STRASS 2 target trial emulation: Bridging the gap between trial efficacy and real-world effectiveness

The Surgery With or Without Neoadjuvant Chemotherapy in High Risk RetroPeritoneal Sarcoma (STRASS 2) trial is evaluating the impact of neoadjuvant chemotherapy versus surgery in patients with high-risk, resectable retroperitoneal sarcoma. To evaluate the real-world effectiveness of this approach, we performed a target trial emulation using the STRASS 2 trial as the foundation.

Using the national cancer database (2010-2022), we identified patients with dedifferentiated liposarcoma and leiomyosarcoma within the STRASS 2 trial eligibility criteria who underwent definitive surgery. We compared those undergoing neoadjuvant chemotherapy followed by surgery to upfront surgery. Multivariable-adjusted and inverse probability of treatment-weighted Cox proportional hazards regression models were used to estimate the impact on overall survival.

Among 2,215 eligible patients, 209 (9.4%) received neoadjuvant chemotherapy followed by surgery, and 2,006 (90.6%) underwent upfront surgery. Neoadjuvant chemotherapy patients were younger, more often privately insured, and more likely treated at academic centers. Compared with upfront surgery, neoadjuvant chemotherapy approach did not improve overall survival in routine multivariable Cox regression (hazard ratio 0.73, 95% confidence interval 0.48-1.10), regression with inverse probability of treatment-weighting (0.74, 0.49-1.11), or target trial emulation analyses (0.75, 0.50-1.12). Neoadjuvant chemotherapy was also not associated with improved R0/R1 resection rates (odds ratio 1.96, 95% confidence interval 0.82-4.74).

The neoadjuvant chemotherapy approach did not confer overall survival advantage in patients with resectable retroperitoneal sarcoma. Target trial emulation offers a valuable framework for generating real-world evidence to complement ongoing randomized trials, particularly in rare and heterogeneous cancers.