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Figure 1.
Enrollment in the Study
Enrollment in the Study

Patients with histologically confirmed stage IB to IIIA cutaneous melanoma and no evidence of metastasis were eligible to participate in the study. They were divided into a propranolol cohort and a nonpropranolol cohort.

Figure 2.
Disease-Free Survival by Propranolol Use
Disease-Free Survival by Propranolol Use

After 3 years of treatment, disease progression was observed in 41.2% of the patients in the untreated cohort compared with only 15.8% in the propranolol cohort.

Table.  
Melanoma Recurrence From Cox Multivariate Regression Model
Melanoma Recurrence From Cox Multivariate Regression Model
1.
Sanzo  M, Colucci  R, Arunachalam  M, Berti  S, Moretti  S.  Stress as a possible mechanism in melanoma progression.  Dermatol Res Pract. 2010;2010(2):483493. doi:10.1155/2010/483493PubMedGoogle Scholar
2.
Fitzgerald  PJ.  Is norepinephrine an etiological factor in some types of cancer?  Int J Cancer. 2009;124(2):257-263.PubMedGoogle ScholarCrossref
3.
Huang  XY, Wang  HC, Yuan  Z, Huang  J, Zheng  Q.  Norepinephrine stimulates pancreatic cancer cell proliferation, migration and invasion via β-adrenergic receptor-dependent activation of P38/MAPK pathway.  Hepatogastroenterology. 2012;59(115):889-893.PubMedGoogle Scholar
4.
Glasner  A, Avraham  R, Rosenne  E,  et al.  Improving survival rates in two models of spontaneous postoperative metastasis in mice by combined administration of a β-adrenergic antagonist and a cyclooxygenase-2 inhibitor.  J Immunol. 2010;184(5):2449-2457.PubMedGoogle ScholarCrossref
5.
Talarico  G, Orecchioni  S, Dallaglio  K,  et al.  Aspirin and atenolol enhance metformin activity against breast cancer by targeting both neoplastic and microenvironment cells.  Sci Rep. 2016;6:18673.PubMedGoogle ScholarCrossref
6.
Pasquier  E, Ciccolini  J, Carre  M,  et al.  Propranolol potentiates the anti-angiogenic effects and anti-tumor efficacy of chemotherapy agents: implication in breast cancer treatment.  Oncotarget. 2011;2(10):797-809.PubMedGoogle ScholarCrossref
7.
Sloan  EK, Priceman  SJ, Cox  BF,  et al.  The sympathetic nervous system induces a metastatic switch in primary breast cancer.  Cancer Res. 2010;70(18):7042-7052.PubMedGoogle ScholarCrossref
8.
De Giorgi  V, Grazzini  M, Gandini  S,  et al.  Treatment with β-blockers and reduced disease progression in patients with thick melanoma.  Arch Intern Med. 2011;171(8):779-781.PubMedGoogle ScholarCrossref
9.
Léauté-Labrèze  C, Dumas de la Roque  E, Hubiche  T, Boralevi  F, Thambo  JB, Taïeb  A.  Propranolol for severe hemangiomas of infancy.  N Engl J Med. 2008;358(24):2649-2651.PubMedGoogle ScholarCrossref
Brief Report
February 8, 2018

Propranolol for Off-label Treatment of Patients With Melanoma: Results From a Cohort Study

Author Affiliations
  • 1Department of Dermatology, Azienda Sanitaria Toscana Centro, University of Florence, Florence, Italy
  • 2Department of Health Sciences, Clinical Pharmacology and Oncology Unit, University of Florence, Florence, Italy
  • 3Cardiothoracovascular Department, Careggi University Hospital, Florence, Italy
  • 4Cancer Registry of Norway, Oslo, Norway
  • 5Surgical Department Melanoma, European Institute of Oncology, Milan, Italy
  • 6Division of Epidemiology and Biostatistics, European Institute of Oncology, Milan, Italy
JAMA Oncol. 2018;4(2):e172908. doi:10.1001/jamaoncol.2017.2908
Key Points

Question  Does propranolol improve progression-free survival in patients with thick melanoma?

Findings  We conducted a prospective study in patients with melanoma treated with propranolol for off-label use. After adjusting for known prognostic factors, Cox models confirmed that use of propranolol at the time of diagnosis was significantly inversely associated with recurrence of melanoma with approximately an 80% risk reduction for propranolol users.

Meaning  The study supports recent observation that β-blockers protect patients with thick cutaneous melanoma from disease recurrence and death.

Abstract

Importance  Preclinical and retrospective studies showed that β-blockers inhibit angiogenesis and disrupt migration of melanoma cells via inhibition of noradrenaline-dependent responses.

Objective  To study the clinical effectiveness of β-blocker therapy in patients with melanoma and to determine whether propranolol improves progression-free survival in patients with melanoma.

Design, Setting, and Participants  We conducted a prospective study in patients treated for melanoma in our center with propranolol for off-label use. Patients with histologically confirmed stage IB to IIIA cutaneous melanoma and no evidence of metastasis were eligible for the study. At the time of diagnosis, they were asked to take propranolol (80 mg daily) as an off-label adjuvant treatment. If they accepted the treatment, they were considered part of the propranolol cohort (PROP). If they refused treatment but agreed to participate in the study control group, they were considered part of the nonpropranolol cohort (No-PROP).

Main Outcomes and Measures  The primary outcome was progression-free survival. Disease progression was assessed by evaluating the presence of lymphatic, in-transit, or visceral metastases, and the cause of death was recorded.

Results  Among the 53 patients (median [interquartile range] age 63 [48-75] years; 33 men) included in the study, 19 were eligible for the PROP cohort. Thirty-four patients otherwise eligible but unwilling to take propranolol were enrolled in the No-PROP cohort. The 2 cohorts were comparable in terms of demographic characteristics and primary prognostic factors at baseline. After adjusting for known prognostic factors, Cox models confirmed that use of propranolol at the time of diagnosis was significantly inversely associated with recurrence of melanoma with approximately an 80% risk reduction for propranolol users (hazard ratio, 0.18; 95% CI, 0.04-0.89; P = .03).

Conclusions and Relevance  In the absence of randomized, double-blind, placebo-controlled clinical trials, this study is the first off-label study of which we are aware of propranolol for melanoma treatment. These results confirm recent observation that β-blockers protect patients with thick cutaneous melanoma from disease recurrence. This study is in accordance with the present policy of “drug repurposing” in oncology. Repurposing the vast arsenal of approved drugs with a nononcology primary purpose may prove an attractive and inexpensive strategy for offering more effective treatment options to patients with cancer.

Introduction

Epidemiological and clinical studies have linked psychosocial factors such as chronic stress and depression with cancer progression and, to a lesser extent, cancer onset.1-3 The results of experiments conducted in vitro confirm the assumption that stress is a cofactor in melanoma progression.4 Moreover, preclinical studies have shown that β-blockers and propranolol in particular inhibit angiogenesis and disrupt migration of cancer cells via inhibition of noradrenaline-dependent responses.5-7 The first article describing the use of β-blockers in patients with melanoma was published by De Giorgi et al.8 In this study, after a median follow-up of 2.5 years, 34% of patients not using β-blockers had evidence of disease progression, while only 3% of those who used β-blockers (administered for other diseases) at the time of diagnosis showed melanoma progression. Thus, we conducted a prospective study in patients with melanoma in our center to compare those treated with propranolol for off-label use with those not treated. We designed 2 cohorts of patients with stage IB to IIIA melanoma, for whom no standard treatment is available, to verify the role of off-label propranolol on melanoma recurrence and mortality. Propranolol was chosen among the nonselective β-blockers because it has been shown to exhibit anticancer effects in cancer cell lines, animal models, and in the majority of studies published in the literature. In addition, the recent observation that propranolol successfully treated cases of infantile hemangioma9 and simultaneously reduced vascular endothelial growth factor levels further supported our decision to use a nonselective β-blocker for this off-label treatment.

Methods

We conducted a prospective cohort study in patients with cutaneous melanoma at the Department of Dermatology at the University of Florence, Italy, between January 1, 2011, and April 1, 2013. This study was approved by the ethics committee of the Local Health Unit 10 (Florence, Italy). Patients older than 18 years with histologically confirmed stage IB to IIIA cutaneous melanoma and no evidence of metastasis or contraindication to propranolol use were eligible to participate in the study. Thus, at the time of diagnosis, after the patients signed informed consent, they were asked to take propranolol (80 mg daily) as an off-label adjuvant treatment. Patients who accepted the treatment protocol were considered part of the propranolol cohort (PROP). Those who refused the treatment protocol but agreed to participate in the study as a control group were considered part of the nonpropranolol cohort (No-PROP) (eTable 1 in the Supplement). The physician performed a complete physical examination, including measurement of body weight, blood pressure, pulse rate, and echo cardiogram, to assess the general health of the study participants. We collected updated information about the health status of the participants and used imaging and physical examinations to evaluate signs of melanoma recurrence during routine follow-up visits, as outlined in the protocols currently in use (about every 4 months). Treatment was discontinued in cases of confirmed disease progression as determined by the modified World Health Organization criteria, or in cases of adverse events. Study participants were able to withdraw from the study at any time. Disease progression was assessed by evaluating the presence of lymphatic, in-transit, or visceral metastases, and the cause of death was recorded.

Statistical Analysis

As an exploratory trial, we calculated that a minimum of 53 patients (34 in the control cohort and 19 in the treatment cohort) would allow us to detect a 65% reduction in the risk of melanoma recurrence in the PROP vs No-PROP group with 86% power at a .05 significance level.

Median values, the interquartile ranges, frequencies, and results from nonparametric tests (Wilcoxon signed-rank tests or χ2 tests) were used to present and analyze the differences in characteristics between the PROP and No-PROP groups.

Time to death and time to recurrence were defined as the time from surgery until the event of interest. All patients alive or free of disease at the last follow-up date were considered right censored. Survival curves were estimated by the Kaplan-Meier method and comparisons between the groups were carried out by log-rank tests. Cox proportional hazards models were used to assess if propranolol use was independently associated with events, adjusting for prognostic factors. Statistical tests were 2 sided. Analyses were performed with SAS software, version 9.2 (SAS Institute).

Results

Of the 79 patients who received a diagnosis of thick melanoma during the study period, 53 (67%) were included in the present study and 26 (33%) were not included (Figure 1). Among the 53 patients included in the prospective study, 19 (35%) were eligible for PROP. Thirty-four (65%) patients who were otherwise eligible but unwilling to take propranolol were enrolled in the No-PROP group (Figure 1). The 2 cohorts were comparable in terms of demographic characteristics and primary prognostic factors at baseline (eTable 2 in the Supplement). We had a significant imbalance between the 2 groups only with regard to ulceration (35% vs 63%; P = .05). There were significantly more cases of ulcerated melanoma in the PROP group, which presents a greater risk of disease progression. There were no adverse events in the PROP group. After a median follow-up of 3 years, 14 patients in the No-PROP group (41.2%) showed disease progression, while only 3 patients in the PROP group (15.8%) had evidence of disease progression. In the No-PROP group, 6 patients (17.7%) died, 5 of them due to melanoma, while 2 patients (10.5%) died in the PROP group, with 1 death attributed to melanoma. When time to progression was analyzed, a log-rank test showed an improved disease-free survival for the PROP group (89% vs 64% at 3 years; P = .04) (Figure 2). Cox models adjusted for age, Breslow thickness, and ulceration confirmed that use of propranolol at the time of diagnosis was significantly inversely associated with recurrence with approximately an 80% risk reduction for propranolol users (hazard ratio, 0.18; 95% CI, 0.04-0.89; P = .03) (Table). The association between use of propranolol and overall survival was not statistically significant.

Discussion

In the absence of randomized, double-blind, placebo-controlled clinical trials, this study is the first off-label prospective study to our knowledge of propranolol for melanoma treatment. These results provide the basis for larger trials of longer duration to measure the clinical efficacy of propranolol.

These results support our previous observation that β-blockers protect patients with thick cutaneous melanoma from disease recurrence and death. In fact, after only 3 years of treatment, disease progression was observed in 41.2% of the patients in the untreated cohort compared with only 15.8% in the propranolol cohort. The multivariate Cox model found a significant reduction in the risk of recurrence of melanoma of approximately 80% (hazard ratio, 0.18; 95% CI, 0.04-0.89; P = .03). This result is important because in the propranolol cohort histopathological examinations showed a greater number of cases with ulceration, which is considered a poor prognostic factor. Even overall survival, although not significant, showed a trend toward decreased mortality in the propranolol group after 3 years of follow-up.

Furthermore, this study is the first we know of to evaluate the administration of a β-blocker to patients as adjuvant therapy at the time of diagnosis of melanoma. To date, the medical literature on melanoma and β-blockers (administered for other diseases) has consisted of published reviews or observational studies.

Limitations

Our study has several limitations. It is a prospective study with a small sample size, though 14 patients (41%) experienced recurrent events in the untreated cohort of patients. In addition, given the study design, a risk of selection bias cannot be excluded. However, the 2 cohorts of patients (propranolol and untreated cohorts) had similar baseline demographics and clinical characteristics except for the greater prevalence of ulceration in the propranolol cohort. Finally, the short follow-up did not allow us to have enough statistical power to observe an effect on mortality.

Conclusions

The development of randomized placebo-controlled clinical trials is necessary to clarify a definitive role for β-blockers in protecting against the risk of progression of melanoma and to potentially identify the receptor subtype involved in the protective effect.

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Article Information

Corresponding Author: Vincenzo De Giorgi, MD, Department of Dermatology, University of Florence, Via Michelangelo 41, 50124 Firenze, Italy (vincenzo.degiorgi@unifi.it).

Accepted for Publication: June 30, 2017.

Published Online: September 28, 2017. doi:10.1001/jamaoncol.2017.2908

Author Contributions: Dr De Giorgi had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: De Giorgi, Grazzini, Marchionni, Geppetti.

Acquisition, analysis, or interpretation of data: De Giorgi, Grazzini, Benemei, Botteri, Pennacchioli, Gandini.

Drafting of the manuscript: De Giorgi, Grazzini, Benemei, Botteri, Gandini.

Critical revision of the manuscript for important intellectual content: De Giorgi, Marchionni, Botteri, Pennacchioli, Geppetti.

Statistical analysis: Botteri, Gandini.

Administrative, technical, or material support: Grazzini, Benemei.

Study supervision: De Giorgi, Geppetti.

Conflict of Interest Disclosures: None reported.

References
1.
Sanzo  M, Colucci  R, Arunachalam  M, Berti  S, Moretti  S.  Stress as a possible mechanism in melanoma progression.  Dermatol Res Pract. 2010;2010(2):483493. doi:10.1155/2010/483493PubMedGoogle Scholar
2.
Fitzgerald  PJ.  Is norepinephrine an etiological factor in some types of cancer?  Int J Cancer. 2009;124(2):257-263.PubMedGoogle ScholarCrossref
3.
Huang  XY, Wang  HC, Yuan  Z, Huang  J, Zheng  Q.  Norepinephrine stimulates pancreatic cancer cell proliferation, migration and invasion via β-adrenergic receptor-dependent activation of P38/MAPK pathway.  Hepatogastroenterology. 2012;59(115):889-893.PubMedGoogle Scholar
4.
Glasner  A, Avraham  R, Rosenne  E,  et al.  Improving survival rates in two models of spontaneous postoperative metastasis in mice by combined administration of a β-adrenergic antagonist and a cyclooxygenase-2 inhibitor.  J Immunol. 2010;184(5):2449-2457.PubMedGoogle ScholarCrossref
5.
Talarico  G, Orecchioni  S, Dallaglio  K,  et al.  Aspirin and atenolol enhance metformin activity against breast cancer by targeting both neoplastic and microenvironment cells.  Sci Rep. 2016;6:18673.PubMedGoogle ScholarCrossref
6.
Pasquier  E, Ciccolini  J, Carre  M,  et al.  Propranolol potentiates the anti-angiogenic effects and anti-tumor efficacy of chemotherapy agents: implication in breast cancer treatment.  Oncotarget. 2011;2(10):797-809.PubMedGoogle ScholarCrossref
7.
Sloan  EK, Priceman  SJ, Cox  BF,  et al.  The sympathetic nervous system induces a metastatic switch in primary breast cancer.  Cancer Res. 2010;70(18):7042-7052.PubMedGoogle ScholarCrossref
8.
De Giorgi  V, Grazzini  M, Gandini  S,  et al.  Treatment with β-blockers and reduced disease progression in patients with thick melanoma.  Arch Intern Med. 2011;171(8):779-781.PubMedGoogle ScholarCrossref
9.
Léauté-Labrèze  C, Dumas de la Roque  E, Hubiche  T, Boralevi  F, Thambo  JB, Taïeb  A.  Propranolol for severe hemangiomas of infancy.  N Engl J Med. 2008;358(24):2649-2651.PubMedGoogle ScholarCrossref
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