Neoadjuvant therapies ready to cure?

Neoadjuvant therapy has become a cornerstone in the treatment of rectal cancer. Its primary objectives include tumor size reduction, improved surgical outcomes, decreased local and distant recurrence rates, and organ preservation through a watch-and-wait strategy in patients with a clinical complete response. Recently, total neoadjuvant therapy approaches have become the new curative-intent standard therapy for high-risk rectal cancer and in patients with intention for organ preservation [1‐3]. Groundbreaking efficacy with dostarlimab immunotherapy for patients with high microsatellite instability (MSI-h) rectal cancer was shown in an interim analysis from an ongoing study led by Andrea Cercek [4, 5]. It seems that this therapy has the potential to cure MSI‑h rectal cancer using immunotherapy alone without the need for radiotherapy, chemotherapy, or a quality-of-life-limiting surgery. However, long-term outcome and overall survival data are awaited. By contrast, neoadjuvant therapy remains less established in colon cancer and is still under investigation. Currently, upfront surgery is the standard of care, with adjuvant chemotherapy recommended for patients with stage III and high-risk stage II colon cancer [6]. The optimal duration of adjuvant treatment (3 vs. 6 months) is guided by risk stratification, as demonstrated by the IDEA collaboration [7]. At ASCO 2025, the ATOMIC trial was reported to demonstrate a practice-changing adjuvant therapy standard in stage III MSI‑h colon cancer with the addition of atezolizumab immunotherapy to FOLFOX for 6 months, followed by atezolizumab monotherapy for a further 6 months [8]. In stage II colon cancer, circulating tumor DNA (ctDNA) is a biomarker of significant research interest, with a number of randomized controlled trials comparing a ctDNA-informed approach to adjuvant decision-making in stage II colon cancer against standard of care [9, 10]. However, there are several reasons to consider neoadjuvant treatment in patients with high-risk colon cancer. Resections with an R1 status are associated with an increased risk of local and distant recurrence [11]. Additionally, 3‑year disease-free survival (DFS) rates remain suboptimal, particularly for T4 and/or node-positive tumors [12]. This has led to growing interest in neoadjuvant therapy to reduce surgical complexity and the risk of systemic relapse in localized colon cancer. Microsatellite status serves as a key biomarker for treatment selection. While patients with MSI‑h tumors generally exhibit favorable prognoses, they tend to respond poorly to adjuvant 5‑flourouracil chemotherapy. Approximately 15% of locally advanced colorectal cancers harbor DNA mismatch repair deficiency (dMMR), leading to MSI‑h status and a high tumor mutational burden (TMB). These tumors frequently demonstrate high sensitivity to immune-checkpoint inhibitors (ICIs) in the metastatic setting, leading to impressive long-term survival [13, 14].

Unlike MSI‑h tumors, MSS colorectal cancers generally exhibit low immunogenicity and are not responsive to ICIs. Based on the observed benefit—not just in rectal cancer but also in other gastrointestinal cancers—three randomized phase 2 studies investigated the role of neoadjuvant chemotherapy in patients with high-risk locally advanced colon cancer [21‐24].

The French multicenter PRODIGE-22 study [21] evaluated 120 patients with high-risk stage II or III colon cancer (cT3, T4, and/or N2), randomizing them to receive either 6 months of adjuvant postoperative FOLFOX or perioperative FOLFOX, consisting of four cycles preoperatively and eight cycles postoperatively. The primary endpoint was pathological response. Compliance in the perioperative group was notably high, with > 95% of patients completing all pre- and postoperative cycles, compared to 73% in the adjuvant group. Tumor regression—defined as tumor response grade 1–2—was significantly more frequent in the perioperative group (44% vs. 8%). No significant differences were observed in R0 resection rates (94% vs. 98%), and overall mortality and morbidity rates were similar between groups. The 3‑year OS and DFS did not differ significantly between the perioperative and adjuvant cohorts [22].

In the FOxTROT trial, 1053 patients were randomized to a similar FOLFOX regimen, although only three of the 12 cycles were given preoperatively in the perioperative treatment arm [23]. The primary endpoint was residual disease or recurrence within 2 years. The R0 resection rate was higher in the experimental group (94% vs. 89%), and residual or recurrent disease at 2 years was significantly lower (16.9% vs. 21.5%). Additionally, tumor regression was more frequently observed in pMMR cancers compared to dMMR tumors (23% vs. 7%).

In the NeoCol trial, 248 patients were randomized to upfront surgery or neoadjuvant chemotherapy, receiving either three cycles of CAPOX or four cycles of FOLFOX [24]. Adjuvant therapy was not given as standard but was based on the final pathological staging. The primary endpoint was DFS. No significant differences were noted in 2‑year DFS or OS. Each of the three trials included an additional arm investigating anti-epidermal growth factor receptor (EGFR) antibodies in patients with RAS wild-type cancers. However, in contrast to their established benefit in the metastatic setting, no advantage was observed in the neoadjuvant setting.

The role of neoadjuvant therapy in localized colon cancer remains uncertain. Key concerns include the limitations of current clinical staging, particularly nodal staging accuracy, as well as the potential overtreatment of patients with low-risk disease. As ongoing research refines patient stratification, neoadjuvant approaches may be considered in high-risk locally advanced colon cancer, and microsatellite status should be used for treatment selection. In rectal cancer, neoadjuvant therapy is standard of care and has the potential to cure patients without the need for surgery; in particular, neoadjuvant immunotherapy has revolutionized the treatment landscape for high microsatellite instability (MSI-h) rectal cancer. Ongoing trials provide further insights, with precision oncology continuing to refine neoadjuvant strategies and optimizing personalized treatment approaches for localized microsatellite stable and MSI‑h colorectal cancer.