Table 3.
Published observational studies (prospective, retrospective, and meta-analyses) investigating the inhibition of adrenergic signaling pathway in cancer patients.
| Cancer | Beta-blockers | Conventional anticancer agents | Results | Study | Ref. |
|---|---|---|---|---|---|
| Brain cancer | β-blockers | NA | 225 patients included. Control of tumor growth (p=0.001), tumor progression (p=0.0001) and higher survival (p=0.015). Strong correlation between β-blockers and survival (p=0.049) | Retrospective | 150 |
| Breast cancer (HER2+) | Atenolol, bisoprolol, carvedilol, propranolol |
Trastuzumab | PFS adjusted HR=2.21, 95%CI[1.56–3.12]; p<0.001 OS adjusted HR=2.46, 95% CI[1.69–3.57]; p<0.001 |
Retrospective | 165 |
| Breast cancer (HER2-) | Atenolol, bisoprolol, metoprolol, propranolol |
Docetaxel and/or ramucirumab | Improved PFS (15.5 vs 8.3 months); p=0.038 No significant difference in OS |
Retrospective | 151 |
| Breast cancer | Atenolol, bisoprolol, propranolol, timolol |
NA | Reduction in metastasis (p=0.026), tumor recurrence (p=0.001) and longer disease-free interval (p=0.01). A 57% reduction in risk of metastasis (HR=0.430; 95%CI[0.200–0.926], p=0.031). A 71% reduction in mortality after 10 years (HR=0.291; 95%CI[0.119–0.715]; p=0.007). No significant difference in vascular invasion. | Retrospective | 152 |
| Breast cancer | β-blockers | NA | 46 245 patients included. Survival HR=0.44; 95%CI[0.26–0.73] with I2=78%. DFS HR=0.71; 95%CI[0.19–1.03] | Meta-analysis | 195 |
| Colo-rectal cancer | β-blockers | Chemotherapy (2628 patients) Radiotherapy (1427 patients) |
4794 patients included. β-blockers decreased mortality (adjusted OR=0.88; 95%CI[0.77–1.00]; p=0.04) | Retrospective | 153 |
| Hepato-cellular carcinoma | Carvedilol, nadolol, propranolol, timolol |
NA | 47 studies (28 RCT + 19 cohorts) included. No significant association between propranolol (OR=0.94;95%CI [0.62–1.44]) or timolol (OR=1.32; 95%CI [0.44–3.95]) and HCC incidence. Risk of HCC decreased by 26% and 38% with nadolol (OR=0.74; 95%CI[0.64–0.86]; p=0.796) and carvedilol (OR=0.62; 95%CI[0.52–0.74]; p=0.776). | Meta-analysis | 154 |
| Hepato-cellular carcinoma | Carvedilol, propranolol, nadolol, timolol |
NA | 23 studies were included (totaling 2618 patients). β-blockers do not reduce mortality. | Meta-analysis | 196 |
| Lung cancer | Landiolol | Adjuvant chemotherapy (8 patients) | 28 patients included in the landiolol group and 29 in the control group. HR for RFS in the landiolol group was 0.41; 95%CI[0.13–1.34]; p = 0.1294. HR for RFS in the landiolol group without adjuvant chemotherapy was 0.50; 95%CI[0.15–1.62]; p = 0.2363. |
Retrospective | 197 |
| Lung cancer | Selective agents: atenolol, bisoprolol, metoprolol Non selective agents: carvedilol, labetolol, nadolol, propranolol, sotalol |
Radiotherapy (100% patients) Chemotherapy (90% patients) |
722 patients (155 patients received β-blockers). Univariate analysis: better Distant Metastasis Free Survival (p<0.01), DFS (p<0.01), and OS (p=0.01) compared with no β-blockers. Multivariate analysis: better DMFS (HR=0.67; p=0.01), DFS (HR=0.74; p=0.02), and OS (HR=0.78; p=0.02) | Retrospective | 155 |
| Melanoma | β-blockers | NA | 121 patients (30 patients treated with β-blockers). A 36% risk reduction of progression each year in the treated group (95%CI[11%-54%]; p=0.002) | Retrospective | 156 |
| Melanoma | Selective agents: acebutolol, atenolol, betaxolol, bisoprolol, celiprolol, esmolol, metoprolol, nebivolol Non-selective agents: carteolol, carvedilol, labetatol, levobunolol, metipranolol, nadolol, oxprenolol, penbutolol, pindolol, practolol, propranolol, sotalol, timolol |
± pembrolizumab | No prognostic effect of β-blockers on RFS (HR=0.67; 95%CI [0.38–1.19] in the pembrolizumab group and HR=1.15; 95%CI [0.80–1.66] in the placebo group). | Retrospective | 164 |
| Ovary cancer | Atenolol, bisoprolol, metoprolol, oxprenolol, pindolol, propranolol | NA | Extension of at least 8 years post-surgery if use non selective β-blockers | Retrospective | 157 |
| Ovary cancer | Metoprolol | No chemotherapy (9 patients) IV platinum (146 patients) IV-IP platinum (30 patients) |
Metoprolol given before and during cytoreduction for 70 patients vs 115 patients (control group). OS was significantly higher in β-blocker group (44.2 vs 39.3 months; p=0.01). In multivariate analysis, β-blocker was associated with significant improvement in OS (HR 0.68; 95%CI[0.46–0.99]; p=0.046). | Retrospective | 158 |
| Ovary cancer | Acebutolol, atenolol, betaxolol, bisoprolol, metoprolol, nebivolol, penbutolol, propranolol, talinolol, soltalol | carboplatin, gemcitabine | No difference in PFS (7.79 vs 7.62 months; p=0.95) and OS (21.2 vs 17.3 months; p=0.18) between β-blockers group and control group. | Retrospective | 163 |
| Prostate cancer | β-blockers | No hormono- radio- or chemotherapy prior surgery (exclusion criteria) | 11 117 men were included. β-blockers at time of surgery were significantly associated with a lower risk of treatment for cancer recurrence (adjusted HR=0.64; 95% CI[0.42–0.96]; p=0.03) | Prospective | 159 |
| Solid tumors | Atenolol, bisoprolol, carvedilol, labetalol, metoprolol, nebivolol, solatol | Immunotherapy (PD-1, PD-L1, CTLA-4 inhibitors) ± chemotherapy |
11 studies included (=10 156 patients). No association between β-blockers and OS (HR=0.97; 95%CI[0.85–1.11]) or PFS (HR=0.98; 95%CI[0.90–1.06]). Significant better response to immunotherapy in the cohort (OR=0.42; 95%CI[0.19–0.94]; p=0.036) and lung cancer subgroup (OR= 0.25; 95%CI [0.08–0.83]); p=0.024) | Meta-analysis | 162 |
| Solid tumors | Acebutolol, atenolol, bisoprolol, carvedilol, celiprolol, labetolol, metoprolol, nadolol, nebivolol, oxprenolol, pindolol, propranolol, timolol | NA | Reduction in risk of cancer (HR=0.33 95%CI[0.13; 0.83]; p=0.019). In the meta-analysis sub-analysis: lower risk of cancer (MH-OR=0.93 95%CI[0.86; 1.01]; p=0.070). | Observational and meta-analysis | 160 |
| Solid tumors | β-blockers | Chemotherapy and radiotherapy in some studies | 20 cohorts and 4 case controls (76 538 patients). β-blockers were given after the diagnosis of cancer. HR all causes mortality=0.89 (95%CI [0.81–0.98]). HR cancer mortality=0.89 (95%CI [0.79–0.99]). | Meta-analysis | 161 |
| Solid tumors | β-blockers | Immunotherapy (PD-1, PD-L1, CTLA-4 inhibitors) | 13 studies included (=3 331 patients). Concomitant use of NSAIDs, β-blockers and metformin is not associated with improved OS or PFS. | Meta-analysis | 198 |
Abbreviations: CI, confidence interval; DMFS, distant metastasis free survival; HR, hazard ratio; IV, intravenous; IP, intraperitoneal; NSAIDs, non-steroidal anti-inflammatory drugs; OS, overall survival; PFS, progression free-survival; RFS, recurrence free-survival.