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International Journal of Colorectal Disease 07/2011; 27(5):687-8. · 2.38 Impact Factor
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Andreas Schnitzbauer, Carl Zuelke,
Christian Graeb,
Justine Rochon,
Itxarone Bilbao,
Patrizia Burra,
de Jong Koert,
Christophe Duvoux,
Norman Kneteman,
Rene Adam, [......],
Heiner Wolters,
Darius Mirza,
Tim Scholz,
Rudolf Steininger,
Gunnar Soderdahl,
Simone Strasser,
Karl-Walter Jauch,
Peter Neuhaus,
Hans Schlitt,
Edward Geissler
[show abstract]
[hide abstract]
ABSTRACT: Abstract
Background
The potential anti-cancer effects of mammalian target of rapamycin (mTOR) inhibitors are being intensively studied. To date, however, few randomised clinical trials (RCT) have been performed to demonstrate anti-neoplastic effects in the pure oncology setting, and at present, no oncology endpoint-directed RCT has been reported in the high-malignancy risk population of immunosuppressed transplant recipients. Interestingly, since mTOR inhibitors have both immunosuppressive and anti-cancer effects, they have the potential to simultaneously protect against immunologic graft loss and tumour development. Therefore, we designed a prospective RCT to determine if the mTOR inhibitor sirolimus can improve hepatocellular carcinoma (HCC)-free patient survival in liver transplant (LT) recipients with a pre-transplant diagnosis of HCC.
Methods/Design
The study is an open-labelled, randomised, RCT comparing sirolimus-containing versus mTOR-inhibitor-free immunosuppression in patients undergoing LT for HCC. Patients with a histologically confirmed HCC diagnosis are randomised into 2 groups within 4-6 weeks after LT; one arm is maintained on a centre-specific mTOR-inhibitor-free immunosuppressive protocol and the second arm is maintained on a centre-specific mTOR-inhibitor-free immunosuppressive protocol for the first 4-6 weeks, at which time sirolimus is initiated. A 2<sup>1/2</sup> -year recruitment phase is planned with a 5-year follow-up, testing HCC-free survival as the primary endpoint. Our hypothesis is that sirolimus use in the second arm of the study will improve HCC-free survival. The study is a non-commercial investigator-initiated trial (IIT) sponsored by the University Hospital Regensburg and is endorsed by the European Liver and Intestine Transplant Association; 13 countries within Europe, Canada and Australia are participating.
Discussion
If our hypothesis is correct that mTOR inhibition can reduce HCC tumour growth while simultaneously providing immunosuppression to protect the liver allograft from rejection, patients should experience less post-transplant problems with HCC recurrence, and therefore could expect a longer and better quality of life. A positive outcome will likely change the standard of posttransplant immunosuppressive care for LT patients with HCC.
Trial Register
Trial registered at http://www.clinicaltrials.gov : NCT00355862
(EudraCT Number: 2005-005362-36)
BMC Cancer. 01/2010;
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Andreas A Schnitzbauer, Carl Zuelke,
Christian Graeb,
Justine Rochon,
Itxarone Bilbao,
Patrizia Burra,
Koert P de Jong,
Christophe Duvoux,
Norman M Kneteman,
Rene Adam, [......],
Heiner Wolters,
Darius F Mirza,
Tim Scholz,
Rudolf Steininger,
Gunnar Soderdahl,
Simone I Strasser,
Karl-Walter Jauch,
Peter Neuhaus,
Hans J Schlitt,
Edward K Geissler
[show abstract]
[hide abstract]
ABSTRACT: The potential anti-cancer effects of mammalian target of rapamycin (mTOR) inhibitors are being intensively studied. To date, however, few randomised clinical trials (RCT) have been performed to demonstrate anti-neoplastic effects in the pure oncology setting, and at present, no oncology endpoint-directed RCT has been reported in the high-malignancy risk population of immunosuppressed transplant recipients. Interestingly, since mTOR inhibitors have both immunosuppressive and anti-cancer effects, they have the potential to simultaneously protect against immunologic graft loss and tumour development. Therefore, we designed a prospective RCT to determine if the mTOR inhibitor sirolimus can improve hepatocellular carcinoma (HCC)-free patient survival in liver transplant (LT) recipients with a pre-transplant diagnosis of HCC.
The study is an open-labelled, randomised, RCT comparing sirolimus-containing versus mTOR-inhibitor-free immunosuppression in patients undergoing LT for HCC. Patients with a histologically confirmed HCC diagnosis are randomised into 2 groups within 4-6 weeks after LT; one arm is maintained on a centre-specific mTOR-inhibitor-free immunosuppressive protocol and the second arm is maintained on a centre-specific mTOR-inhibitor-free immunosuppressive protocol for the first 4-6 weeks, at which time sirolimus is initiated. A 21/2 -year recruitment phase is planned with a 5-year follow-up, testing HCC-free survival as the primary endpoint. Our hypothesis is that sirolimus use in the second arm of the study will improve HCC-free survival. The study is a non-commercial investigator-initiated trial (IIT) sponsored by the University Hospital Regensburg and is endorsed by the European Liver and Intestine Transplant Association; 13 countries within Europe, Canada and Australia are participating.
If our hypothesis is correct that mTOR inhibition can reduce HCC tumour growth while simultaneously providing immunosuppression to protect the liver allograft from rejection, patients should experience less post-transplant problems with HCC recurrence, and therefore could expect a longer and better quality of life. A positive outcome will likely change the standard of posttransplant immunosuppressive care for LT patients with HCC. TRIAL REGISTER: Trial registered at http://www.clinicaltrials.gov: NCT00355862(EudraCT Number: 2005-005362-36).
BMC Cancer 01/2010; 10:190. · 3.01 Impact Factor
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BMJ (Clinical research ed.). 02/2009; 338:b1893.
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Helmut Oettle,
Stefan Post,
Peter Neuhaus,
Klaus Gellert,
Jan Langrehr,
Karsten Ridwelski,
Harald Schramm,
Joerg Fahlke, Carl Zuelke,
Christof Burkart,
Klaus Gutberlet,
Erika Kettner,
Harald Schmalenberg,
Karin Weigang-Koehler,
Wolf-Otto Bechstein,
Marco Niedergethmann,
Ingo Schmidt-Wolf,
Lars Roll,
Bernd Doerken,
Hanno Riess
[show abstract]
[hide abstract]
ABSTRACT: The role of adjuvant therapy in resectable pancreatic cancer is still uncertain, and no recommended standard exists.
To test the hypothesis that adjuvant chemotherapy with gemcitabine administered after complete resection of pancreatic cancer improves disease-free survival by 6 months or more.
Open, multicenter, randomized controlled phase 3 trial with stratification for resection, tumor, and node status. Conducted from July 1998 to December 2004 in the outpatient setting at 88 academic and community-based oncology centers in Germany and Austria. A total of 368 patients with gross complete (R0 or R1) resection of pancreatic cancer and no prior radiation or chemotherapy were enrolled into 2 groups.
Patients received adjuvant chemotherapy with 6 cycles of gemcitabine on days 1, 8, and 15 every 4 weeks (n = 179), or observation ([control] n = 175).
Primary end point was disease-free survival, and secondary end points were overall survival, toxicity, and quality of life. Survival analysis was based on all eligible patients (intention-to-treat).
More than 80% of patients had R0 resection. The median number of chemotherapy cycles in the gemcitabine group was 6 (range, 0-6). Grade 3 or 4 toxicities rarely occurred with no difference in quality of life (by Spitzer index) between groups. During median follow-up of 53 months, 133 patients (74%) in the gemcitabine group and 161 patients (92%) in the control group developed recurrent disease. Median disease-free survival was 13.4 months in the gemcitabine group (95% confidence interval, 11.4-15.3) and 6.9 months in the control group (95% confidence interval, 6.1-7.8; P<.001, log-rank). Estimated disease-free survival at 3 and 5 years was 23.5% and 16.5% in the gemcitabine group, and 7.5% and 5.5% in the control group, respectively. Subgroup analyses showed that the effect of gemcitabine on disease-free survival was significant in patients with either R0 or R1 resection. There was no difference in overall survival between the gemcitabine group (median, 22.1 months; 95% confidence interval, 18.4-25.8; estimated survival, 34% at 3 years and 22.5% at 5 years) and the control group (median, 20.2 months; 95% confidence interval, 17-23.4; estimated survival, 20.5% at 3 years and 11.5% at 5 years; P = .06, log-rank).
Postoperative gemcitabine significantly delayed the development of recurrent disease after complete resection of pancreatic cancer compared with observation alone. These results support the use of gemcitabine as adjuvant chemotherapy in resectable carcinoma of the pancreas.
isrctn.org Identifier: ISRCTN34802808.
JAMA The Journal of the American Medical Association 01/2007; 297(3):267-77. · 30.03 Impact Factor
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[show abstract]
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ABSTRACT: Development of cancer in transplant recipients may be influenced by different immunosuppressive agents. Recent publications suggest that rapamycin (RAPA), or possibly mycophenolate mofetil (MMF), may reduce established tumor growth; however, experimental data is lacking for de novo cancer prevention.
We tested the effects of long-term immunosuppression on spontaneous tumor formation in p53 knock-out mice. Mice received no treatment, or were given RAPA, MMF, or cyclosporine (CsA) starting on week nine after birth, with the experimental endpoint being week 29.
All (9/9) untreated mice developed clinically evident tumors before week 26, as confirmed by histology (6 lymphomas, 2 sarcomas, 1 lymphoma+sarcoma). All CsA-treated mice (9/9) also developed clinical tumors before the endpoint (7 lymphomas, 1 sarcoma, 1 lymphoma+sarcoma). With MMF, 7/10 mice showed clinical evidence of tumor before the experimental endpoint (4 lymphomas, 2 sarcomas, 1 lymphoma+sarcoma), however, histologic tissue analysis revealed that the remaining three mice had subclinical cancer (3 lymphomas). In contrast, RAPA treatment resulted in only three mice with clinical tumors (all lymphomas), with histology revealing subclinical lymphomas in three additional mice, but no evidence of cancer in four animals. Statistically, cancer development was decreased with RAPA treatment (P=0.002), but was not affected with either MMF or CsA (P>0.10).
These experiments are the first to show immunosuppression under RAPA can reduce spontaneous de novo cancer associated with p53 mutations. Although neither CsA nor MMF treatment affects p53-associated tumor incidence, MMF may have some tendency to reduce clinical tumor appearance.
Transplantation 09/2006; 82(6):741-8. · 4.00 Impact Factor
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[show abstract]
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ABSTRACT: There is an accumulating body of evidence indicating that soluble major histocompatibility complex (sMHC) molecules have donor-specific immunosuppressive properties. One classic, but still unproven, theory is that production of sMHC by liver transplants induces a potent immunosuppressive effect. To mimic this possible effect, we have developed a replication deficient adenovirus (Ad-RQ) to express high levels of donor sMHC class I molecules (sRT1.A(a)) in the liver. Ad-RQ produced sRT1.A(a) was measured by enzyme-linked immunosorbent assay (ELISA) after in vitro infection of Lewis (RT1(l)) hepatocytes, and in vivo following intravenous virus injection into Lewis rats. Results indicated high sRT1.A(a) expression in Lewis hepatocyte cultures and, in vivo, high expression was also demonstrated and maintained for at least 1 week. A strong immunosuppressive potential of sMHC in vivo was revealed by prolongation of cardiac (ACI, RT1(a)) heart allograft survival in high-responder Lewis rat recipients treated with Ad-RQ alone. Furthermore, limiting dilution cytotoxic T-lymphocyte precursor (CTLp) analysis of lymphocytes from Ad-RQ-treated Lewis recipients receiving an ACI heart transplant indicated a marked decrease in antidonor CTLp frequency. In conclusion, our results demonstrate that viral vectors can be used effectively to express high levels of sMHC molecules, and their immunosuppressive effect, without concurrent immunosuppression, is sufficiently potent to prolong heart transplant survival.
Human Immunology 11/2002; 63(10):844-52. · 2.84 Impact Factor
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Markus Guba,
Philipp von Breitenbuch,
Markus Steinbauer,
Gudrun Koehl,
Stefanie Flegel,
Matthias Hornung,
Christiane J Bruns, Carl Zuelke,
Stefan Farkas,
Matthias Anthuber,
Karl-Walter Jauch,
Edward K Geissler
[show abstract]
[hide abstract]
ABSTRACT: Conventional immunosuppressive drugs have been used effectively to prevent immunologic rejection in organ transplantation. Individuals taking these drugs are at risk, however, for the development and recurrence of cancer. In the present study we show that the new immunosuppressive drug rapamycin (RAPA) may reduce the risk of cancer development while simultaneously providing effective immunosuppression. Experimentally, RAPA inhibited metastatic tumor growth and angiogenesis in in vivo mouse models. In addition, normal immunosuppressive doses of RAPA effectively controlled the growth of established tumors. In contrast, the most widely recognized immunosuppressive drug, cyclosporine, promoted tumor growth. From a mechanistic perspective, RAPA showed antiangiogenic activities linked to a decrease in production of vascular endothelial growth factor (VEGF) and to a markedly inhibited response of vascular endothelial cells to stimulation by VEGF. Thus, the use of RAPA, instead of cyclosporine, may reduce the chance of recurrent or de novo cancer in high-risk transplant patients.
Nature Medicine 03/2002; 8(2):128-35. · 22.46 Impact Factor
