The ongoing debate in oncological treatment regarding the optimal approach for locally advanced rectal cancer (LARC) has taken a significant turn following a comprehensive study comparing neoadjuvant chemoradiotherapy (nCRT) and neoadjuvant chemotherapy (nCT) alone. For years, the role of radiotherapy in neoadjuvant protocols has been questioned due to concerns about radiation-induced toxicity, despite radiotherapy’s established efficacy in tumor control. This retrospective analysis provides critical insights into patient stratification and clinical decision-making that could revolutionize treatment paradigms in LARC.
Neoadjuvant therapy aims to reduce tumor burden before surgery, improving the prospects for curative resection and long-term survival. The primary modalities under scrutiny are chemoradiotherapy, which combines radiation with concurrent chemotherapy, and chemotherapy alone. While chemoradiotherapy has historically been preferred to optimize tumor downstaging and pathologic complete response (pCR), chemotherapeutic strategies without radiation are gaining traction as they potentially minimize adverse effects without compromising efficacy.
This study systematically collected data from 380 patients diagnosed with rectal cancer located within 10 cm of the anal verge, all with clinical staging indicative of either T2N+M0 or T3-4NanyM0 disease. The patients were divided into two cohorts: one treated with nCRT consisting of radiotherapy doses ranging from 45.0 to 50.4 Gy across 25 to 28 fractions, combined with concurrent oral Capecitabine; and the other receiving nCT consisting solely of chemotherapy without radiation.
Remarkably, the findings revealed a pronounced disparity in pathologic complete response rates favoring the nCRT group, with 22.4% of these patients achieving pCR compared to only 9.2% in the nCT cohort. Tumor downstaging, a critical indicator of treatment success, was also significantly higher in the nCRT arm at 69.4% versus 47.8%. Furthermore, the tumor regression grade (TRG) 1–2, indicative of substantial tumor cell eradication, was observed in 59.7% of patients undergoing chemoradiotherapy, starkly contrasting with 24.5% for those receiving chemotherapy alone.
A deeper analysis stratified patients into distinct risk categories and tumor location subgroups, unveiling nuanced differences in treatment outcomes. Notably, patients categorized as bad-risk or advanced-risk tumors, along with those whose tumors were situated less than 8 cm from the anal verge (subgroup A), demonstrated superior responses to nCRT. Conversely, for tumors positioned 8 cm or greater from the anal verge (subgroup B), the therapeutic outcomes between nCRT and nCT groups were comparable, suggesting that radiation’s added benefit might be limited in more proximally located tumors.
Beyond pathological response, survival metrics offer pivotal perspectives on long-term benefits. In the bad-risk subgroup, nCRT yielded a significantly improved three-year locoregional relapse-free survival (LRFS) rate of 98.1%, markedly surpassing the 88.0% observed in the nCT group. However, disease-free survival (DFS) and overall survival (OS) rates between the two cohorts did not differ significantly, indicating that while local control benefitted from radiotherapy, systemic disease control might require additional considerations.
Despite these promising oncological outcomes, nCRT was associated with an increased incidence of several adverse events. The study reports substantially higher rates of grade 1–2 myelosuppression and diarrhea within the chemoradiotherapy group compared to chemotherapy alone. Moreover, there was a notable increase in preventive stoma formation, postoperative bowel obstruction, and anastomotic stenosis, complications that can adversely affect patient quality of life and surgical recovery.
The therapeutic dilemma thus centers on balancing efficacy and toxicity. This research importantly proposes tumor location and risk categorization as pragmatic clinical indices to tailor neoadjuvant strategies. Specifically, patients exhibiting bad-risk features or tumors located closer to the anal verge may derive pronounced benefits from the inclusion of radiotherapy, while those with higher tumor positioning could potentially avoid radiation-associated toxicities without compromising treatment success.
Mechanistically, radiation enhances local tumor control through DNA damage and microenvironmental modulation, facilitating more effective downstaging. However, the collateral damage to surrounding healthy tissues underscores the importance of selective application. Chemotherapy alone, while systemic and less morbid in localized adverse effects, might fall short in achieving optimal locoregional control in specific high-risk contexts identified by this study.
These findings carry substantial implications for personalized medicine in colorectal oncology. Clinicians may now leverage tumor anatomical landmarks and risk stratification to optimize neoadjuvant therapy selection, thereby maximizing clinical benefits while minimizing unnecessary treatment-related morbidity.
Future prospective clinical trials with larger cohorts and longer follow-up periods will be instrumental in validating these retrospective observations. Additionally, molecular and genomic profiling might further refine patient selection, integrating biological characteristics with anatomical and clinical risk factors.
The research advances the clinical discourse by pinpointing a subset of LARC patients poised to benefit most from intensified local therapy, offering hope for improved outcomes through strategic treatment customization. Integrating such data into evidence-based guidelines could enhance multidisciplinary cancer care, ensuring radiation is judiciously employed where its benefits unequivocally outweigh risks.
This evolving understanding underscores the critical need for continued innovation in neoadjuvant therapies, harnessing novel agents and radiotherapy techniques to amplify efficacy while mitigating toxicities. Advanced radiotherapy modalities such as intensity-modulated radiation therapy (IMRT) and proton therapy may further optimize the therapeutic ratio in future applications.
In summary, this landmark study delivers robust evidence endorsing a nuanced approach to neoadjuvant treatment selection in locally advanced rectal cancer. By advocating tumor location and risk stratification as decision-making anchors, it heralds a more precise, patient-centric therapeutic paradigm. Such progress embodies the broader oncology field’s shift towards individualized interventions aimed at maximizing clinical outcomes and patient quality of life.
As these insights permeate oncological practice, they will shape future consensus recommendations and inform patient discussions about treatment options and expected trajectories. Ultimately, the ability to precisely tailor neoadjuvant therapy promises to improve survival metrics while sparing patients from undue treatment-related hardship.
Subject of Research: Comparison of efficacy and safety between neoadjuvant chemoradiotherapy and chemotherapy alone for locally advanced rectal cancer.
Article Title: Efficacy and safety of neoadjuvant chemoradiotherapy versus chemotherapy alone in locally advanced rectal cancer.
Article References: Zhang, C., Zhang, F., Hong, H. et al. Efficacy and safety of neoadjuvant chemoradiotherapy versus chemotherapy alone in locally advanced rectal cancer. BMC Cancer 25, 1749 (2025). https://doi.org/10.1186/s12885-025-14616-9
Image Credits: Scienmag.com
DOI: 11 November 2025
Keywords: Locally advanced rectal cancer, neoadjuvant chemoradiotherapy, neoadjuvant chemotherapy, pathologic complete response, tumor regression grade, locoregional relapse-free survival, toxicity, tumor location, risk stratification
