Combined Bisoprolol and Megestrol Acetate Improves Survival and Preserves Cardiac Performance in a Rat Model of Cancer Cachexia.

BACKGROUND

Cancer cachexia is associated with rapid body wasting and cardiac dysfunction. Bisoprolol (BIS) and megestrol acetate (MA) improve selected cachexia phenotypes in the Yoshida AH-130 model, but their combined effects are not defined. We tested reduced-dose combined treatment of BIS and MA (COMB) on survival and organ-specific outcomes.

METHODS

Male Wistar Han rats (approx. 200 g) received intraperitoneal Yoshida AH-130 hepatoma cells and were treated with placebo (PL, n = 49), BIS (5 mg/kg/day, n = 23), MA (100 mg/kg/day, n = 10) or COMB (BIS 3.75 mg/kg/day + MA 75 mg/kg/day, n = 16). Outcomes included survival, echocardiography (baseline and Day 11), body composition (EchoMRI), terminal tissue weights, food intake and spontaneous locomotor activity.

RESULTS

COMB reduced mortality versus placebo (HR = 0.21, p < 0.0001) and had the lowest HR among treatment groups. BIS also reduced mortality versus PL (HR = 0.32, p = 0.0007), whereas MA did not reach statistical significance (HR = 0.49, p = 0.082). COMB did not differ significantly from BIS (HR for COMB vs. BIS = 0.48, p = 0.28) or MA (HR for COMB vs. MA = 0.23, p = 0.06). On Day 11, COMB showed higher LVEF than PL (64.1% ± 9.7% vs. 50.5% ± 12.8%, p < 0.01), higher LV stroke volume (186 ± 49 μL vs. 112 ± 55 μL, p < 0.001) and higher LV mass (515 ± 95 mg vs. 429 ± 65 mg, p < 0.01); changes from baseline were smaller in COMB than PL for LVEF (Δ -12.0% ± 8.9% vs. -24.3% ± 16.2%, p < 0.05) and LV mass (Δ -57 ± 93 mg vs. -137 ± 79 mg, p < 0.05). Body weight, fat mass and lean mass decreased in all groups; COMB showed smaller reductions than PL (p < 0.05) but did not differ from BIS or MA (p > 0.05). BAT weight was higher in COMB than PL (p < 0.001) and higher than BIS (p < 0.001). Food intake on Day 11 was higher than PL in all active groups, and locomotor activity was higher than PL in MA and COMB.

CONCLUSIONS

COMB reduced mortality versus placebo and showed the lowest HR among treatment groups, accompanied by preserved cardiac performance and a distinct BAT response. Differences versus monotherapy were not statistically significant. Future studies should test optimized dosing and include exposure assessment and tissue profiling to determine benefit over monotherapy and to clarify the basis of the cardiac and BAT phenotypes.