Toxicity and efficacy profile of cardioprotective vs conventional doxorubicin: A meta-analysis

Abstract INTRODUCTION: Anthracycline induced toxicity is a well known consequence of dose related cumulative effects accounting to cardiotoxicity in nearly 26% of patients at doses ≥450 mg/m. Several cardioprotective alternatives like the liposomal formulations and continuous infusion protocols have been introduced to mitigate this affect. This meta-analysis was undertaken to assess the comparative effectiveness and overall safety amongst cardioprotective and conventional therapy groups. METHODOLOGY: We systematically searched PubMed, Cochrane Library, Scopus, and Embase databases through December 2024 following PRISMA guidelines. Randomized controlled trials comparing cardioprotective interventions (liposomal formulations or continuous infusion) with conventional bolus anthracycline therapy in adults ≥18 years of age were included. Primary outcome was cardiotoxicity incidence defined as decline in Left ventricular ejection fraction (LVEF). Secondary outcomes included overall survival (OS) and progression-free survival (PFS) to assess for efficacy. Random-effects meta-analysis was performed using the DerSimonian-Laird method. Risk of bias was assessed using Cochrane RoB 2 tool. RESULTS: Nine studies involving 1,998 participants compared cardioprotective anthracycline strategies (liposomal formulations or continuous infusion protocols) with conventional bolus anthracycline therapy. LVEF decline occurred in 77 of 1,014 participants (7.6%) receiving cardioprotective strategies versus 186 of 984 participants (18.9%) receiving conventional therapy. Cardioprotective strategies significantly reduced cardiotoxicity risk (risk ratio 0.420, 95% CI 0.326-0.540; P < 0.001) with no heterogeneity between studies (I² = 0%, P = 0.642). This represents a 58% relative risk reduction, 11.3% absolute risk reduction, and number needed to treat of 9.1. Secondary outcomes demonstrated preserved antitumor efficacy, with no significant differences in overall survival (hazard ratio 0.94, 95% CI 0.82-1.08; P = 0.39) or progression-free survival (hazard ratio 1.02, 95% CI 0.89-1.17; P = 0.78) between cardioprotective strategies and conventional therapy.Subgroup analysis by intervention type showed consistent benefits for both liposomal formulations (risk ratio 0.418, 95% CI 0.271-0.645; P < 0.001; 4 studies, 1,136 participants) and continuous infusion protocols (risk ratio 0.372, 95% CI 0.250-0.555; P < 0.001; 5 studies, 862 participants), with overlapping confidence intervals indicating no significant difference between the two cardioprotective approaches. Liposomal formulations showed significant reductions in grade 3-4 neutropenia (10.6% vs 17.3%, P = 0.001), alopecia (19.4% vs 92.8%, P < 0.001) and mucositis (3.3% vs 13.4%, P < 0.001). However, liposomal formulations were associated with hand-foot syndrome in 10.7% of patients compared to 0% with continuous infusion (P < 0.001). CONCLUSION: This meta-analysis demonstrates a 53% relative risk reduction in LVEF decline with cardioprotective strategies of drug administration with comparable efficacy. Subgroup analysis highlights that neither of the cardioprotective strategies showed any statistically significant difference in cardioprotective effectiveness.Notably, the liposomal formulation showed other beneficial endpoints like reduced incidence of grade 3 neutropenia, alopecia and mucositis when compared to non-liposomal formulations. Thus, even though acquiring liposomal infusions can be costlier upfront, less frequent intervention for toxicities yield a decreased overall treatment cost. [2] Additionally, with improved outcomes, there is a potential to move from routine to selective cardiac surveillance. In conclusion, while cardioprotective strategies have comparable cardioprotective efficacy, liposomal formulations appear to be superior in the context of their non-cardiac toxicity profile and decreased total costs. This meta-analysis calls for more prospective studies to assess for cost-effectiveness and patient reported outcomes.