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Sirolimus does double duty after organ transplantation
Newsdesk
More negative results for vitamin E Alpha-tocopherol (vitamin E) supplements increase the rate at which patients with head and neck cancer develop second primary cancers after treatment, according to a chemoprevention trial. Patients at high risk of second primary cancers who were given supplements had more frequent recurrence of primary cancer and were less likely to survive, cancer-free, than were those assigned placebo. “There is some concern about extrapolating the results to individuals in the population who are at low risk of a first primary cancer. But, our results suggest caution when considering the use of high-dose alphatocopherol supplements for cancer prevention”, says study head Isabelle Bairati (Cancer Research Centre, Laval University, Quebec, Canada). The double-blind, placebo-controlled, multicentre randomised trial enrolled 540 patients with stage I or II head and neck cancer who had had radiotherapy.
Patients were assigned 30 mg/day -carotene and 400 IU/day alphatocopherol on the first day of radiotherapy for 3 years or to placebo. -carotene was discontinued in some patients after recent trial results were reported elsewhere, and the study focused mainly on the effect of alphatocopherol supplements. More patients receiving alpha-tocopherol had recurrent disease or second primary cancers compared with those given placebo. Low rates were recorded after supplements were discontinued (J Natl Can Inst 2005; 97: 481–88). “Many large-scale chemoprevention trials have now failed to show adequate benefit for patients with cancer”, says Edward Kim, University of Texas, Houston, TX, USA (J Natl Can Inst 2005; 97: 468–70). He expects future trials to focus on risk models that include identification and integration of biomarkers to affect treatment. “Once we
have found agents that target the genetic differences in people with a poor prognostic genotype, there will be stronger evidence to test these agents in phase III trials using important health outcomes as endpoints”, he predicts.
Kathryn Senior
Eat your greens? No chemopreventive role for vitamin E
Sirolimus does double duty after organ transplantation A new study shows that treatment of kidney-transplant recipients with an immunosuppressive and antiproliferative drug sirolimus (rapamycin) completely clears Kaposi’s sarcoma (KS) skin lesions while preserving immunosuppression and kidney-graft function (N Engl J Med 2005; 352: 1317–23). The dual action of sirolimus could provide new strategies for reducing the risk of cancer in organ-transplant recipients. Cancer is a frequent cause of death after a successful organ transplant. The need for chronic immunosuppression creates a high risk of cancer, and virusrelated cancers, like KS, are common. “In our centre, KS represents between 40 and 50% of all neoplastic disease seen after transplantation”, says Giuseppe Grandaliano, the study’s senior investigator (University of Bari, Italy). “Before, the only thing we could do for patients with KS was to turn down the immunotherapy, which http://oncology.thelancet.com Vol 6 May 2005
could lead to graft rejection and graft loss.” This dilemma stimulated the Italian researchers to investigate the anticancer potential of sirolimus in transplantation patients. Previous studies hinted that the drug could directly halt tumour-cell growth, and could prevent angiogenesis by blocking expression of vascular endothelial growth factor (VEGF). Because the growth of KS cells depends on VEGF, they selected 15 transplantation patients who presented with KS while using ciclosporin, and switched them to sirolimus. Within 1 month, KS lesions began to regress, and 6 months later all signs of the sarcoma were gone on biopsy. The researchers also measured decreased VEGF production by tumours and surrounding skin cells. “These results demonstrate a clinical procedure which is safe and works to cure KS after transplantation in human
patients”, says Jean-Paul Soulillou (Institute for Transplantation and Research in Transplantation, Nantes University, France) and author of an accompanying editorial (N Engl J Med 2005; 352: 1371–73). “Clinically speaking, it’s quite clear cut, but understanding the mechanism will require more work”, he adds. Defining whether sirolimus blocks tumour-cell growth or angiogenesis will help predict the effectiveness of the drug against other tumours. Grandaliano and Soulillou are now undertaking retrospective studies of the effect of sirolimus-based immunosuppressive regimens on other transplant-related tumours, including skin cancer, lymphoma, and leukaemia. The Italian group plans to start testing sirolimus for treatment of other cancers in transplantation patients.
Pat McCaffrey 261
More negative results for vitamin E Alpha-tocopherol (vitamin E) supplements increase the rate at which patients with head and neck cancer develop second primary cancers after treatment, according to a chemoprevention trial. Patients at high risk of second primary cancers who were given supplements had more frequent recurrence of primary cancer and were less likely to survive, cancer-free, than were those assigned placebo. “There is some concern about extrapolating the results to individuals in the population who are at low risk of a first primary cancer. But, our results suggest caution when considering the use of high-dose alphatocopherol supplements for cancer prevention”, says study head Isabelle Bairati (Cancer Research Centre, Laval University, Quebec, Canada). The double-blind, placebo-controlled, multicentre randomised trial enrolled 540 patients with stage I or II head and neck cancer who had had radiotherapy.
Patients were assigned 30 mg/day -carotene and 400 IU/day alphatocopherol on the first day of radiotherapy for 3 years or to placebo. -carotene was discontinued in some patients after recent trial results were reported elsewhere, and the study focused mainly on the effect of alphatocopherol supplements. More patients receiving alpha-tocopherol had recurrent disease or second primary cancers compared with those given placebo. Low rates were recorded after supplements were discontinued (J Natl Can Inst 2005; 97: 481–88). “Many large-scale chemoprevention trials have now failed to show adequate benefit for patients with cancer”, says Edward Kim, University of Texas, Houston, TX, USA (J Natl Can Inst 2005; 97: 468–70). He expects future trials to focus on risk models that include identification and integration of biomarkers to affect treatment. “Once we
have found agents that target the genetic differences in people with a poor prognostic genotype, there will be stronger evidence to test these agents in phase III trials using important health outcomes as endpoints”, he predicts.
Kathryn Senior
Eat your greens? No chemopreventive role for vitamin E
Sirolimus does double duty after organ transplantation A new study shows that treatment of kidney-transplant recipients with an immunosuppressive and antiproliferative drug sirolimus (rapamycin) completely clears Kaposi’s sarcoma (KS) skin lesions while preserving immunosuppression and kidney-graft function (N Engl J Med 2005; 352: 1317–23). The dual action of sirolimus could provide new strategies for reducing the risk of cancer in organ-transplant recipients. Cancer is a frequent cause of death after a successful organ transplant. The need for chronic immunosuppression creates a high risk of cancer, and virusrelated cancers, like KS, are common. “In our centre, KS represents between 40 and 50% of all neoplastic disease seen after transplantation”, says Giuseppe Grandaliano, the study’s senior investigator (University of Bari, Italy). “Before, the only thing we could do for patients with KS was to turn down the immunotherapy, which http://oncology.thelancet.com Vol 6 May 2005
could lead to graft rejection and graft loss.” This dilemma stimulated the Italian researchers to investigate the anticancer potential of sirolimus in transplantation patients. Previous studies hinted that the drug could directly halt tumour-cell growth, and could prevent angiogenesis by blocking expression of vascular endothelial growth factor (VEGF). Because the growth of KS cells depends on VEGF, they selected 15 transplantation patients who presented with KS while using ciclosporin, and switched them to sirolimus. Within 1 month, KS lesions began to regress, and 6 months later all signs of the sarcoma were gone on biopsy. The researchers also measured decreased VEGF production by tumours and surrounding skin cells. “These results demonstrate a clinical procedure which is safe and works to cure KS after transplantation in human
patients”, says Jean-Paul Soulillou (Institute for Transplantation and Research in Transplantation, Nantes University, France) and author of an accompanying editorial (N Engl J Med 2005; 352: 1371–73). “Clinically speaking, it’s quite clear cut, but understanding the mechanism will require more work”, he adds. Defining whether sirolimus blocks tumour-cell growth or angiogenesis will help predict the effectiveness of the drug against other tumours. Grandaliano and Soulillou are now undertaking retrospective studies of the effect of sirolimus-based immunosuppressive regimens on other transplant-related tumours, including skin cancer, lymphoma, and leukaemia. The Italian group plans to start testing sirolimus for treatment of other cancers in transplantation patients.
Pat McCaffrey 261