Impacts of neoadjuvant therapy on subsequent surgical difficulty, safety, and outcomes in locally advanced rectal cancer: a narrative review

Introduction

Colorectal cancer is one of the most prevalent malignancies, ranking third in incidence and second in mortality among all malignancies globally (1). Rectal cancer accounts for approximately 30% of all colorectal cancer cases, and this proportion has gradually increased over recent decades (2). Moreover, despite existing screening tools, such as the fecal occult blood test, fecal DNA methylation test, and colonoscopy, half of rectal cancer patients are diagnosed at a locally advanced stage and have a suboptimal prognosis (3). Most of those patients, pathologically characterized as pMMR/MSS (proficient mismatch repair/microsatellite stable), are usually managed with multimodal therapy, including radiotherapy, systemic therapy, and surgery, to reduce locoregional and metastatic recurrence while preserving quality of life (QoL) (4). Notably, over the past two decades, the treatment paradigm has shifted from primary surgery to neoadjuvant radiotherapy combined with systemic therapy followed by total mesorectal excision (TME) (5-7). Evidence indicated that neoadjuvant therapy, particularly total neoadjuvant therapy (TNT), can induce tumor downstaging, enhance locoregional control, yielding local recurrence rates of approximately 5–9% (8), and may improve long-term overall survival (9). Meanwhile, neoadjuvant therapy yields potential benefits in achieving organ preservation, especially for low rectal cancer (7,10,11). The evolution of treatment patterns and surgical approaches for locally advanced rectal cancer (LARC) with pMMR/MSS phenotype is illustrated in Figure 1.

Figure 1 Schematic diagram illustrating the evolution of treatment modalities and surgical approaches for locally advanced rectal cancer with pMMR/MSS phenotype. CRT, chemoradiotherapy; IO, immunotherapy; MSS, microsatellite stable; NAT, neoadjuvant therapy; pMMR, proficient mismatch repair; RT, radiotherapy; sc-RT, short-course radiotherapy; TME, total mesorectal excision; TNT, total neoadjuvant therapy.

Nevertheless, it has been reported that 10% of patients with LARC underwent upfront surgery (UFS) in real-world clinical practice in the United States (12), and this proportion even reaches 36.9% in some regions (13). Meanwhile, a study conducted in China found that only 39.55% of patients with clinical T4 stage rectal cancer adhered to guidelines (14). This considerable discrepancy between real-world practice and clinical guidelines may undermine the optimal oncological outcomes (15,16). Multiple factors, including patient-related factors, clinician-related factors, healthcare resource availability, and socioeconomic conditions, have been recognized as contributors to this phenomenon. Among these determinants, the treating hospital has been identified as one of the significant factors (15). A survey further revealed that only 40.50% and 43.37% of clinical specialists directly engaged in the diagnosis and treatment of colorectal cancer patients in Hainan Province, China, explicitly acknowledged that TNT does not increase surgical difficulty or compromise perioperative tolerance, respectively (17). Another German real-world study demonstrated that only 20% of eligible patients received TNT despite meeting the guideline criteria, identifying advanced age, comorbidities, and patient refusal as the primary barriers to its adoption (18). These findings highlight an urgent need to mitigate these barriers, such as by establishing designated rectal cancer treatment centers or referral-based networks to ensure that rectal cancer patients receive care from board-certified colorectal specialists well-versed in the latest literature on TNT and watch-and-wait protocols (19).

Hence, by reviewing relevant references, this review explored whether neoadjuvant therapy exerted negative effects on surgical procedures from four aspects: operative difficulty, surgical procedure outcomes, postoperative complications, and surgery-related oncological outcomes, thereby aiming to guide standardization of clinical practice and the improvement of guideline adherence. We present this article in accordance with the Narrative Review reporting checklist (available at https://jgo.amegroups.com/article/view/10.21037/jgo-2026-0328/rc).

Methods

Literature searches were performed in PubMed and Web of Science using the following search terms: locally advanced rectal cancer, neoadjuvant therapy, radiotherapy, chemotherapy, immunotherapy, surgery, operative difficulty, surgical procedure outcomes, postoperative complications, and surgery-related oncological outcomes (Table 1), and similar terms. Eligible literature included original research such as clinical trials, real-world studies, and review articles including meta-analyses, systematic reviews, and other review articles published in English between January 2000 and February 2026.

Meanwhile, this review categorized the effects of neoadjuvant therapy on surgery into four aspects. The specific indicators for each aspect are presented in Table 2.

Effects of neoadjuvant chemoradiotherapy (NACRT) versus UFS on surgical procedures and outcomes

Early landmark randomized trials, including CAO/ARO/AIO-94 (20), the Korean trial (21), and NSABP R-03 (22), compared NACRT with UFS in LARC. Collectively, these studies demonstrated that NACRT achieved comparable complete resection rates, overall postoperative complication profiles, anastomotic leakage risk and perioperative safety to UFS, with no significant between-group differences in overall sphincter preservation rates in general population. In terms of oncological outcomes, NACRT induced prominent tumor and nodal downstaging, yielded a considerable pathological complete response (pCR) rate, and significantly improved pathological nodal status compared with primary surgery. Given the consistent evidence from pivotal trials, NACRT has now become the standard of care for LARC, and UFS is no longer routinely adopted as the primary treatment strategy in contemporary clinical practice.

Impact of the evolution in surgical approaches on operative procedures and outcomes following NACRT for rectal cancer

It is noteworthy that the three afore-mentioned clinical trials (20-22) enrolled patients between the 1990s and 2000s. In recent years, remarkable technological advances have been made in minimally invasive surgery for rectal cancer, and the era of robot-assisted surgery has commenced (23). Consequently, whether the conclusions from those earlier studies regarding the influence of NACRT on surgery remain applicable warrants further examination. Comparing operative difficulty, surgical procedure outcomes, and postoperative complications among open, laparoscopic, and robot-assisted surgery in LARC after NACRT can help clarify this issue.

The LASRE trial enrolled patients with early or locally advanced rectal adenocarcinoma located within 5 cm from the dentate line, who were randomly assigned to the laparoscopic surgery group and the open surgery group at a 2:1 ratio. In terms of operative difficulty, the laparoscopic surgery group had a longer operative time than the open surgery group (195.0 vs. 180.0 min, P<0.001), while the estimated blood loss was significantly lower (50 vs. 100 mL, P<0.001). There was no significant between-group difference in the rate of intraoperative complications (1.8% vs. 2.0%, P=0.80). Regarding surgical procedural outcomes, no significant differences were observed between the laparoscopic surgery and open surgery groups in the rates of complete TME (85.3% vs. 85.8%, P=0.78), negative circumferential resection margin (CRM) (98.2% vs. 99.7%, P=0.09), negative distal resection margin (99.4% vs. 100%, P=0.36), and the number of harvested lymph nodes (13.0 vs. 12.0, P=0.39). However, the laparoscopic surgery group achieved a significantly higher sphincter-preserving surgery rate (71.7% vs. 65.0%, P=0.03). For postoperative complications, the overall postoperative complication rate (13.0% vs. 17.2%, P=0.07) and the rate of severe complications (Clavien-Dindo grade ≥ III) (0.7% vs. 2.0%, P=0.07) were comparable between the two groups. The laparoscopic surgery group showed significantly lower rates of anastomotic leakage (2.5% vs. 6.1%, P=0.01) and incision-related complications (2.6% vs. 5.1%, P=0.04), as well as a shorter length of hospital stay (8.0 vs. 9.0 days, P=0.008). In terms of surgery-related oncological outcomes, the 3-year locoregional recurrence rate was 3.7% in the laparoscopic surgery group and 2.3% in the open surgery group, with no significant statistical difference (P=0.22). Overall, this study demonstrates that laparoscopic surgery performed by experienced surgeons is non-inferior to open surgery in patients with low rectal cancer, thereby supporting the application of laparoscopic surgery in the treatment of low rectal cancer (24,25).

With the emergence of robot-assisted surgery, additional studies have focused on comparisons with other minimally invasive techniques. The ROLARR trial randomized 471 rectal adenocarcinoma patients to the robotic-assisted laparoscopic group (robotic group) and the conventional laparoscopic group (laparoscopic group). For operative difficulty, the robotic group had a mean operative time that was 37.5 minutes longer than the laparoscopic group (298.5 vs. 261.0 min). The conversion rate to open surgery was comparable between the two groups (8.1% vs. 12.2%, P=0.16). Preoperative radiotherapy or chemoradiotherapy showed no significant impact on the conversion rate to open surgery (9.8% vs. 10.3%, P=0.86). In addition, the incidence of intraoperative complications was similar between the two groups (15.3% vs. 14.8%, P=0.94). Regarding surgical procedural outcomes, both groups achieved a satisfactory number of harvested lymph nodes (mean: 23.2 vs. 24.1). The rates of complete TME (76.4% vs. 77.6%, P=0.14) and CRM positivity (5.1% vs. 6.2%, P=0.56) were comparable between the robotic and laparoscopic groups. The prophylactic stoma rate in the robotic group was 8.1% lower than that in the laparoscopic group (60.2% vs. 68.3%). In terms of postoperative complications, the length of hospital stay was nearly equivalent between the two groups (8.0 vs. 8.2 days). There were no significant differences in the postoperative complication rate within 30 days (33.1% vs. 31.7%, P=0.84) and the complication rate from 30 days to 6 months postoperatively (14.4% vs. 16.5%, P=0.25). When analyzing individual complications within 30 days after surgery, the two groups showed similar rates in gastrointestinal complications (14.8% vs. 17.4%), surgical site infection (8.9% vs. 8.3%), and urinary complications (7.2% vs. 6.1%). Furthermore, no significant between-group differences were observed in patient-reported bladder function at 6 months postoperatively (P=0.27), as well as sexual function in male patients (P=0.75) and female patients (P=0.60) (26).

In summary, the evolution and technical refinements in surgical approaches do not appear to exert a significant adverse effect on rectal cancer surgery following NACRT. On the contrary, minimally invasive techniques such as robot-assisted surgery may offer certain advantages in specific surgical parameters.

Influence of omitting radiotherapy from neoadjuvant therapy on surgical procedure and outcomes

As mentioned previously, most studies have demonstrated that NACRT did not exert adverse effects on surgical procedure and outcomes. Yet concerns regarding the potential adverse impacts of radiotherapy on surgery have persisted and are far more prevalent than concerns regarding chemotherapy. The primary concern is that acute edema and chronic fibrosis of pelvic tissues following radiotherapy may increase surgical difficulty, postoperative anastomotic leakage, as well as the rate of prophylactic stoma (27-29). Several studies have attempted to replace radiotherapy with intensified chemotherapy regimens in neoadjuvant therapy, which have yielded a potentially acceptable tumor response and disease-free survival (30-33).

The PROSPECT trial stands as one of the most representative investigations. Between 2012 and 2018, this trial enrolled 1,194 patients with LARC who were clinically staged as cT2N+, cT3N0, or cT3N+ and eligible for sphincter-preserving surgery. Participants were randomly assigned in a 1:1 ratio to receive either neoadjuvant chemotherapy alone with the FOLFOX regimen (NACT group) or standard long-course neoadjuvant chemoradiotherapy (lc-NACRT group). For patients in the NACT group, salvage chemoradiotherapy was administered if the primary tumor shrinkage was less than 20% or if treatment was discontinued due to chemotherapy-related adverse events. In terms of surgical procedure outcomes, both the NACT and lc-NACRT groups achieved high R0 resection rates (98.9% vs. 97.1%). Regarding surgery-related oncological outcomes, the two groups showed comparable rates of pCR (21.9% vs. 24.3%), ypT0 stage (22.7% vs. 24.7%), and ypN0 stage (74.8% vs. 76.5%), while both groups exhibited low local recurrence rates (1.8% and 1.6%, respectively). Additionally, trial data indicated that only 9.1% of patients in the NACT group required preoperative salvage chemoradiotherapy, and 1.4% received postoperative chemoradiotherapy. Accordingly, the trial concluded that more than 90% of patients could safely omit pelvic radiotherapy, which conferred potential benefits in reducing the rate of prophylactic stoma placement and minimizing pelvic radiotherapy-associated tissue injury, without increasing the long-term risk of tumor recurrence (34).

Accordingly, whether omitting radiotherapy from neoadjuvant therapy can reduce surgical difficulty and postoperative complications warrants further exploration, and the CONVERT trial provides valuable evidence addressing this clinical question. This trial compared the efficacy and safety of preoperative capecitabine plus long-course radiotherapy (lc-NACRT group) with CapOX chemotherapy (NACT group) in LARC patients without mesorectal fascia involvement. Regarding surgical procedure outcomes, the rate of preventive ileostomy was significantly higher in the lc-NACRT group than in the NACT group (63.6% vs. 52.2%, P=0.008). However, no significant differences were observed between the two groups in 30-day postoperative complications, including anastomotic leakage (6.1% vs. 5.9%, P=0.913), bowel obstruction (1.9% vs. 2.9%, P=0.577), intestinal function disorder (7.3% vs. 5.9%, P=0.515), clinical fistula (1.5% vs. 0%, P=0.057), wound infection (8.8% vs. 5.1%, P=0.096), abscess (1.9% vs. 1.8%, P>0.99), septicemia (0.8% vs. 0.4%, P=0.617) and urinary complications (1.5% vs. 1.1%, P=0.720); 60-day postoperative mortality also showed no notable variance between the two cohorts (0.4% vs. 0%, P=0.490). Furthermore, for surgery-related oncological outcomes, no significant differences were detected in ypT stage (P=0.524) and pCR rate (P=0.333) between the two groups, while the lc-NACRT group exhibited significantly better ypN stage (P=0.038), overall tumor regression grade (TRG) (P<0.001) and TRG 0-1 (P<0.001) compared with the NACT group (32).

Meanwhile, the GRECCAR4 trial stratified patients with LARC into a favorable response stratum and an unfavorable response stratum based on tumor regression after four cycles of neoadjuvant FOLFIRINOX chemotherapy. Patients with a favorable response subsequently underwent surgery alone (NACT group) or surgery following chemoradiotherapy (NACRT group). For surgical procedure outcomes, the proportion of coloanal anastomosis (94.7% vs. 50%) and minimally invasive surgery (89.5% vs. 77.8%) was significantly higher in the NACRT group. Regarding postoperative complications, the overall rate was unexpectedly lower in the NACRT group than in the NACT group (42.1% vs. 50.0%), particularly for fistula incidence (5.3% vs. 20.0%). Nevertheless, the NACRT group had a slightly higher incidence of severe complications (Clavien-Dindo grade 3–4: 26.3% vs. 20.0%) and reoperation rate (15.8% vs. 10.0%) relative to the NACT group. In terms of surgery-related oncological outcomes, the NACRT group achieved superior tumor downstaging, with a higher proportion of tumors ≤ T2 stage (64.7%) compared to the NACT group (50.0%), suggesting that radiotherapy-induced tumor regression may facilitate surgery (35).

However, a limited number of studies have indicated that NACRT was associated with more detrimental effects on surgery compared to NACT. Sun et al. used the FOWARC trial cohort to compare low anterior resection syndrome (LARS) and QoL between patients who underwent lc-NACRT followed by TME and those treated with NACT alone followed by TME, aiming to further explore the impact of radiotherapy in neoadjuvant settings on postoperative bowel function. The results demonstrated that the overall severity of LARS was significantly higher in the lc-NACRT group than in the NACT group (P<0.001), including flatus incontinence (P=0.003), liquid stool incontinence (P<0.001), daily bowel movement frequency (P<0.001), and defecatory urgency (P=0.003). For QoL assessed by the QLQ-CR29 and QLQ-C30 questionnaires, the lc-NACRT group exhibited significantly worse outcomes than the NACT group in terms of stool frequency (P=0.009), flatulence (P=0.003), fecal incontinence (P<0.001), perianal skin soreness (P=0.03), social embarrassment (P<0.001), as well as global health status, role functioning, social functioning (28).

In summary, there remains controversy regarding the influence of neoadjuvant radiotherapy on surgery-related complications and oncological outcomes, as different studies have yielded inconsistent findings, and more high-quality data are needed to guide clinical decision-making.

Impact of different neoadjuvant radiotherapy modalities on subsequent surgery

Neoadjuvant radiotherapy for LARC includes long-course radiotherapy and short-course radiotherapy. Whether different radiotherapy modalities have distinct impacts on subsequent surgery is a critical issue for clinical practice.

A single-center retrospective study compared the association of two neoadjuvant regimens with perioperative complications: short-course radiotherapy followed by 2–6 months of chemotherapy prior to surgery (short-course NACRT, sc-NACRT, n=156) and lc-NACRT (n=259). In terms of operative difficulty, the operative time was significantly shorter in the sc-NACRT group than in the lc-NACRT group (213±65 vs. 237±93 min, P=0.01), whereas no significant differences were observed in estimated blood loss (342±332 vs. 410±585 mL, P=0.17) and intraoperative complications (4.5% vs. 5.0%, P=0.81). Regarding surgical procedure outcomes, the two groups showed no statistically significant differences in completeness of TME (94.9% vs. 93.8%, P=0.65), negative distal resection margin rate (100% vs. 97.7%, P=0.06), and negative radial resection margin rate (98.7% vs. 96.5%, P=0.18). With respect to postoperative complications, there were no significant between-group differences in the overall perioperative complication rate (39.7% vs. 37.5%, P=0.64), Clavien-Dindo grade ≥3 complication rate (9.6% vs. 12.0%, P=0.46), reoperation rate (3.2% vs. 5.0%, P=0.38), length of hospital stay (6.5±4.0 vs. 7.0±6.3 days, P=0.27), and 30-day mortality (0% vs. 0%) (36).

A meta-analysis incorporating 7,507 patients across 14 cohorts investigated this topic. The analysis categorized patients into three groups: short-course radiotherapy followed by consolidation chemotherapy and delayed surgery (short-course neoadjuvant chemoradiotherapy, sc-NACRT), short-course radiotherapy followed by delayed surgery without consolidation chemotherapy (short-course neoadjuvant radiotherapy, sc-NART), and lc-NACRT. For surgical procedure outcomes, no statistically significant differences in R0 resection rates were noted between sc-NACRT or sc-NART and lc-NACRT [risk ratio (RR): 1.02, 95% confidence interval (CI): 0.99–1.05, P=0.11; RR: 1.01, 95% CI: 0.93–1.09, P=0.87; respectively]. By contrast, sc-NACRT achieved a significantly higher sphincter preservation surgery rate than lc-NACRT (RR: 1.06; 95% CI: 1.01–1.11; P=0.02), whereas the rate in the sc-NART group was significantly lower than that in the lc-NACRT group (RR: 0.86; 95% CI: 0.75–1.00; P=0.05). Concerning postoperative complications, neither sc-NACRT nor sc-NART showed significant differences versus lc-NACRT (RR: 1.09, 95% CI: 0.98–1.22, P=0.12; RR: 1.12, 95% CI: 0.92–1.36, P=0.26, respectively). Regarding surgery-related oncological outcomes, sc-NACRT demonstrated superiority over lc-NACRT in pCR rate (RR: 1.60, 95% CI: 1.35–1.91, P<0.00001), ypT (RR: 0.87, 95% CI: 0.74–1.01, P=0.07), and ypN (RR: 1.06, 95% CI: 1.01–1.22, P=0.02), while tumor downstaging was comparable (RR: 1.00, 95% CI: 0.75–1.32, P=0.98). In contrast, sc-NART was inferior to lc-NACRT in pCR (RR: 0.47, 95% CI: 0.35–0.63, P<0.00001), ypT (RR: 1.15, 95% CI: 1.01–1.31, P=0.03), ypN (RR: 0.85, 95% CI: 0.80–0.91, P<0.00001), and tumor downstaging (RR: 0.82, 95% CI: 0.74–0.91, P=0.0002). Furthermore, no significant differences were found between sc-NACRT or sc-NART and lc-NACRT in rates of negative CRM (RR: 1.00, 95% CI: 0.98–1.02, P=0.97; RR: 1.00, 95% CI: 0.97–1.04, P=0.86, respectively) (37).

In summary, long-course and short-course radiotherapy demonstrated comparable R0 resection rates and postoperative complication profiles. Short-course radiotherapy combined with consolidation chemotherapy conferred superior tumor regression and sphincter preservation benefits relative to long-course radiotherapy.

Impact of interval between neoadjuvant radiotherapy completion and surgery on surgical procedure and outcomes

Meanwhile, prolonging the time interval between neoadjuvant radiotherapy completion and surgery allows patients to receive more adequate neoadjuvant chemotherapy and may facilitate tumor regression before surgery. However, as progressive pelvic tissue fibrosis develops after radiotherapy, an excessively long interval might increase surgical difficulty and surgical complications. The interval varied considerably in different clinical trial protocols, warranting investigation into whether this variability affects surgical outcomes.

Garcia-Aguilar et al. stratified patients following lc-NACRT into two groups. Patients in the SG1 group (n=60) underwent surgical resection 6 weeks after chemoradiotherapy. Patients in the SG2 group (n=67) who achieved a clinical response at 4 weeks after chemoradiotherapy received two cycles of chemotherapy, followed by TME 3–5 weeks later, with surgery performed approximately 11–13 weeks after the completion of chemoradiotherapy. In terms of operative difficulty, there were no significant differences between the SG1 and SG2 groups in operative time (249±55 vs. 314±317 min, P=0.3310) or estimated blood loss (263±235 vs. 328±117 mL, P=0.1224). Although the degree of pelvic fibrosis was milder in the SG1 group than in the SG2 group (2.4±1.7 vs. 4.0±2.6, P=0.0003), no significant difference was observed in the subjective surgical technical difficulty score between the two groups (4.5±2.7 vs. 5.1±2.7, P=0.2220). Regarding surgical procedure outcomes, the two groups showed no significant differences in R0 resection rate (97% vs. 96%, P=1.000), sphincter-preserving surgery rate (77% vs. 75%, P=0.8382), or number of harvested lymph nodes (13±7 vs. 15±7, P=0.3341). In terms of postoperative complications, the overall postoperative complication rate was comparable between the two groups (40% vs. 40%). The incidences of Clavien-Dindo grade ≥3 complications were low in both cohorts, including ileus or intestinal obstruction (12% vs. 9%), superficial surgical site infection (8% vs. 9%), anastomotic leakage or pelvic abscess (10% vs. 6%), urinary tract infection (3% vs. 4%), and urinary retention (5% vs. 12%). With respect to surgery-related oncological outcomes, the SG1 group had a lower pCR rate (18% vs. 25%, P=0.0217) and a lower ypT0 rate (23% vs. 31%, P=0.0008) compared with the SG2 group, whereas no significant differences were found in the ypN0 rate (75% vs. 75%, P=0.6606) between the two groups. This study concluded that the addition of chemotherapy after lc-NACRT with delayed surgery may modestly increase the pCR rate without raising the risk of complications associated with TME (38).

Another study enrolled patients who underwent lc-NACRT from three centers and stratified them into two groups based on a 12-week cutoff for the interval: the standard-interval group (n=48; median interval, 7 weeks; interquartile range, 6–11 weeks) and the prolonged-interval group (n=76; median interval, 15 weeks; interquartile range, 12–100 weeks). The study found that for operative difficulty, no significant differences were observed between the two groups in surgical approach (P=0.203), operative procedure (P=0.117), operative time (255 min vs. 240 min, P=0.475), estimated blood loss (20 vs. 20 mL, P=0.194), or the rate of conversion to open surgery (4.8% vs. 2.9%, P=0.630). For postoperative complications, there were no notable disparities in anastomotic leakage (0% vs. 5.7%, P=0.547), 30-day readmission rate (12.5% vs. 5.3%, P=0.183), 30-day reoperation rate (4.2% vs. 3.9%, P=1.000), or 30-day mortality (4.2% vs. 0%, P=0.148) between the two cohorts. In terms of surgery-related oncological outcomes, no statistically significant differences were detected in ypT0 (8.3% vs. 15.8%, P=0.280) or CRM clearance (89.6% vs. 96.1%, P=0.164) between the two groups. In conclusion, the study concluded that delaying the interval ≥12 weeks had no impact on surgical procedures or surgery-associated outcomes (39).

By comparison, the large randomized phase 3 RAPIDO trial stratified patients into two groups. Patients in the total neoadjuvant treatment (TNT) arm received short‑course radiotherapy followed by 18 weeks of chemotherapy before surgery, while patients in the lcNACRT arm underwent surgery approximately 8 weeks after chemoradiotherapy. The results demonstrated that patients undergoing sphincter‑preserving surgery in the TNT group had a significantly higher locoregional recurrence rate than those in the lc-NACRT group [12.1% vs. 4.8%, hazard ratio (HR) =2.60]. Surgical factors including breached mesorectal fascia and incomplete TME were considered the main contributors to this outcome, indicating that NACRT and prolonged intervals between neoadjuvant therapy and surgery may exert adverse effects on subsequent surgical procedures (8,40).

Collectively, prolonging the interval between neoadjuvant radiotherapy completion and surgery did not increase surgical complexity or compromise perioperative safety, and might increase the pCR and tumor downstaging rates. However, emerging evidence suggested a potential risk of impaired long-term locoregional control with excessively prolonged intervals, warranting further investigation into optimal timing strategies.

Impact of different systemic treatment regimens in neoadjuvant therapy on surgery

Concurrently, escalating the intensity of chemotherapy, combining immunotherapy, and extending treatment cycles in neoadjuvant systemic therapy for LARC to achieve better tumor control and pCR rates has become a major research focus to date. However, it remains to be elucidated whether the escalation of systemic therapeutic intensity exerts adverse effects on subsequent surgery.

A study compared the impact on surgical outcomes of different chemotherapy regimens administered during concurrent chemoradiotherapy in LARC patients receiving lc-NACRT. After propensity score matching, 191 patients were enrolled in the XELOX doublet group and 319 in the capecitabine single-agent group. Regarding surgical procedure outcomes, the number of lymph nodes retrieved was higher in the capecitabine group than in the XELOX group [13 vs. 11, standardized mean difference (SMD) =0.291]. With respect to postoperative complications, no significant differences were observed between the XELOX group and the capecitabine group in overall complications (HR: 1.477, P=0.138), anastomotic leakage (HR: 0.830, P=0.714), bowel obstruction (HR: 2.554, P=0.150), incision infection (HR: 2.745, P=0.080), abdominal or pelvic infection (HR: 0.661, P=0.489), urinary tract infection (HR: 0.832, P=0.797), or pulmonary infection (HR: 1.563, P=0.296). For surgery-related oncological outcomes, there were no significant disparities between the two groups in pCR rate (SMD =0.037), tumor downstaging (71.7% vs. 78.1%, SMD =−0.101), ypTNM (SMD =0.059), ypT (SMD =0.069), ypN (SMD =0.073), or rectal cancer regression grade (SMD =−0.096) (41).

The CinClare trial compared two neoadjuvant regimens: long-course radiotherapy concurrently with capecitabine followed by sequential oxaliplatin plus capecitabine (CapRT group) versus long-course radiotherapy concurrently with capecitabine and irinotecan followed by sequential irinotecan plus capecitabine (CapIriRT group). The study found that for surgical procedure outcomes, both the CapIriRT and CapRT groups had high complete resection rates with no significant difference (97% vs. 96%). In terms of postoperative complications, the rates of grade 3–4 complications were comparable between the CapIriRT and CapRT groups (15% vs. 11%, P=0.268), and the rates of wound infection (5% vs. 3%), anastomotic leakage (5% vs. 3%), anastomotic stenosis (1% vs. 1%), ileus/obstruction (1% vs. 2%), and delayed wound healing (2% vs. 3%) were also similar between the two groups. For surgery-related oncological outcomes, the proportions of patients with CRM ≤1 mm were 2% and 5%, and ypN0 were 74% and 73% in the CapIriRT and CapRT groups, respectively. In the modified intention-to-treat population, the pCR rates were 30% and 15% for the two groups, showing a significant difference (P=0.001) (42). Collectively, the two studies suggested that intensifying neoadjuvant chemotherapy regimens did not exert significant adverse effects on surgical procedure outcomes or postoperative complications, with the latter study indicating a potential benefit for improving the pCR rate.

Meanwhile, in the current era of immunotherapy, the potential impact of adding neoadjuvant immunotherapy to NACRT on surgery has attracted extensive attention. A study addressed this question by conducting a post-hoc analysis of the POLARSTAR clinical trial. Patients were categorized into three groups based on treatment: chemoradiotherapy combined with concurrent PD-1 inhibitor (Concurrent group, n=52), chemoradiotherapy combined with sequential PD-1 inhibitor (Sequential group, n=46), and chemoradiotherapy alone (Control group, n=52). The study reported that for surgical procedure outcomes, the rates of sphincter-sparing surgery plus one-stage anastomosis were 92%, 96%, and 87% in the concurrent, sequential, and control groups, respectively; the proportions of patients without stoma were 21%, 17%, and 11%, respectively; and the numbers of resected lymph nodes were 12.0, 10.5, and 12.0, respectively. With respect to postoperative complications, the overall complication rates were 12%, 24%, and 13% in the three groups, and the grade 3/4 complication rates were 4%, 7%, and 4%, respectively. The incidences of anastomotic leak, anastomosis bleeding, subcutaneous hematoma around stoma, ileus, rectovaginal fistula, wound infection, intra-abdominal abscess, and urinary retention were all below 10% across the three groups. The 30-day readmission rates were 4%, 7%, and 0%, respectively; the 30-day reoperation rates were 0% in all groups; the median postoperative hospital stays were 7.0, 6.5, and 7.0 days, respectively; and the median postoperative urethral catheter indwelling times were all 3.0 days. No significant intergroup differences were detected for any of the surgical and surgical safety indices. For surgery-related radiologic oncological outcomes, the radiological response rates in the concurrent and sequential groups were significantly higher than that in the control group (44% vs. 22%, P=0.023; 52% vs. 22%, P=0.003, respectively); the lymph node downstaging rates were 70%, 59%, and 54% in the concurrent, sequential, and control groups, respectively; and the rates of CRM conversion to negative were 42%, 67%, and 42%, respectively. Regarding surgery-related pathologic oncological outcomes, the proportions of patients with ypT0/Tis and ypN0 were 33%, 39%, and 20% in the three groups, respectively; the proportions of patients with TRG 0 were 31%, 37%, and 18%, respectively; and the negative CRM rates were 100%, 98%, and 96%, respectively. Statistically significant differences were observed between the sequential group and the control group in the proportions of patients with ypT0/Tis and ypN0 (P=0.046), as well as TRG 0 (P=0.040). The study concluded that the combination of PD-1 inhibitors with NACRT could enhance the pathological regression of tumors and facilitate the performance of TME (43).

Taken together, intensified chemotherapy and immunotherapy-integrated neoadjuvant regimens did not adversely affect surgical feasibility or perioperative safety. Moreover, some intensified systemic regimens may improve surgery-related oncological outcomes.

Briefly, the impacts of neoadjuvant therapy on subsequent surgical procedures in LARC are summarized in Table 3.

Integrative analysis and discussion

Neoadjuvant therapy for LARC has been a recognized standard treatment modality for two decades. However, clinical concerns regarding whether it increases surgical difficulty and postoperative complications, together with the insufficient availability of qualified rectal cancer treatment centers and referral-based networks, remain core factors leading to suboptimal guideline adherence in real-world clinical practice (12,14,17-19). Head-to-head studies comparing NACRT with UFS provide direct evidence to address such concerns. Although most of these studies were conducted from the 1990s to the early 2000s, and no subsequent large-scale randomized controlled trials have been launched due to the establishment of neoadjuvant therapy as the standard modality, the core conclusions of these studies were highly consistent and reliable (20,21). NACRT showed no significant differences from UFS in terms of surgical procedures and postoperative complications, and it significantly improved the sphincter-preserving surgery rate through tumor downstaging, especially for low rectal cancer patients. More importantly, with the evolution of surgical techniques for rectal cancer, the advances of minimally invasive techniques including laparoscopic surgery, transanal TME and robot-assisted surgery may further alleviate clinical concerns about the potential surgical impacts of neoadjuvant therapy and suggested that advances in surgical techniques synergize with neoadjuvant therapy to optimize overall treatment outcomes (23,44).

In this review, we systematically evaluated the impact of neoadjuvant therapy on subsequent surgery from four dimensions: operative difficulty, surgical procedure outcomes, postoperative complications, and surgery-related oncological outcomes. This evaluation system considered the immediate procedural feasibility, therapeutic efficacy and short-term safety of surgery. Specifically, operative difficulty is a direct reflection of surgeons’ intraoperative maneuvers, but relevant research data are currently relatively limited. Most studies adopted operative time, blood loss or the relatively subjective visual analog scale (VAS) or surgeons’ intuitive intraoperative perception for assessment. Consequently, such assessments lack intuitive and objective evaluation indicators. Furthermore, each surgeon evaluates only a limited number of cases, with judgments highly dependent on individual surgical experience; coupled with potential subjective bias caused by non-blinded evaluation, these factors collectively impose inherent limitations on the reliability of relevant findings. Surgical procedure outcomes reflect the immediate implementation effect of surgery through indicators such as complete resection, sphincter-preserving, and prophylactic stoma. Postoperative complications focus on perioperative safety. Surgery-related oncological outcomes are not only the core goal of neoadjuvant therapy but also can indirectly reflect the degree of optimization of surgical conditions. Effective tumor downstaging and regression can significantly improve the surgical field and reduce the difficulty of TME, which is also one of the core advantages of neoadjuvant therapy over UFS. Notably, the included studies adopted different indicators to assess operative difficulty and surgical procedure outcomes. Such significantly heterogeneous indicators reduce the comparability of results across studies and hinder the interpretation of relevant findings. In addition, this review mainly focuses on short-term surgical outcomes and pays limited attention to long-term oncological outcomes. Given that the fundamental purpose of neoadjuvant therapy is to improve long-term oncological prognosis, clinical decision-making should comprehensively integrate both the short-term surgical impacts and long-term prognostic benefits of different neoadjuvant strategies.

Clinical concerns about neoadjuvant therapy have mostly centered on the potential of radiotherapy-related adverse effects to increase surgical difficulty and the risk of anastomotic leakage (27-29). However, most studies included in this review indicated that NACRT did not significantly elevate the risk of major postoperative complications such as anastomotic leakage compared with NACT. Moreover, NACRT achieved favorable tumor downstaging and regional lymph node control, and further improved sphincter-preserving rates and overall surgical outcomes (32,35). Conversely, some studies have demonstrated that NACRT was associated with longer operative time, higher overall postoperative complication rates, and poorer long-term bowel function and QoL. More importantly, NACRT might impair mesorectal integrity, thereby increasing the risk of locoregional recurrence in patients undergoing sphincter-preserving surgery. Accordingly, the impact of neoadjuvant radiotherapy on surgical outcomes remains a controversial issue.

It is clinically noteworthy that temporary prophylactic stoma and sphincter preservation represent two distinct clinical concepts: the former is a perioperative strategy to reduce anastomotic leakage risk, and the latter a therapeutic goal linked to long-term QoL. Current evidence indicated neoadjuvant therapy did not significantly increase the clinical need for prophylactic stoma (32,45) yet might improve sphincter preservation in low rectal cancer patients (20,21), a benefit for enhancing patient QoL (28,29). The OPRA trial demonstrated that approximately half of patients with stage II–III rectal cancer treated with TNT achieved long-term organ preservation (10). Furthermore, 5-year follow-up data from the OPERA trial demonstrated that adding contact X-ray brachytherapy boost to lc-NACRT significantly improved long-term organ preservation rates without compromising bowel function in patients with operable cT2-cT3b low-mid rectal adenocarcinoma (46). Notably, although intensified neoadjuvant therapy and advances in surgical techniques, such as intersphincteric resection, have facilitated sphincter-preserving surgery, overly aggressive pursuit of sphincter-preserving surgery may compromise oncological safety and increase local recurrence rates. Balancing oncological efficacy and functional preservation by integrating pretreatment and post-neoadjuvant tumor status remains a critical issue requiring further investigation (47).

In addition, cT4 disease, ultra-low rectal cancer, or patients requiring lateral pelvic lymph node dissection (LLND) present unique surgical challenges. In ultra-low rectal cancer, neoadjuvant therapy can reduce the technical difficulty of distal transection and reconstruction by inducing tumor shrinkage and mitigating distal tumor extension (48). The ongoing STAR-TREC trial will prospectively compare long-course chemoradiation, short-course radiotherapy, and radical TME to define optimal organ-preservation strategies for early rectal cancer (49). However, some patients exhibit a poor response to neoadjuvant therapy. Therefore, close monitoring of treatment response during neoadjuvant therapy is essential, and subsequent surgical selection should be guided by the extent of tumor regression (10,50). Additionally, LLND may increase surgical difficulty and the risk of perioperative complications, and its clinical value in the neoadjuvant era remains controversial. Some studies have demonstrated that routine LLND following NACRT does not significantly reduce lateral pelvic recurrence or improve overall survival in unselected patients (51,52), and it prolongs operative time (52). Nevertheless, patients with lateral pelvic lymph node short-axis diameter ≥5 mm after NACRT (51,53), tumors located ≤5 cm from the anal verge regardless of NACRT response (54), or those with lateral pelvic lymph nodes showing heterogeneous signal intensity or irregular margins on MRI before initial treatment (53) may benefit from LLND. High-quality clinical evidence and detailed discussion of the surgical challenges and therapeutic trade-offs associated with LLND are warranted to provide actionable guidance for clinical decision-making.

Within the framework of neoadjuvant therapy, radiotherapy modalities, the interval between the completion of radiotherapy and surgery, and systemic treatment regimens are the core issues of current clinical interest. The analysis in this review confirmed that none of these three regimen optimization strategies exerted significant adverse effects on the feasibility and safety of surgery (37,43,45). This provided a feasibility guarantee for the individualized optimization of neoadjuvant therapy regimens aiming to improve local tumor control and long-term survival, without increasing surgical burden and compromising perioperative safety.

There are several limitations in this study. First, there are insufficient research data on special subgroup populations. For example, the impact of different neoadjuvant therapy modalities on surgery in patients with cT4 stage disease, ultra-low rectal cancer (tumor ≤3 cm from the anal verge) or pelvic organ invasion needs further exploration. Second, in terms of surgical safety, most current studies have focused on short-term safety, with inadequate attention to long-term QoL indicators such as intestinal and genitourinary function in postoperative patients. This review also did not involve the evaluation of long-term surgical safety, which should also become one of the core evaluation endpoints for the combined therapy of neoadjuvant therapy and surgery. Additionally, narrative reviews may be subject to selection bias in the inclusion of literature, which may compromise reproducibility and the accuracy of the conclusions.

Conclusions

Neoadjuvant therapy and its optimized strategies for LARC do not significantly increase overall surgical difficulty or perioperative complications. However, the impact of neoadjuvant radiotherapy on postoperative complications and outcomes remains controversial to some extent. High-quality prospective data are needed to further elucidate long-term oncologic outcomes and subgroup-specific effects.

Acknowledgments

The authors would like to thank Peng Jiang for English language proofreading.

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://jgo.amegroups.com/article/view/10.21037/jgo-2026-0328/rc

Peer Review File: Available at https://jgo.amegroups.com/article/view/10.21037/jgo-2026-0328/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jgo.amegroups.com/article/view/10.21037/jgo-2026-0328/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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