Letter to the Editor: Total neoadjuvant therapy for locally advanced rectal cancer: Navigating beyond surgical outcomes to holistic patient-centered care

Abstract

Locally advanced rectal cancer (LARC) remains a major challenge in oncology, with traditional treatment centered on long-course chemoradiotherapy (LCCRT) followed by total mesorectal excision. However, this paradigm is limited by suboptimal chemotherapy compliance, persistent metastasis risk, and functional morbidity. Total neoadjuvant therapy (TNT), integrating systemic chemotherapy with chemoradiotherapy upfront, has emerged as a promising alternative, but concerns about surgical safety and complexity hinder its widespread adoption. The retrospective cohort study by Jabbar et al, published in the recent issue of the World Journal of Gastrointestinal Oncology, compared TNT-RAPIDO with standard LCCRT in 99 LARC patients, providing critical evidence on surgical feasibility, functional outcomes, and oncologic potential. This commentary summarizes the study’s core findings, discusses unresolved questions, and proposes future research directions including multicenter validation, long-term oncologic evaluation, patient-reported outcome assessment, and personalized treatment strategies. A concise comparison of key outcomes between TNT-RAPIDO and LCCRT is provided to facilitate quick comprehension of core findings. Emphasizing the shift toward holistic patient-centered care, these advancements aim to optimize both curative efficacy and quality of life for LARC patients.

Key Words: Locally advanced rectal cancer; Total neoadjuvant therapy; Surgical outcomes; Functional preservation; Patient-centered care; Minimally invasive surgery; Biomarker stratification; Long-term survival

Core Tip: Locally advanced rectal cancer treatment is evolving from surgery-centric to multimodal strategies, with total neoadjuvant therapy (TNT) gaining attention for balancing curability and function. Jabbar et al’s study confirms that TNT-RAPIDO is surgically safe, achieving comparable R0 resection rates to standard chemoradiotherapy while reducing stoma duration and permanent stoma risk. We highlight the study’s contributions to resolving TNT-related uncertainties and propose future directions: (1) Validating findings in multicenter cohorts; (2) Evaluating long-term oncologic outcomes; (3) Integrating patient-reported measures; and (4) Developing personalized regimens. This shift toward holistic care ensures locally advanced rectal cancer treatment prioritizes both survival and quality of life.

TO THE EDITOR

Locally advanced rectal cancer (LARC) is a clinically challenging malignancy imposing a substantial morbidity and mortality burden worldwide[1]. For decades, the standard treatment paradigm has been long-course chemoradiotherapy (LCCRT) followed by total mesorectal excision, a strategy focused on maximizing oncologic curability[2]. However, this approach has significant limitations: Postoperative chemotherapy compliance is often suboptimal due to treatment-related toxicity and surgical recovery[3], distant metastasis remains a major cause of treatment failure[4], and functional morbidity, including permanent stomas, bowel dysfunction, and sexual impairment, profoundly impacts patients’ quality of life[5].

In response to these unmet needs, total neoadjuvant therapy (TNT) has emerged as an alternative multimodal strategy. By integrating systemic chemotherapy with chemoradiotherapy upfront before surgery, TNT aims to improve chemotherapy delivery, enhance tumor downstaging, and reduce distant metastasis risk[6]. Additionally, TNT may facilitate organ preservation in patients achieving a pathological complete response (pCR) and minimize functional sequelae[7]. Despite these theoretical advantages, concerns persist regarding TNT’s safety profile: The extended interval from therapy initiation to surgery (often 20-30 weeks) is hypothesized to increase pelvic fibrosis, compromise total mesorectal excision precision, and increase perioperative complication rates[8]. These uncertainties have limited uniform adoption of TNT in clinical practice.

Jabbar et al’s retrospective cohort study[9], published in the recent issue of the World Journal of Gastrointestinal Oncology, addresses this critical clinical dilemma by comparing TNT-RAPIDO with standard LCCRT in 99 LARC patients. Conducted over a 10-year period (2014-2024) with well-matched cohorts, the study provides robust evidence on TNT’s surgical feasibility and functional benefits. By resolving key uncertainties about operative safety and functional outcomes, this work establishes a critical foundation for refining LARC treatment paradigms.

In this letter, we critically analyze the study’s core findings, discuss unresolved questions and limitations, and propose innovative research directions to advance TNT’s role in LARC management. Our goal is to guide future investigations toward a holistic, patient-centered approach that reconciles oncologic curability with functional preservation and quality of life.

KEY FINDINGS OF THE STUDY

Jabbar et al’s study[9] makes a pivotal contribution to LARC treatment research by clarifying TNT’s surgical safety and functional advantages. The study enrolled LARC patients aged 18-75 years with histologically confirmed adenocarcinoma, clinical stage II and III disease, and Eastern Cooperative Oncology Group performance status 0-1 (inclusion criteria); patients with distant metastasis, prior pelvic radiotherapy, or severe comorbidities precluding multimodal therapy were excluded (exclusion criteria). Data were collected prospectively from electronic medical records and follow-up databases, with a median follow-up duration of 36 months. The study compared 29 patients receiving TNT-RAPIDO with 70 patients undergoing standard LCCRT, with balanced demographics, tumor stage, and baseline characteristics ensuring valid comparative analysis.

Surgical safety and oncologic resection quality

A primary concern with TNT is whether the extended treatment-to-surgery interval exacerbates surgical complexity. The study effectively mitigates this worry by demonstrating comparable surgical outcomes between groups.

Operative time, intraoperative complication rates, and 30-day morbidity/mortality were similar across TNT-RAPIDO and LCCRT cohorts. R0 resection rates were high in both groups (93.1% for TNT-RAPIDO vs 90% for LCCRT), confirming that TNT does not compromise surgical radicality; and the TNT-RAPIDO group achieved a significantly larger lymph node harvest (40.7 vs 23.4), a marker of thorough oncologic resection that has been associated with improved long-term disease-free survival in LARC[9], without increasing positive node rates, suggesting enhanced clearance of micrometastatic disease.

Functional outcomes: Stoma-related benefits

A key strength of the study is its focus on patient-centered functional outcomes, which are often overlooked in oncologic trials. TNT-RAPIDO was associated with a 36% shorter total stoma duration (27.1 weeks vs 42.5 weeks), reducing the burden of temporary stoma care. The permanent stoma rate was 61% lower in the TNT-RAPIDO group (13.8% vs 35.7%), a clinically meaningful difference given the profound impact of permanent stomas on daily function and quality of life.

Pathological response

While prior trials have linked TNT to improved pCR rates, the current study reported similar pCR rates between groups (13.8% vs 10.0%; χ² test, P = 0.58). This finding may be attributed to the modest sample size of the TNT-RAPIDO cohort (n = 29), which increases the risk of type II error (failure to detect a true difference), rather than a true lack of efficacy (Table 1).

Table 1 Comparison of outcomes between total neoadjuvant therapy-RAPIDO and standard long-course chemoradiotherapy, median.

Outcome	Total neoadjuvant therapy-RAPIDO (n = 29)	Standard long-course chemoradiotherapy (n = 70)	P value
R0 resection rate	93.1%	90.0%	0.65
Lymph node harvest	40.7	23.4	< 0.001
Total stoma duration (weeks)	27.1	42.5	0.02
Permanent stoma rate	13.8%	35.7%	0.01
Pathological complete response rate	13.8%	10.0%	0.58
30-day morbidity rate	17.2%	21.4%	0.63
Operative time (minutes)	185	178	0.51

Collectively, these findings confirm that TNT-RAPIDO is a safe alternative to standard LCCRT, with comparable oncologic resection quality and superior functional outcomes. The study’s long-term follow-up and well-matched design enhance the credibility of these conclusions, supporting TNT’s potential as a first-line treatment option for LARC.

FUTURE RESEARCH DIRECTIONS: ADVANCING PATIENT-CENTERED LARC CARE

While Jabbar et al’s study[9] is a significant step forward, several gaps remain to be addressed to fully realize TNT’s potential in LARC management. Below, we propose targeted research directions aligned with the study’s findings and unmet clinical needs.

Multicenter prospective validation

The single-center design and modest sample size (29 TNT-RAPIDO patients) limit generalizability. Future research should: (1) Conduct large-scale multicenter prospective randomized controlled trials to validate findings across diverse healthcare settings, patient populations (including those with comorbidities or lower performance status), and tumor subtypes. These randomized controlled trials should adopt standardized eligibility criteria and outcome measures to ensure data comparability; and (2) Ensure representation of both academic and community hospitals to assess TNT’s feasibility in real-world practice.

Long-term oncologic efficacy evaluation

The study focuses on short-term surgical outcomes, leaving long-term oncologic endpoints underexplored: (1) Prioritize assessment of 5-year disease-free survival, overall survival, and local/distant recurrence rates to confirm TNT’s functional benefits translate to sustained oncologic control; (2) Correlative analyses should explore whether the higher lymph node harvest in TNT-treated patients correlates with improved long-term survival, using multivariate Cox proportional hazards models to adjust for confounding factors; and (3) Expand sample sizes to evaluate pCR rate differences, as pCR is a validated surrogate for improved outcomes in LARC.

Refining surgical and treatment regimens

Key questions about TNT delivery and surgical technique require further investigation: (1) Clarify the role of minimally invasive surgery: The TNT-RAPIDO group had a higher proportion of robot-assisted laparoscopic total mesorectal excision (65.5% vs 42.9%), which may have mitigated fibrosis-related complexity. Future studies should compare surgical outcomes of TNT followed by open vs minimally invasive total mesorectal excision to determine if minimally invasive approaches are indispensable for optimizing TNT-related surgical feasibility; (2) Optimize TNT sequencing and intensity: Explore the optimal number of consolidation chemotherapy cycles (e.g., 4 cycles vs 6 cycles of FOLFOX) and whether short-course radiotherapy can replace long-course therapy in select low-risk LARC patients to balance efficacy and toxicity; and (3) Develop de-escalation strategies for low-risk LARC and escalation for high-risk disease to avoid over-treatment or under-treatment.

Integrating patient-reported outcomes and personalization

To advance holistic care, future research must center on patient perspectives and individualization: (1) Incorporate validated patient-reported outcomes instruments such as the European Organisation for Research and Treatment of Cancer QLQ-CR29 (specific for colorectal cancer) to assess quality of life, sexual function, bowel continence, and stoma-related distress, ensuring treatment decisions align with patient values; (2) Develop biomarker-driven stratification: Identify molecular signatures including circulating tumor DNA, microsatellite instability status, and specific gene mutations (e.g., RAS, BRAF) to predict TNT response and toxicity, enabling personalized treatment allocation[10,11]; and (3) Explore adaptive therapy approaches: Adjust TNT regimens based on mid-treatment response assessment (e.g., circulating tumor DNA dynamics, radiologic response) and evaluate organ-preserving non-operative management in patients achieving deep pathological or clinical complete responses.

CONCLUSION

Jabbar et al’s retrospective cohort study[9] provides critical evidence supporting the safety and functional benefits of TNT-RAPIDO for LARC patients. By demonstrating comparable surgical radicality and superior stoma-related outcomes to standard LCCRT, the study resolves key uncertainties and paves the way for broader TNT adoption. However, to fully realize TNT’s potential, future research must address long-term oncologic efficacy, generalizability across diverse populations, optimal treatment delivery, and patient-centered outcomes. The evolution of LARC therapy from single-modality surgery to multimodal TNT reflects a paradigm shift toward holistic care, prioritizing both curative efficacy and quality of life. By building on Jabbar et al’s foundation[9], researchers and clinicians can refine TNT strategies, integrate personalized and patient-centered approaches, and ultimately improve outcomes for patients with this challenging malignancy.