Total neoadjuvant therapy in rectal cancer: Challenging traditions without compromising surgical safety

Abstract

Total neoadjuvant therapy (TNT) is swiftly transforming the therapeutic approach for locally advanced rectal cancer; yet, its integration as a standard practice necessitates meticulous evaluation of surgical safety, long-term outcomes, and patient-centered considerations. The research conducted by Jabbar et al offers an extensive evaluation of the preliminary surgical outcomes of patients using the Rectal Cancer and Preoperative Induction therapy followed by Dedicated Operation based TNT regimen in contrast to conventional long-course chemoradiotherapy. Their data indicate that TNT does not elevate operational complexity, create issues, or negatively affect the quality of oncologic resection, even with a prolonged interval between neoadjuvant therapy and surgery. Conversely, TNT correlated with a reduction in overall stoma duration and the incidence of persistent stomas, data that hold significant implications for postoperative quality of life. This study supports the increasing evidence that TNT is a safe and effective method for enhancing systemic control without negatively impacting surgical performance. However, its retrospective single-center approach restricts external validity, and long-term oncological consequences remain undetermined. The retrospective design presents potential confounders, including selection bias and variability in surgical skill. The experience of surgeons and institutional protocols may impact outcomes, highlighting the necessity for consistent surgical quality indicators in upcoming trials. As TNT begins to solidify its status as a novel treatment standard, multicenter studies and translational research will be essential in the future to determine its effects on survival, functional recovery, and organ preservation. Concerns persist over the long-term toxicity linked to increased chemotherapy regimens, including neuropathy and hematologic consequences. The financial implications of TNT, difficulty in patient adherence, and the danger of overtreatment underscore the importance of rigorous patient selection and thorough supportive care techniques. The study by Jabbar et al contributes to the growing body of literature demonstrating that TNT can be safely incorporated into the modern care of rectal cancer, signifying a notable progression towards individualized and patient-centered multimodal therapy.

Key Words: Total neoadjuvant therapy; Rectal cancer; Chemoradiotherapy; Total mesorectal excision; Rectal Cancer and Preoperative Induction therapy followed by Dedicated Operation trial; FOLFIRINOX; Organ preservation; Surgical safety; Multimodal therapy; Oncology

Core Tip: Total neoadjuvant therapy (TNT) signifies an advancing standard in the treatment of locally advanced rectal cancer, incorporating systemic chemotherapy prior to surgery and radiotherapy. Recent research, including the Rectal Cancer and Preoperative Induction therapy followed by Dedicated Operation based TNT regimen evaluated by Jabbar et al, indicates comparable oncologic safety, comparable oncologic safety and promising postoperative quality-of-life improvements. This editorial synthesizes known data on TNT’s effectiveness, tolerability, and promise for organ preservation, while highlighting ongoing discussions about treatment sequencing, fibrosis risk, and long-term results. The discussion highlights the significance of meticulous patient selection and multidisciplinary supervision in enhancing rectal cancer treatment via personalized, patient-focused multimodal therapy.

INTRODUCTION

Conventional chemoradiotherapy (CRT) succeeded by total mesorectal excision has historically constituted the foundation of rectal cancer treatment; however, ongoing distant relapses and significant functional impairments highlight the necessity for improved treatment sequencing, thereby paving the way for total neoadjuvant therapy (TNT)[1]. The prevailing standard of care for patients with locally advanced rectal cancer (LARC; stages T3, T4, or N+) comprises CRT followed by complete mesorectal resection. This multidisciplinary strategy provides superior local disease management; nonetheless, the rates of distant recurrence persist at approximately 30%. Upfront neoadjuvant chemotherapy, succeeded by preoperative CRT, known as TNT, is an alternate strategy that addresses micrometastases early, administers chemotherapy to the primary tumor site while vascularization is preserved, and may enhance compliance[2]. The administration of systemic chemotherapy prior to surgery, either before or after CRT, constitutes the fundamental principle of TNT, which seeks to enhance compliance with systemic treatment and address micrometastases at an earlier stage[1].

Systemic relapses continue to be a significant challenge in LARC. Three years post-randomization, the cumulative probability of disease-related treatment failure was 23.7% (95%CI: 19.8-27.6) in the experimental group compared to 30.4% (95%CI: 26.1-34.6) in the standard of care group (hazard ratio = 0.75, 95%CI: 0.60-0.95; P = 0.019). The experimental regimen can be regarded as a routine option for high-risk LARC, however its application to wider patient populations is still contested[3]. The increased intensity of treatment with FOLFIRINOX prior to preoperative CRT markedly enhanced outcomes compared to preoperative CRT alone in patients with cT3 or cT4 M0 rectal cancer. The markedly enhanced disease-free survival (DFS) in the neoadjuvant treatment cohort and the reduced neurotoxicity suggest that the perioperative strategy is more effective and more tolerated than adjuvant chemotherapy. Induction therapy utilizing six cycles of FOLFIRINOX did not affect radiation therapy adherence or surgical effectiveness, significantly reduced the incidence of Clavien-Dindo morbidity, and did not elevate local recurrence rates. No difference was observed in the total percentage of major adverse events based on the Clavien-Dindo classification; however, the standard-of-care group experienced considerably more grade IV and V problems[2]. Conclusion: In patients with LARC eligible for sphincter-sparing surgery, preoperative FOLFOX demonstrated noninferiority to preoperative CRT concerning DFS. The minimal occurrence of local recurrence observed in the FOLFOX cohort of our trial substantiates the foundational hypothesis of the study: Contemporary treatments, such as staging magnetic resonance imaging (MRI), oxaliplatin-based chemotherapy, and total mesorectal excision, eliminate the necessity for the widespread use of pelvic radiation[4]. Data regarding the effectiveness of a watch-and-wait approach for organ preservation in patients with LARC undergoing TNT are scarce. Conclusion: Organ preservation is attainable in 50% of patients with rectal cancer undergoing TNT, without a discernible negative impact on survival, in comparison to historical controls receiving CRT, total mesorectal excision, and postoperative chemotherapy. While the order of CRT and systemic chemotherapy did not influence DFS, administering CRT prior to systemic chemotherapy seemed to yield a greater rate of organ preservation than administering CRT subsequent to systemic chemotherapy. The rectum-preserving treatment strategy for LARC seems to be safe for patients exhibiting a complete or near-complete response to TNT, provided they adhere to a rigorous surveillance plan[1]. TNT has been recommended as an improvement over standard long-course CRT (LCCRT) for managing LARC. Concerns have been expressed that the extended delay in surgery linked to TNT, especially in protocols like the Rectal Cancer and Preoperative Induction therapy followed by Dedicated Operation (RAPIDO), may intensify fibrosis, resulting in more complex resections and inferior surgical outcomes. In comparison to LCCRT, TNT-RAPIDO maintains operating time, complication rates, and oncological quality of resection. The findings indicate that TNT can synchronize oncological safety with improved survivorship outcomes, contingent upon the systematic prioritization of stoma reversal. Consequently, the PRODIGE 23 findings may alter clinical practice[2]. Collectively, these data establish the foundation for persistent debates on TNT, specifically the most effective sequencing strategy and the possible compromises associated with increased therapy. These editorial addresses three outstanding controversies: The impact of TNT sequencing on fibrosis and surgical complexity, the potential hazards of overtreatment and long-term toxicity associated with increased chemotherapy, and the identification of patients who genuinely benefit from TNT-based organ preservation regimens. This editorial commentary offers insights on the RAPIDO based TNT findings and the changing dynamics of TNT in LARC. A substantial disagreement persists concerning the ideal timing of chemotherapy within TNT whether to deliver it as induction (before to CRT, e.g., PRODIGE 23, RAPIDO) or as consolidation (subsequent to CRT, e.g., OPRA, CAO/ARO/AIO-12) with current trials investigating this issue. We want to synthesize the therapeutic consequences, current controversies, and new approaches in TNT treatment instead of detailing trial data. This review examines the integration of contemporary research with established multimodal techniques, highlighting the influence of TNT on surgical results, organ preservation, and patient quality of life. Furthermore, we emphasize critical challenges and prospective research pathways to enhance patient selection and treatment sequencing. Microsatellite instability-high cancers exhibit significant responsiveness to immune checkpoint inhibition, suggesting that certain patients might safely forgo TNT or radiotherapy in favor of immunotherapy-first approaches. Post-TNT circulating tumor DNA (ctDNA) provides a dynamic assessment of minimal residual illness and may inform treatment de-escalation in ctDNA-negative patients or intensification in ctDNA-positive patients. Current trials are commencing the incorporation of MSI status, ctDNA dynamics, and improved imaging into risk-adapted TNT algorithms. For TNT to maintain its credibility as a 'new standard', it must transition from a uniform intensification paradigm to a biomarker-informed platform that customizes treatment burden according to individual risk. Surgical outcomes in TNT studies are affected by many significant constraints. The majority of studies were performed in high-volume hospitals with proficient colorectal surgeons, hence constraining the generalizability to lower-resource settings where the quality of TME and pathology evaluations may differ. TNT methods vary significantly among institutions regarding chemotherapy regimens, cycle frequency, and the application of short-course vs long-course radiotherapy, hence hindering standardization. The distinctions between induction and consolidation chemotherapy extend beyond mere logistical sequencing—induction may more effectively target micrometastatic disease at an early stage, while consolidation generally enhances clinical complete response rates, but with ambiguous long-term consequences. Moreover, dependence on surrogate endpoints like pathological response and stoma measurements may lead to an underappreciation of neuropathy, bowel dysfunction, exhaustion, and hematologic toxicity that can manifest months post-treatment. Numerous TNT groups also lack thorough long-term toxicity surveillance, complicating the assessment of the actual cumulative impact of increased therapy. The retrospective analysis conducted by Jabbar et al[5], evaluated early surgical outcomes between individuals with locally advanced rectal cancer treated with TNT-RAPIDO and those treated with standard LCCRT. Even though the TNT group had a much longer time between therapy and surgery, the two methods had similar rates of operational difficulties, complications, lymph node positive, and R0 resection. TNT-RAPIDO was linked to a higher lymph node harvest and better stoma outcomes, such as a shorter stoma duration and a reduced permanent stoma rate. In general, TNT-RAPIDO did not lower the quality of surgery or cancer care, and it may have benefits after surgery compared to LCCRT[5].

CLINICAL AND SOCIOECONOMIC IMPLICATIONS

Preoperative CRT, in contrast to postoperative CRT, enhanced local control and was linked to decreased toxicity. The five-year cumulative incidence of local recurrence was 6% in the preoperative group and 13% in the postoperative group (P = 0.006)[6]. Postponing surgery for 4-8 weeks following short-course radiation led to a reduction in postoperative complications compared to immediate surgery. Short-course radiotherapy followed by delayed surgery demonstrated non-inferiority compared to LCCRT[7]. The preoperative MRI evaluation of the circumferential resection margin forecasted DFS and local recurrence. Furthermore, MRI-predicted circumferential resection margin involvement correlated with markedly poorer 5-year DFS[8].

Together, those clinical implications hold substantial practical importance. Preoperative CRT correlated with a higher rate of sphincter preservation in patients with low-lying tumors. The incidence of acute and chronic toxic effects was reduced in the preoperative therapy group compared to the postoperative therapy group[6]. Short-course radiation, followed by a surgical delay, diminished postoperative complications without adversely affecting oncological results. Moreover, preoperative MRI evaluation of circumferential resection margin status yielded enhanced prognostic insights for local control and DFS relative to traditional staging methods[8]. The MRI-based prognostic findings underscore the necessity of thorough preoperative staging and risk stratification in the selection of patients for TNT compared to more conservative approaches[9]. This editorial contrasts RAPIDO and PRODIGE 23 with developing organ-preservation and biomarker-driven techniques to delineate a pragmatic, risk-stratified strategy to TNT implementation, unlike previous analyses that focus solely on RAPIDO.

TNT must be contextualized within the wider global and socioeconomic framework of colorectal cancer treatment, beyond just trial methods. In 2022, colorectal cancer ranked as the third most frequently diagnosed cancer and the second most common cause of cancer-related mortality globally. Significant geographic and socioeconomic disparities in colorectal cancer incidence and mortality continue to exist between nations and global areas[10]. Financial toxicity was prevalent among partners of colorectal cancer survivors and correlated with diminished health-related quality of life. Furthermore, significant financial strain, indebtedness, and monetary anxiety were correlated with poorer health-related quality of life across various domains[11].

CONCLUSION

TNT is currently most advantageous for high-risk LARC, especially in instances with threatening mesorectal fascia, extramural vascular invasion (EMVI) positive, bulky nodal disease, or unfavorable pelvic anatomy—where early systemic control and optimal downstaging are essential. For standard-risk patients, prolonged CRT with selective application of TNT is suitable, and the indiscriminate substitution of LCCRT with TNT should be eschewed outside adequately resourced multidisciplinary environments. Current evidence endorses TNT as a routine approach for high-risk LARC—specifically threatening mesorectal fascia, EMVI positive tumors, or bulky nodal disease—rather than a universal default for all stage II-III rectal malignancies. Future research targets encompass delineating appropriate sequencing methodologies, standardizing surgical quality measurements, integrating patient-reported outcomes and long-term toxicity evaluations, and systematically assessing biomarker-guided de-escalation. Clinicians implementing TNT must incorporate it into organized routes that include financial counseling, ostomy assistance, and survivorship care, ensuring that intensive therapy results in sustainable, patient-centered advantages rather than increased burdens.