Safety and Efficacy of Laser Versus Cryotherapy in the Treatment of Lentigines: A Systematic Review and Meta-analysis of Randomized Controlled Trials : Short title: Safety and Efficacy of Laser Versus Cryotherapy in the Treatment of Lentigines.

BACKGROUND: Lentignies is one of the pigmentary skin lesions causing abnormal skin color in sun-exposed areas in particular the hands and the face. In this systematic review and meta-analysis, we aimed to study the safety and efficacy of cryotherapy versus laser in lentigines treatment. MATERIALS AND METHODS: Beginning from inception and up to 19th May 2023, we did a comprehensive search strategy including five databases (Web of Science=33, Scopus=79, PubMed=28, Virtual Health Library=30 and Scholar=622). The search strategy was performed according to the search term "("solar lentigines" OR "solar lentigo" OR "lentigines" OR "lentigo") AND ("laser") AND ("cryotherapy")". RESULTS: total of 5 studies (n=13-120, mean age 39-60) comparing lasers (Q-switched Nd:YAG, PDL, argon, CO2, etc.) vs cryotherapy for solar lentigines, mostly using intrapatient randomization, were included. Meta-analysis revealed no significant difference in marked (OR=1.15, 95% CI [-0.42, 2.73], P=0.151, I²=0.6%) or moderate improvement (OR=0.63, 95% CI [-0.01, 1.26], P=0.055, I²=0%), but lasers yielded significantly higher ≥50% improvement in patients (OR=1.36, 95% CI [0.5, 2.21], P=0.002, I²=0.3%), lower mild (OR=-0.96, 95% CI [-1.65, -0.26], P=0.007, I²=0%) and poor response in lesions (OR=-1.72, 95% CI [-3.2, -0.24], P=0.023, I²=0%). Side effects were comparable; heterogeneity remained very low (I²≤0.9%). Four studies showed high risk of bias. One trial demonstrated fractional CO2 or cryotherapy plus 4% pidobenzone significantly outperformed monotherapy. CONCLUSION: Laser may be superior to cryotherapy in the treatment of lentigines with comparable side effects among the two groups. However, we recommend further RCTs comparing the two modalities to confirm our findings which had many limitations.