Total neoadjuvant therapy in rectal cancer: The FOREST protocol, a patient-centered approach that clusters two cohorts with different outcomes.

Rectal cancer treatment has evolved toward individualized strategies that emphasize organ preservation and tailored therapeutic approaches. The FOREST protocol combines total neoadjuvant therapy (TNT), early response evaluation, and prehabilitation within a comprehensive framework designed to optimize outcomes while minimizing overtreatment. In this single-center prospective study, 67 patients with rectal cancer (T1-T4, any N) were enrolled between April 2020 and December 2022. Treatment decisions-radical surgery (RS), watch and wait (WW), or local surgery (LS)-were guided by early and final response assessments. Outcomes were analyzed under an intention-to-treat (ITT) approach, with a median follow-up of 968 days (range: 440-2015). Final treatments included RS in 47.8% (n = 32), WW in 50.7% (n = 34), and LS in 1.5% (n = 1). Completion of TNT was achieved in 79.1% of patients. Organ preservation was accomplished in 44.8% (30/67 = 44.8%, with 34 WW and 1 LS). Systemic recurrence occurred in 22.4% of patients, surpassing the rate of local regrowth or persistence (17.9%). DFS in the WW group (65.7%) was comparable to that of the RS group (71.4%), while OS significantly favored WW (100% vs. 80.7%, p = .014). The FOREST protocol demonstrates that integrating TNT with response-guided strategies is feasible and can lead to high organ preservation rates and favorable oncologic outcomes. A key strength of the protocol is its ability to identify two distinct patient cohorts based on response evaluation.