Improvements in chemoradiotherapy have led to a significantly improved local control. However, this did not translate into improved disease-specific survival (DSS) or overall survival (OS) with distant metastases being substantially more common than local recurrence. Consequently, efforts have been undertaken to improve systemic therapy. Adjuvant chemotherapy after neoadjuvant (chemo)radiotherapy has been extensively studied but results are controversial. There is decent evidence favoring the use of adjuvant chemotherapy. In a Cochrane meta-analysis, Petersen and colleagues found a significant improvement in both disease-free survival (DFS) and OS following adjuvant chemotherapy [4
]. Additionally, the CAO/ARO/AIO-04 trial and the ADORE trial, two randomized controlled trials, showed that the addition of oxaliplatin to a 5-fluorouracil (5-FU) based chemotherapy leads to a further improved DFS [5
]. For patients with ypN2 status and minimally regressed tumors, oxaliplatin even improved OS. Therefore, adjuvant chemotherapy is currently recommended by several guidelines, at least for high-risk tumors [7
]. However, there are also studies that show no improvement in DFS or OS following adjuvant chemotherapy [9
]. Poor compliance with or delayed start of adjuvant therapy due to postoperative complications and suboptimal chemotherapy regimens may explain these unsatisfactory results [13
]. As a consequence, clinical trials have assessed the role of pre- rather than postoperative chemotherapy, commonly referred to as total neoadjuvant therapy (TNT) [14
]. Several advantages have been attributed to TNT, including early systemic treatment to address micrometastases, improved response rates, enhanced R0 resection rates, decreased toxicity, earlier reversal of diverting ileostomy, and the possibility to better select patients for a potential watch-and-wait strategy [6
]. TNT usually consists of an oxaliplatin-containing polychemotherapy, such as FOLFOX (folinic acid, fluorouracil, oxaliplatin), CAPOX (capecitabine, oxaliplatin), or FLOX (fluorouracil, oxaliplatin). While there is no level‑I evidence regarding the comparison of TNT with neoadjuvant chemoradiotherapy and adjuvant chemotherapy, there is an increasing body of level-II evidence that suggests that TNT is a viable alternative. For instance, in a recently published retrospective cohort analysis from the Memorial Sloan Kettering Cancer Center, Cercek and colleagues analyzed 320 patients who received neoadjuvant chemoradiotherapy with planned adjuvant chemotherapy and 308 patients who received oxaliplatin-based TNT [16
]. Importantly, more patients in the TNT cohort completed the planned chemotherapy and the complete response (CR) rates (both pathologic CR [pCR] and clinical CR [cCR] for at least 12 months) were higher in this group (36% vs.
21%). Additionally, significantly more patients after TNT received minimally invasive surgery and ileostomy closure was more likely to be performed within 15 weeks postsurgery in the TNT cohort. However, due to the relatively short follow-up, no data on DFS or OS are shown. There is also no data on treatment-related toxicity. Furthermore, a recent meta-analysis by Petrelli and colleagues has evaluated 28 studies with 2688 patients treated with TNT and 891 patients treated with standard neoadjuvant chemoradiotherapy [17
]. Although most of the included studies were prospective cohort studies, the authors showed a significant increase in pCR rates and a significantly better OS. Importantly, this meta-analysis did not address the value of adjuvant chemotherapy. Since optimal scheduling of chemotherapy and chemoradiotherapy in TNT is not clear, the German Rectal Cancer Study Group conducted a multicenter, randomized, phase 2 study in which 306 patients were assigned to induction chemotherapy either before or after neoadjuvant chemoradiotherapy. Interestingly, chemoradiotherapy-related toxicity, compliance with chemoradiotherapy, and pCR rates were significantly better when chemotherapy was given after chemoradiotherapy [18
]. Therefore, this TNT sequence is currently being tested in an organ preservation phase II trial (CAO/ARO/AIO-16; NCT05361142) and has been selected for additional phase III comparison with standard neoadjuvant chemoradiotherapy (CAO/ARO/AIO-18).