Treating without guidelines: management and outcomes of lung cancer diagnosed during pregnancy - a systematic review.

Background: Lung cancer during pregnancy is exceedingly rare and poses unique diagnostic and therapeutic challenges. Clinical decisions must balance urgent, potentially lifesaving maternal treatment with fetal safety, often in the absence of evidence-based guidelines. This systematic review aimed to characterize clinical features, treatment patterns, and maternal-fetal outcomes among reported cases of primary lung cancer diagnosed during pregnancy, focusing on case reports and case series. Methods: We systematically searched PubMed, Embase, Scopus, and Google Scholar from 1948 through March 2024 for articles reporting primary lung cancer diagnosed during pregnancy. Eligible studies included case reports, case series, or observational reports providing individual-level data. We extracted demographics, tumor characteristics, staging, molecular profile, treatment type and timing (during pregnancy and postpartum), and maternal-fetal outcomes. Descriptive statistics were performed, and exploratory analyses were conducted to assess associations between selected variables and outcomes. Results: A total of 4,411 records were identified, and 88 publications contributing 96 unique cases met the inclusion criteria. The mean maternal age at diagnosis was 32.9 ± 5.0 years (range 18-42). Most patients (65%) presented with stage III-IV disease at diagnosis. Tobacco use was reported in 33% of cases and was significantly associated with advanced stage at presentation (p = 0.0006). Among tumors with reported molecular testing, 58.9% harbored actionable driver alterations, most commonly ALK rearrangements (32.9%) and EGFR mutations (21.4%). Chemotherapy during pregnancy was administered in 22.8% of cases, most commonly platinum-based doublets, with a mean gestational age at initiation of 21.8 weeks (SD ± 10.4). Targeted therapies, including EGFR and ALK tyrosine kinase inhibitors, were typically initiated in the postpartum period in 30 patients (31.6% of the overall cohort). Among reported pregnancies, 69 (71.9%) resulted in live births. Term delivery occurred in 46.9% of cases, while preterm delivery occurred in 25.0%. Pregnancy termination was reported in 17.7% of cases and fetal demise in 1.0%. Advanced maternal disease stage was significantly associated with adverse fetal outcomes, including preterm delivery, pregnancy termination, or fetal demise (p < 0.0001). Conclusion: Lung cancer during pregnancy most often presents at advanced stages, with a high prevalence of actionable molecular alterations. Multidisciplinary management and routine molecular profiling are essential. In the limited case-based literature, chemotherapy administered during the second and third trimesters has not demonstrated a clear signal of major congenital toxicity; however, these findings should be interpreted with caution, given the small sample size, heterogeneity of reporting, and lack of long-term follow-up. Targeted therapies are generally deferred until the postpartum period. Early diagnosis, optimized imaging protocols, and coordinated maternal-fetal care are critical. International registries and consensus guidelines are urgently needed to guide treatment decisions and improve maternal and fetal outcomes in this rare clinical scenario.