Preclinical studies have shown that β-adrenergic receptor (β-AR) signaling can inhibit multiple cellular processes involved in melanoma progression and metastasis. These observations suggest the possibility that β-AR blockers, drugs originally intended for the treatment of cardiovascular diseases, may provide new therapeutic opportunities for the control of tumor progression. A large number of observational studies have demonstrated the protective effect of β-blockers in breast cancer but, more recently, similar findings were also reported in other cancers, such as prostate cancer and melanoma. Regarding melanoma, three recently published studies demonstrate a great reduction in the risk of disease progression for each year of treatment with β-blockers. The results from these studies have suggested a potential role for targeting the β-AR pathway in melanoma patients. The purpose of this thesis is to present the clinical data obtained from two analyses: a retrospective study and an open-label trial, both aimed at evaluating the role of β-blockers in melanoma patients. In the retrospective study, two subgroups were identified from the medical records of 121 consecutive patients with a thick melanoma. Of these, 30 had been prescribed β-blockers for 1 year or more (treated subgroup), whereas the other 91 were untreated. 45 percent of patients in the untreated group showed disease progression, which occurred in only 30% of the patients in the treated group; 8 (27%) deaths were observed in the treated group, whereas in the untreated group 38 (42%) 5 patients died. In the open-label clinical trial, we selected adult patients who were at higher risk of disease progression. We divided patients in two groups: treated with β-blockers, and untreated. Treated patients were eligible for the study with no exclusion criteria, and fulfilled inclusion criteria. Patients included in the treated group voluntarily accepted to take propranolol 80 mg/R as an off-label treatment for their melanoma. Patients included in the untreated group were those who had contraindications to propranolol or who refused to take an off-label treatment for their melanoma but accepted to be part of the study as controls. The participants were asked to return to the recruitment clinic every 6 months. We enrolled 54 subjects, 19 in the treated group and 34 in the untreated group. After a median follow-up of 3 years, 41.2% (n=14) of the patients in the untreated group showed disease progression, which occurred in only 15.8% (n=3) of the patients in the treated group. It is notable that in the untreated group six patients (17.7%) died for melanoma but only two patients (10.5%) died in the treated group and one of them died for a reason unrelated to melanoma, from a traumatic event. When time to progression was analyzed, log-rank test showed that an improved disease-free survival (DFS) for the treated group (P=0.04). Despite the numerous limitations, these studies reinforce the hypothesis that β-blockers could provide clinically valuable benefits against melanoma progression, possibly by inhibiting the pro-metastatic effects of β-AR signaling on tumor immune responses and the tumor microenvironment.

Melablock: Trial clinico randomizzato per l’utilizzo del Propranololo in pazienti affetti da melanoma cutaneo / Grazzini, Marta. - (2016).

Melablock: Trial clinico randomizzato per l’utilizzo del Propranololo in pazienti affetti da melanoma cutaneo

GRAZZINI, MARTA
2016

Abstract

Preclinical studies have shown that β-adrenergic receptor (β-AR) signaling can inhibit multiple cellular processes involved in melanoma progression and metastasis. These observations suggest the possibility that β-AR blockers, drugs originally intended for the treatment of cardiovascular diseases, may provide new therapeutic opportunities for the control of tumor progression. A large number of observational studies have demonstrated the protective effect of β-blockers in breast cancer but, more recently, similar findings were also reported in other cancers, such as prostate cancer and melanoma. Regarding melanoma, three recently published studies demonstrate a great reduction in the risk of disease progression for each year of treatment with β-blockers. The results from these studies have suggested a potential role for targeting the β-AR pathway in melanoma patients. The purpose of this thesis is to present the clinical data obtained from two analyses: a retrospective study and an open-label trial, both aimed at evaluating the role of β-blockers in melanoma patients. In the retrospective study, two subgroups were identified from the medical records of 121 consecutive patients with a thick melanoma. Of these, 30 had been prescribed β-blockers for 1 year or more (treated subgroup), whereas the other 91 were untreated. 45 percent of patients in the untreated group showed disease progression, which occurred in only 30% of the patients in the treated group; 8 (27%) deaths were observed in the treated group, whereas in the untreated group 38 (42%) 5 patients died. In the open-label clinical trial, we selected adult patients who were at higher risk of disease progression. We divided patients in two groups: treated with β-blockers, and untreated. Treated patients were eligible for the study with no exclusion criteria, and fulfilled inclusion criteria. Patients included in the treated group voluntarily accepted to take propranolol 80 mg/R as an off-label treatment for their melanoma. Patients included in the untreated group were those who had contraindications to propranolol or who refused to take an off-label treatment for their melanoma but accepted to be part of the study as controls. The participants were asked to return to the recruitment clinic every 6 months. We enrolled 54 subjects, 19 in the treated group and 34 in the untreated group. After a median follow-up of 3 years, 41.2% (n=14) of the patients in the untreated group showed disease progression, which occurred in only 15.8% (n=3) of the patients in the treated group. It is notable that in the untreated group six patients (17.7%) died for melanoma but only two patients (10.5%) died in the treated group and one of them died for a reason unrelated to melanoma, from a traumatic event. When time to progression was analyzed, log-rank test showed that an improved disease-free survival (DFS) for the treated group (P=0.04). Despite the numerous limitations, these studies reinforce the hypothesis that β-blockers could provide clinically valuable benefits against melanoma progression, possibly by inhibiting the pro-metastatic effects of β-AR signaling on tumor immune responses and the tumor microenvironment.
2016
Niccolo Marchionni
ITALIA
Grazzini, Marta
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Utilizza questo identificatore per citare o creare un link a questa risorsa: https://hdl.handle.net/2158/1036230
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