, L. Barrera, J.M. Sousa, F.J. Padillo, and M.A. Gómez-Bravo ABSTRACT Introduction. The reported incidences of de novo malignancy following orthotopic liver transplantation (OLT) are significantly greater than those in the general population. We have analyzed the efficacy of mammalian target of rapamycin inhibitor (mTORi) as immunosuppressant therapy in patients with de novo malignancies or those engrafted because of a primary liver cancer. Methods. We performed a case-control study of patients with hepatocellular carcinoma (HCC; n ⫽ 119), cholangiocarcinoma (n ⫽ 1) or de novo malignancies (n ⫽ 73). Thirty-seven patients with these tumors were treated with mTORi, and 167, with calcineurin inhibitors (CNI). Switching to mTORi was performed progressively, withdrawing the CNI over 15 days, until obtaining levels of 5–10 ng/dL. Results. No incidence of rejection, serious adverse events, or death was observed with an overall actuarial survival of 68.5% in the mTORi group versus 45.7% among the CNI group. Overall rates of tumor recurrence were 15.2% and 36.8%, respectively (P ⬍ .05). Among patients with HCC, survival was 100% of mTORi with and 61.5% among CNI patients, with tumor recurrence rates of 6.2% and 19.1%, respectively (P ⬍ .05). Discussion. Surprising differences in survival and tumor recurrence rates were observed among the mTORi-treated group compared with controls. Switching from CNI to mTORi immunosuppressant therapy appeared to be safe. It seems to be reasonable to employ this strategy in liver transplant patients with primary hepatic or “de novo” neoplasms. HE REPORTED INCIDENCES of de novo malignancy following orthotopic liver transplant (OLT) are significantly greater than those in the general population. This observation has been attributed, at least in part, to the lifelong immunosuppression following transplantation.1 The risk of skin cancer is greatly increased2 and the incidences of other common malignancies are also increased but not as greatly. Some series have shown increased risks of colorectal,2 lung,3 head and neck,4 urologic,2 and hepatocellular carcinomas (HCC).5 Firstgeneration mammalian target of rapamycin inhibitors (mTORi)—sirolimus derivatives (rapalogs)— have been evaluated extensively in cancer patients. Everolimus and temsirolimus are already approved for the treatment of renal-cell carcinoma. Future research should evaluate the optimal drug regimens, schedules, patient populations, and

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combination strategies for this novel class of agents. We have analyzed the safety and efficacy of mTORi (sirolimus or everolimus) as immunosuppressant therapy in patients with de novo malignancies or those transplanted because of a primary liver cancer compared with a control group treated with a calcineurin inhibitors (CNI; tacrolimus or cyclosporine). METHODS This case-control study of a liver transplant database between 1990 and 2011 included 119/884 transplanted patients, who were affected From the Liver Transplant Unit, Virgen del Rocío Hospital, Seville, Spain. Address reprint requests to Manuel Siurot st no number, 41013, Seville, Spain. E-mail: [email protected]

© 2012 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710

0041-1345/–see front matter http://dx.doi.org/10.1016/j.transproceed.2012.07.079

Transplantation Proceedings, 44, 2089 –2092 (2012)

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by HCC (n ⫽ 119), cholangiocarcinoma (n ⫽ 1), or de novo malignancies (n ⫽ 73). Thirty-seven subjects were treated with mTORi, and 167 with CNI. Table 1 shows the number of patients of each cancer type. Follow-up was 3 to 53 (mean ⫽ 16) months in mTORi group and 3 to 89 (mean ⫽ 29) months in the CNI group. Switching to mTORi was performed progressively with CNI withdrawal by 15 days until obtaining new drug levels of 5 to 10 ng/dL. Continuous variables were compared using Student t test; categorical data, by the ␹2 or Fisher exact test as appropriate. All P values were two-tailed with P ⬍ .05 considered to be statistically significant. All calculations were performed using SPSS statistical software version 15.0.

RESULTS

There was no incidence of rejection after the immunosuppressant change, nor were there serious adverse events, deaths, abandonment, or discontinuation of treatment due to mTORi toxicity. We found no differences in toxicity and efficacy between sirolimus and everolimus. The overall actuarial survival was 68.5% in the mTORi group versus 45.7% among the CNI group. The overall rates of tumor recurrence were 15.2% and 36.8%, respectively (P ⬍ .05; Table 1). Among patients with HCC, patient survival was 100% with mTORi and 61.5% with CNI with tumor recurrence rates of 6.2% and 19.1%, respectively (P ⬍ .05). Note that survival in relapsed cases was 100% in the mTORi and 0% in the CNI cohort. When starting mTORi treatment in patients with recurrent HCC, survival was 60% showing a 7.5-months median survival time of those who succumbed the control group revealed 0% survival with 3.8 months, respectively. The patients with nonmelanoma skin carcinoma showed 100% survival in both groups, although the incidences of recurrence were nil in the mTORi group and 18% in the CNI group (P ⬍ .05). Regarding lymphoproliferative syndromes, there was no recurrence among patients treated with mTORi, and 50% for CNI, with survivals of 66.6% and 50% respectively. The patients with laryngopharyngeal (LF) cancers experienced 100% survival in the mTORi compared with 50% in the control group; there was no tumor recurrence among subjects treated with mTORi versus 20% in the control group. The only patient with gastric cancer who was treated with mTORi has displayed no recurrence at present remaining alive, while the two

control individuals displayed 0% survival with recurrent cancer in one of them. With regard to urologic cancers, survivals were 100% and 50% and recurrence rates 0% and 100% for mTORi and CNI, respectively. Multivariate analysis in Table 2 confirmed the significance of these results. Among women with breast cancer, 50% of the mTORi group survived with 50% tumor recurrence; whereas the control group rates were 66.6% and 33.3%, respectively. In subjects converted to mTORi for palliation due to untreatable malignancies, no lung cancer patient survives today, but their median survival times were 12 months for mTORi patients versus 5.4 months for the CNI group. A patient with recurrent cholangiocarcinoma survived 36 months, and one with recurrent breast cancer, survived 20 months (5.4 months in the control group). Median survival of patients with incurable LF cancer was 29 in mTORi versus 10 months in the control group. DISCUSSION

MTORi has shown anticancer properties in in vitro and in animal models, either alone or in combination with doxorubicin or sorafenib.6,7 Sirolimus prevents angiogenesis by interfering with vascular endothelium growth factormediated pathways in endothelial cells, thus limiting tumor growth.6 It also impacts established tumors by inducing extensive microthrombi that inhibit tumor growth. The immunosuppressive and antitumor effects of sirolimus share a common mechanism of action: inhibition of mTOR, which prevents acute graft rejection mediated by blockade of transduction of interleukin-2 and of other cytokine signals, thus directly inhibiting tumor cell proliferation. The effects have been supported by clinical results with mTORi in liver transplantation with HCC.8 Some prospective multicenter studies and meta-analyses have confirmed these results in HCC.9,10 In our series, HCC liver transplant patients treated with mTORi showed better survivals than the CNI group, namely, no occurrence of mortality and a low recurrence index. It is important to say that the only mTORi patient who experienced HCC recurrence did so while treatment was suspended due to an hepaticojejunostomy procedure for biliary stenosis. Survival was improved among patients with recurrent HCC who were treated with mTORi than with a CNI drug.

Table 1. Recurrence and Actuarial Survival in Patients with mTORi and CNI Depending on Malignancy Diagnosis Malignancy

mTORi (n)

Actuarial Survival (%)

Recurrence (%)

CNI (n)

Actuarial Survival (%)

Recurrence (%)

Hepatocellular carcinoma Skin cancer non-melanoma Lymphoproliferative syndrome Otolaryngologic cancer Prostatic cancer Gastric cancer Breast cancer Total

16 4 3 4 2 1 2 32

100 100 66.6 100 100 100 50 68.5

6.2 0 0 0 0 0 50 15.2

89 22 2 10 2 2 3 130

61.5 100 50 50 50 0 66.7 45.7

19.5 18.8 50 20 100 50 33.3 36.8

mTORi, mammalian target of rapamycin; CNI, calcineurin inhibitor.

ANTITUMOR EFFICACY OF MTORI THERAPY

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Table 2. OR of Influence of mTORi Treatment in Tumor Recurrence in Different Histological Types of Cancer

HCC Skin cancer Lymphoproliferative syndrome ORL cancer Prostatic cancer Gastric cancer Breast cancer

OR

95% CI

P Value

2.1 1.8 4.8

1.6–3.2 1.6–2.5 2.8–7.2

.05 .19 .03

2.5 4.6 1.3 0.7

1.2–2.4 3.2–6.8 1.2–2.1 0.6–0.9

.05 .04 .23 .36

OR, odds ratio; CI, confidence interval; HCC, hepatocellular carcinoma; ORL, otorhinolaringologic cancer.

There is convincing evidence that sirolimus reduces the morbidity and mortality of skin cancers, particularly among transplanted patients.11 Our study confirmed these data: there was no recurrence in the mTORI group versus 18% in CNI patients. Among nontransplanted patients, the recurrence rate of skin cancer is 30% to 90%. It seems reasonable to consider sirolimus immunosuppression in any transplant patient with a history or new occurrence of multiple or aggressive skin cancers, a significant complication after OLT. Among patients diagnosed with posttransplant lymphoproliferative disease, management options include reduction of immunosuppression, rituximab, radiation, surgical excision, monoclonal antibodies, interferon-alfa, chemotherapy, and adoptive immunotherapy.12 Our data suggested that mTORi played a role in this malignancy; there was no tumor recurrence among three patients versus 50% in the control group. Evidence of mTOR activation has been demonstrated in patient-derived gastric cancer cells and tumors.13 Our data suggested that mTORi treatment could be useful in liver transplant patients with gastric cancer: no recurrence or no mortality versus no survival and 50% recurrent gastric cancers among the control group. With respect to LF cancer, mTOR appeared to be a significant predictor of disease-free survival in univariate and multivariate models in another report.14 Our data suggest than mTORi may achieve prolonged survivals; there was no incidence of recurrence among our patients: 50% of controls died with 20% experiencing recurrence of LF cancer. We observed prolonged 29-months survival with mTORi among palliative patients due to untreatable LF cancer versus 10 months in a CNI group and 9 to 12 months in nontransplanted patients. With respect to breast cancer, some studies have suggested that mTOR play a more important role to blunt tumor progression.15 Our data did not confirm differences in survivals or recurrences between mTORi or CNI immunosuppressant therapy. In palliative patients, mTORi treatment prolonged survival to 20 months. It has been demonstrated that signaling between androgen receptor and mTOR may be crucial for prostate cancer cells to endure the low androgen and suboptimal nutrient conditions produced by androgen deprivation therapy.16 Our findings suggested that mTORi-based therapy yielded no recurrences and 100% survival; not so with CNI

treatment. Recent reports have indicated a growth inhibitory effect of temsirolimus on non–small-cell lung carcinomas.6,17 These data support our findings in liver transplant patients with lung cancer who were switched to mTORi namely better survival (12 months) than subjects treated with CNI (5.4 months) or those non–liver transplant patients (6 –9 months). mTORi have been studied in cholangiocarcinoma with good results.18 Potentially important was the finding that one mTORi-treated patient with recurrent cholangiocarcinoma and mediastinal metastases showed a survival of 36 months, which was greater than the 5 to 8 months among nontransplanted patients with untreatable cholangiocarcinoma. The limitations of this study were that it did not have a randomized design, that there were differences in follow-up periods, and that the sample size was small for each tumor except for the HCC group. In conclusion, surprising differences were observed in survivals and tumor recurrence rates among the mTORitreated compared with the control group. Switching from CNI to mTORi immunosuppressant therapy appeared to be safe, so it seems to be reasonable to attempt the conversion to mTORi-based immunosuppressive therapy in liver transplant patients with primary liver neoplasms (HCC, cholangiocarcinoma) or those with de novo malignancies. However, further prospective studies with a larger number of cancer patients and long-term mTORi therapy are needed to confirm these findings. REFERENCES 1. Jain AB, Yee LD, Nalesnik MA, et al: Comparative incidence of de novo nonlymphoid malignancies after liver transplantation under tacrolimus using surveillance epidemiologic end result data. Transplantation 66:1193, 1998 2. Haagsma EB, Hagens VE, Schaapveld M, et al: Increased cancer risk after liver transplantation: a population-based study. J Hepatol 34:84, 2001 3. Fung JJ, Jain A, Kwak EJ, et al: De novo malignancies after liver transplantation: a major cause of death. Liver Transpl 7:S109, 2001 4. Herrero JI, Alegre F, Quiroga J, et al: Usefulness of a program of neoplasia surveillance in liver transplantation. A preliminary report. Clin Transplant 23:532, 2009 5. Hoffmann CJ, Subramanian AK, Cameron AN, et al: Incidence and risk factors for hepatocellular carcinoma after solid organ transplantation. Transplantation 86:784, 2008 6. Guba M, von Breitenbuch P, Steinbauer M, et al: Rapamycin inhibits primary and metastatic tumor growth by antiangiogenesis: involvement of vascular endothelial growth factor. Nat Med 8:128, 2002 7. Guba M, Graeb C, Jauch KW, et al: Pro- and anti-cancer effects of immunosuppressive agents used in organ transplantation. Transplantation 77:1777, 2004 8. Toso C, Merani S, Bigam D, et al: SRLolimus-based immunosuppression is associated with increased survival after liver transplantation for hepatocellular carcinoma. Hepatology 51:1237, 2010 9. Schnitzbauer AA, Zuelke C, Graeb C, et al: A prospective randomised, open-labeled, trial comparing sirolimus-containing versus mTOR-inhibitor-free immunosuppression in patients undergoing liver transplantation for hepatocellular carcinoma. BMC Cancer 10:190, 2010

2092 10. Liang W, Wang D, Ling X, et al: Sirolimus-based immunosuppression in liver transplantation for hepatocellular carcinoma: a meta-analysis. Liver Transpl 18:62, 2012 11. Leblanc KG Jr, Hughes MP, Sheehan DJ: The role of sirolimus in the prevention of cutaneous squamous cell carcinoma in organ transplant recipients. Dermatol Surg 37:744, 2011 12. Kamdar KY, Rooney CM, Heslop HE: Posttransplant lymphoproliferative disease following liver transplantation. Curr Opin Organ Transplant 16:274, 2011 13. Al-Batran SE, Ducreux M, Ohtsu A: mTOR as a therapeutic target in patients with gastric cancer. Int J Cancer 130:491, 2012 14. Marioni G, Staffieri A, Giacomelli L, et al: Mammalian target of rapamycin expression and laryngeal squamous cell carci-

ÁLAMO, BERNAL, MARíN ET AL noma prognosis: novel preliminary evidence. Histopathology 58: 1148, 2011 15. Walsh S, Flanagan L, Quinn C, et al: mTOR in breast cancer: differential expression in triple-negative and non-triplenegative tumors. Breast 21:178, 2012 16. Wu Y, Chhipa RR, Cheng J, et al: Androgen receptormTOR crosstalk is regulated by testosterone availability: implication for prostate cancer cell survival. Anticancer Res 30:3895, 2010 17. Ohara T, Takaoka M, Toyooka S: Inhibition of mTOR by temsirolimus contributes to prolonged survival of mice with pleural dissemination of non-small-cell lung cancer cells. Cancer Sci 102: 1344, 2011 18. Okada T, Sawada T, Kubota K: Rapamycin inhibits growth of cholangiocarcinoma cells. Hepatogastroenterology 56:6, 2009