The Sant Pau Research Institute (IR Sant Pau) and Hospital de Sant Pau have participated in a major international study that evaluated the efficacy and safety of total neoadjuvant therapy (TNT) in patients with locally advanced rectal cancer in a real-world clinical practice setting.
The study, recently published in the journal JAMA Oncology, included 1,585 patients treated outside the context of clinical trials between September 2012 and December 2023. It involved 61 hospitals across 21 countries, reflecting both its global reach and the strength of its findings. Results were also presented at the latest Congress on Gastrointestinal Tumors of the European Society for Medical Oncology (ESMO GI), held in Barcelona from July 2 to 5, 2025. They confirm that TNT provides solid clinical benefits even in real-world healthcare conditions, beyond the standardized protocols of clinical trials.
Total neoadjuvant therapy consists of delivering radiotherapy and non-radiosensitizing chemotherapy before surgery, with the goal of reducing tumor size, improving local disease control, and, in some cases, avoiding surgical intervention. In patients who achieve a complete response to treatment, whether clinical or pathological, a strategy called watch and wait may be applied, involving close monitoring of the patient without immediate surgery. This approach, increasingly adopted by specialized centers managing this condition, aims to preserve rectal function and avoid the sequelae of major surgery, provided there are sufficient guarantees of proper oncologic control.
In this study, 79.5% of patients presented with at least one high-risk feature—such as extensive nodal involvement, extramural venous invasion, or threatened mesorectal fascia—and were treated with different TNT regimens, reflecting the diversity of real-world clinical practice.
Patients received one of the following treatment types: the PRODIGE 23 regimen (intensive chemotherapy with FOLFIRINOX or FOLFOXIRI followed by long-course radiotherapy, 17.7%), the RAPIDO regimen (short-course radiotherapy followed by consolidation chemotherapy with FOLFOX or CAPOX, 33.4%), an induction OPRA regimen (initial chemotherapy followed by long-course radiotherapy, 12%), a consolidation OPRA regimen (long-course radiotherapy followed by chemotherapy, 16.2%) or other regimens (22.7%).
Clinical outcomes were consistent with those observed in controlled studies. 23.2% of patients achieved a complete response to treatment. Among them, 192 patients (12.1%) were managed with the watch-and-wait approach, and 30 patients (1.9%) underwent local excision. At three years, event-free survival was 68%, and overall survival at five years was 79%, validating the effectiveness of TNT in routine clinical settings. Regarding disease progression, 8.5% of cases showed local progression and 16.4% distant progression.
In the overall analysis, patients treated with the PRODIGE 23 regimen achieved better local control and survival outcomes than those treated with RAPIDO, OPRA-induction, or OPRA-consolidation regimens, although they also experienced a higher incidence of serious adverse events. However, after applying an adjustment analysis using propensity score matching to balance clinical characteristics across groups, no significant differences in survival outcomes were observed between the various TNT regimens. This reinforces the idea that all of them may be valid options in routine clinical practice.
Dr. David Páez, medical oncologist at Hospital de Sant Pau and co-investigator in the study, highlighted the importance of these findings.
“This study confirms that total neoadjuvant therapy is also effective outside the controlled environment of clinical trials, reinforcing its role as a standard treatment in patients with locally advanced rectal cancer. It is especially valuable to see that different regimens can offer similar outcomes, which provides flexibility to tailor treatment to each clinical case.”
Sant Pau’s participation in this study comes at a time of strategic advancement in the management of rectal cancer at the hospital. A functional rectal cancer unit has recently been established, a multidisciplinary team comprising professionals from Medical Oncology, General Surgery, Radiation Oncology, Radiology, Gastroenterology, Pathology, and other involved specialties.
This unit aims to improve coordination among departments, apply uniform treatment criteria, and promote applied clinical research. In Dr. Páez’s words, “The creation of this functional unit allows us to work more integratively and efficiently and facilitates participation in international projects like this one, which generate evidence with a real impact on patient care.”
Through the combination of specialized care, teamwork, and active participation in international studies, IR Sant Pau and Hospital de Sant Pau reaffirm their commitment to continuous improvement in colorectal cancer treatment and to clinical research in service of healthcare practice.
Audisio A, Gallio C, Velenik V, Meillat H, Ruiz-Garcia E, Riesco MC, Alecha JS, Rasschaert G, Carvalho C, Randrian V, Kirac I, Hernando J, Artaç M, O’Connor JM, Waldhorn I, Braam PM, Shamseddine A, Moretto R, De la Pinta C, De Felice F, Dulskas A, Páez López-Bravo D, Vanden Bulcke A, Bock F, Deleporte A, Van Den Eynde M, Geboes KP, Loi M, Messina M, Houlzé-Laroye C, Puccini A, Pastorino A, Papamichael D, Fiore M, Sur D, Eid M, Antoun C, Salati M, Garajovà I, Jakubauskas M, Tomášek J, Sousa Pinto CM, Schwingel J, Morano F, Adams RA, Dermine A, Chau A, Javed MA, Ghidini M, Fiorica F, Montenegro P, Petrillo A, Spolverato G, Mulet Margalef N, Diaz M, Baratelli C, Puleo F, Karampeazis A, Sert F, Gilliaux Q, De Stefano A, Liberale G, Moretti L, Martinive P, Deltuvaite Thomas V, Staggs V, Saad ED, Van Laethem J-L, Sclafani F, International Real-World TNT Study Consortium. Total neoadjuvant therapy for locally advanced rectal cancer. JAMA Oncol 2025. https://doi.org/10.1001/jamaoncol.2025.2026
