Treatment protocols for locally advanced esophageal cancer include the FLOT treatment and the CROSS trimodality regimen. This propensity-matched study compared outcomes including tolerance, toxicity, impact on sarcopenia and pulmonary physiology, surgical complications, and oncologic metrics where data from randomized controlled trials (RCTs) were unavailable. A total of 222 participants from 2 high-volume facilities (111 in each arm) were enrolled. Sarcopenia was assessed by computed tomography, and pre- and post-treatment differences in pulmonary function (forced expiratory volume in the first second, forced vital capacity, and carbon monoxide diffusion capacity) were analyzed. For this study, researchers used the criteria established by the Esophageal Complications Consensus Group (ECCG) and the scale of severity established by the Clavien-Dindo criteria to characterize surgical complications. Kaplan-Meier analysis was used to estimate survival after determining the grade of tumor regression and R status. Males made up 83% of the sample, and the cT3/cN+ percentages for FLOT were 92%/68% and for CROSS, 86%/60%. Comparatively, only 40% of FLOT patients and 92% of CROSS patients were able to complete their whole regimen. From 16% to 33% of FLOT patients and 14% to 30% of CROSS patients developed sarcopenia (P<0.01 across groups). When comparing the 2 groups, a significant difference was found between the FLOT and CROSS groups, with a median decrease in carbon monoxide diffusion capacity of -8.25% (-34 to 25) and -13.8% (-38 to 29), respectively (P=0.01). About 27% of FLOT patients and 44% of CROSS patients showed a major pathologic response (P=0.03). Respiratory failure was raised by CROSS at 13% versus 3% (P<0.001). In-hospital mortality was 1% versus 2% (P=0.9), and Clavien Dindo >III was 22% versus 27% (P=0.59). Both 63% (FLOT) and 60% (CROSS) (P=0.42) had comparable three-year survival rates. The rates of survival were similar for CROSS and FLOT. The CROSS regimen was associated with a higher risk of postoperative respiratory failure and atrial fibrillation, although producing equivalent operational outcomes. Even though toxicity rates were manageable, only about half of the patients were given the full FLOT regimen. These results lend credence to the concept of clinical equivalence; nonetheless, extreme caution may be warranted when administering CROSS to individuals with a high respiratory risk.