Melablock: A Multicentre Randomized, Double---blinded and Placebo---controlled Clinical Trial on the Efficacy and Safety of Once Daily Propranolol 80 mg Retard for the Prevention of Cutaneous Malignant Melanoma Recurrence

Cutaneous malignant melanoma (CMM) represents a major public health problem.Although melanoma accounts for only 4% of all dermatologic cancers, it is responsible for 80% of deaths from skin cancer; only 14% of patients with metastatic melanoma survive for five years . The probability of survival for melanoma stage II/IIIA at 15 years is around 50%.

Treatment with dacarbazine, fotemustine, temozolomide, interferon---α and interleukin---2 has been proposed in metastatic melanoma, but these drugs exert poor efficacy. More recently, ipilimumab, which blocks cytotoxic T---lymphocyte-associated antigen 4 to potentiate an antitumor T---cell response has been approved for the treatment of HLA---A*0201-positive patients with unresectable stage III or IV melanoma . This treatment has been found to delay mortality by about 4 months, although, in clinical trials a fraction of patients lived much longer . However, the drug caused severe or fatal side effects in almost 13% of patients, prompting the FDA to qualify its approval with a mitigation strategy. There were 14 deaths related to the study drugs (2.1%), and 7 were associated with immune---related adverse events. These findings do not suggest the use of ipilimumab in non metastatic patients. After surgical resection no specific pharmacotherapy is recommended for patients with stage II/IIIA CMM until metastases are found.

β---adrenoceptor antagonists (β---blockers) belong to one of the most widely used classes of drugs in clinical practice. Their use is mainly directed to the chronic management of hypertension , although they are also prescribed for ischemic heart disease, heart failure, anxiety, tremor, migraine and glaucoma , Initial pharmacoepidemiological evidence shows that β---blockers may reduce cancer risk. Indeed, β--- blockers have been reported to exert a certain degree of protection against prostate cancer . More recently, β---blocker treatment for concomitant diseases has been found to significantly reduce distant metastases, cancer recurrence, and cancer---specific mortality in breast cancer patients .

Infantile hemangiomas are the most common benign tumor of infancy. Over the last few years, propranolol has become a popular and successful treatment for infantile hemangiomas. The ability of ß---adrenoceptors to increase the vascular endothelial growth factor (VEGF) and the subsequent angionenetic pathway has contributed to the identification of this mechanism as a primary target of ß---blockers to limit cancer progression and to treat hemangiomas. The recent observation that propranolol treated successfully a case of infantile lymphangiomatosis and simulatneously reduced VEGF levels further strengthens this hypothesis. Preclinical studies have proposed that activation of β--- adrenoceptors play a detrimental role in melanoma, as in vitro studies showed that melanoma tissues expressed both β1--- and β2---adrenoceptors and that isoproterenol is a potent inducer of VEGF, IL---8 and IL---6 gene expression in human melanoma cells supporting the role of β--- adrenoceptors in this pathway. Thus, the role of ß---adrenoceptors to promote angiogenesis, supported by both basic and clinical evidence, represents the most robust working hypothesis explaining the beneficial effect of ß-blockers indifferent models of cancers,including melanoma.

In a prospective cohort of 121 consecutive patients with thick melanoma (Breslow >1), the investigators recently found that the use of β---blockers for concomitant diseases for 1 year or more is associated with a reduced risk of CMM recurrence. After a median follow---up time of 2.5 years, tumor progression was observed in 3.3% of the treated (n=30) subgroup and in 34.1% of the untreated (n=91) subgroup . Cox model on progression indicated a 36% (95%CI: 11%---54%; P=.002) risk reduction for each year of β---blocker use. No death was observed in the treated group, whereas in the untreated group 24 patients died. This study suggested for the first time that exposure to β---blockers is associated with a reduced risk of progression of thick CMM. In a larger group of 741 patients with thick and thin CMM the invetigators have recently confirmed the association between β---blocker prescription (79 patients) and the reduction in the risk of CMM recurrence and death.