The primary goal of intensified preoperative RTX, RCTX, and CTX is to achieve the earliest and most effective medical intervention against micrometastases, thereby reducing the long-term risk of systemic tumor metastases [19]. These protocols, known as total neoadjuvant therapy (TNT), aim to clinically downstage the primary tumor to preserve the organ whenever possible [20].

Total neoadjuvant therapy is defined as the extension of preoperative RTX or RCTX with additional systemic chemotherapy given before surgery. This approach is especially indicated in high-risk scenarios, such as locally advanced tumors, and appears to potentially lower the rate of distant metastases, improve survival, and increase the rate of complete histopathological remission.

The Rectal Cancer and Preoperative Induction Therapy followed by Dedicated Operation (RAPIDO) trial was a randomized, international, multicenter trial involving patients with locally advanced rectal cancer (mrT4, cN2, EMVI, or CRM positivity) [21]. The trial found a significant 7% reduction in distant metastasis after 3 years in the experimental group (20.0% vs. 26.8%, hazard ratio [HR] 0.69; 95% confidence interval [CI]: 0.54–0.90; p = 0.005). Disease-related treatment failure—including local recurrence, distant metastasis, or death—was also significantly lower (23.7% vs. 30.7%, p = 0.019); however, the overall survival rates showed no difference. The pathologic complete response rate was 28% in the experimental arm compared to 14% in the control arm (p < 0.0001). Grade III or higher toxicity during preoperative therapy was 48% compared to 25%, with an additional 34% during adjuvant therapy. Interestingly and critically, more locoregional recurrences (10% versus 6%) were observed in long-term follow-up.

The French PRODIGE 23 study involved 461 patients with locally advanced rectal adenocarcinoma located up to 15 cm from the anus, staged cT3 (with a high risk of recurrence) or cT4 M0 [22, 23]. The 5‑ and 7‑year disease-free survival rates were significantly better in patients who received intensified neoadjuvant CTX (73.1% vs. 65.5%; 67.6% vs. 62.5%). Metastases occurred less often (20.7% vs. 27.7%). The 5‑ and 7‑year overall survival rates were higher in the neoadjuvant CTX group (86.9% vs. 79.9% and 81.9% vs. 76.1%, respectively). However, it is important to note that FOLFIRINOX has significant toxicity, and not all patients can tolerate this treatment.

The American Organ Preservation for Rectal Adenocarcinoma (OPRA) trial examined the importance of the sequence of neoadjuvant therapy components for distal rectal carcinomas in UICC stages II/III [24, 25]. Induction CTX followed by RCTX was tested against consolidation CTX after RCTX. Surgical tumor removal was only performed if incomplete clinical response (iCR) was identified during restaging. In cases of achieved cCR or nearly complete clinical response (ncCR), the study protocol used a watch-and-wait (W&W) approach. cCR or ncCR was achieved in 72% of patients in the induction group and in 76% in the consolidation group, sparing the patients primary surgery.

No significant difference was found between the two groups in terms of disease-free survival, overall survival, local-recurrence-free survival, or distant metastasis-free survival [24]; 40% of patients in the induction group and 27% in the consolidation group experienced local tumor recurrence and required secondary surgical treatment. The 3‑year organ-preserving survival rate, defined as TME-free survival, was 53% in the consolidation group and 41% in the induction group. After 5 years of follow-up, the results remained mostly the same in both groups [26, 27]. An important conclusion from this study is that consolidation CTX after RCTX should be preferred when preservation of the rectum is the main goal.

Response evaluation after neoadjuvant therapy should apply a T2-weighted MRI protocol. The important MRI features that indicate residual tumor include an intermediate signal in the T2 sequence, diffusion restriction, persistent enlarged lymph nodes, and an abnormal lymph node shape [28].

A pooled analysis of the OPRA and CAO/ARO/AIO-12 studies was conducted by Williams et al. to examine whether W&W after TNT is inferior to radical tumor resection with TME in patients with a very good clinical response [29]. Patients in the CAO/ARO/AIO-12 trial more frequently had cT3/4 and N+ tumors, while those in the OPRA study more often had tumors in the distal third of the rectum. Compliance with TNT and grade 3 toxicity levels did not differ between the two studies, although the OPRA study administered more cycles of CTX and a higher radiation dose. No differences were observed in 3‑year disease-free survival or overall survival. It can be concluded that the W&W approach is a safe treatment option. Still, the OPRA trial used more aggressive TNT therapy than CAO/ARO/AIO-12, which may have compensated for the potential disadvantages of non-operative treatment management. Based on the findings from the RAPIDO, PRODIGE 23, OPRA, and CAO/ARO/AIO-12 trials, as well as the guidelines of the National Comprehensive Cancer Network (NCCN), the American Society of Clinical Oncology (ASCO), and the German Cancer Society (DKG), TNT should be considered the preferred new treatment option for patients with locally advanced rectal cancer.

The oncological benefits of TNT have been supported by high-quality, randomized controlled trials (RCTs) and meta-analyses. These studies demonstrated an improved histopathological response and superior disease-free survival rates [30,31,32]. However, long-term analyses have also highlighted adverse effects of TNT, particularly concerning local tumor control and the quality of TME [33]. The meta-analysis conducted by Lin et al. aimed to compare TNT with long-course RCTX in terms of surgical complications and histopathological outcomes [34]. It included 11 RCTs with 3185 patients between 2012 and 2022. Regarding major complications and mortality, no significant differences were found between TNT and RTX or RCTX. However, TNT was associated with a higher rate of incomplete TME specimens. The rates of R0 resection, positive CRMs, and sphincter preservation did not differ significantly.

The impact of TNT on oncological outcomes was examined in a meta-analysis by Wu et al. [35]. They identified oncological benefits for TNT without adverse effects on perioperative outcomes. The analysis included 11 RCTs published between 2012 and 2022 with 3165 patients. The pathological complete response rate after TNT was significantly higher (22.5% vs. 13.3%). T0 downstaging was achieved in 23.6% of cases following TNT compared to 14.9% after standard neoadjuvant RCTX. No differences were observed in terms of R0 resection rates, sphincter preservation, anastomotic leakage, or severe adverse events. Additionally, the 3‑year disease-free and overall survival rates significantly improved following TNT.

The goal of the meta-analysis by Tan et al. was to compare the oncologic outcomes of a W&W strategy versus a surgical approach (TME or local excision [LE]) for treating rectal cancer in complete remission [36]. As to the rates of overall survival, 5‑year disease-free survival, distant metastasis, mortality, and organ preservation, no significant differences were found between the W&W strategy and surgical treatments (TME and LE).

The organ-preservation strategy of W&W is an appealing alternative to oncologic tumor resection with TME in patients with locally advanced rectal cancer who achieve cCR after neoadjuvant therapy (Fig. 4a, b). Of these patients, 25%–30% will experience local regrowth, and most of these patients can undergo salvage surgery without negatively affecting local tumor control [37,38,39]. However, an analysis of two international W&W databases showed that patients with local regrowth who underwent salvage surgery had a significantly higher rate of distant metastases compared to those with ncCR who underwent oncologic tumor resection [40].

We believe that W&W strategies must be discussed in detail and with some caution due to the potential of local regrowth in about 30%, the strict need of surveillance for 5 years, and the high requirements in patient compliance. To avoid endangering patients, it must be borne in mind that the oncological outcome in W&W situations is highly dependent on the center’s experience and knowledge of salvage surgery.