Do We Have Enough Evidence to Propose a Preferred Total Neoadjuvant Therapy Sequence for Patients With Locally Advanced Rectal Cancer?

To the Editor I read with great interest the secondary analysis of the CAO/ARO/AIO-12 phase 2 randomized clinical trial reported recently in JAMA Oncology.¹ The study group should be congratulated on the long-term results with additional data on late toxic effects, quality of life, and functional outcomes. However, I am respectfully skeptical about the conclusion that the CAO/ARO/AIO-12 trial already proved chemoradiotherapy (CRT) followed by consolidation chemotherapy as the preferred total neoadjuvant therapy (TNT) sequence for organ preservation. After a median follow-up of 43 months, there are no differences between both TNT schedules. As previously discussed, the higher pathological complete response (pCR) rate for the sequence with consolidation therapy is probably based on the significant difference in the time interval between completion of CRT and surgery. Independent of that discussion, the higher pCR rate did not result in improved survival or lower local recurrence rates. Previous studies have shown that adding oxaliplatin to CRT may result in higher pCR (with the costs of toxicity) but did not increase overall survival.² Therefore, the results of both the initial and the secondary analysis of the CAO/ARO/AIO-12 trial do not convincingly support the need for a TNT regimen with oxaliplatin-based CRT (in addition to induction/consolidation chemotherapy with oxaliplatin). The TNT regimen of the PRODIGE23-trial,³ which had similar inclusion criteria as the CAO/ARO/AIO-12 trial but compared TNT with induction chemotherapy (FOLFIRINOX [leucovorin, fluorouracil, irinotecan, and oxaliplatin]) followed by CRT (capecitabine based) vs standard CRT (and adjuvant chemotherapy for both arms), resulted in a significant benefit in 3-year disease-free survival without compromising local recurrence. For a treatment goal of organ preservation, TNT could be a preferred option for patients with locally advanced rectal cancer and distal location, but final results from randomized trials are still awaited.⁴ As we have learned from definitive CRT in anal cancer, earlier assessment of complete clinical response after CRT could lead to unnecessary surgery.⁵ When aiming for organ preservation in rectal cancer, it may be more important to focus on patient selection and the time interval between completion of CRT and response assessment (to decide whether to proceed to surgery or watch and wait) than on the sequence of TNT.