SUMMARY: Colorectal cancer (CRC) is the third most common cancer diagnosed in both men and women in the United States. The American Cancer Society estimates that approximately 49,990 new cases of rectal cancer CRC will be diagnosed in the United States in 2026.
The management of Locally Advanced Rectal Cancer (LARC) has historically relied on a multimodality approach centered on neoadjuvant chemoradiotherapy (nCRT), followed by total mesorectal excision and adjuvant chemotherapy. While this paradigm has improved local control, it comes at the cost of treatment-related morbidity, particularly long-term bowel, urinary, and sexual dysfunction. As systemic therapies and surgical techniques have advanced, the necessity of routine radiotherapy, especially in biologically lower-risk disease, has come under increasing scrutiny.
In this context, neoadjuvant chemotherapy (nCT) has emerged as a potential strategy to reduce treatment burden without compromising oncologic outcomes. Total Neoadjuvant Therapy (TNT) has gained traction, supported by trials such as RAPIDO and PRODIGE 23, particularly for patients with high-risk features. However, as outcomes improve and local recurrence rates decline, the routine use of pelvic radiotherapy in all patients is increasingly being questioned, especially in those with more favorable disease biology.
CONVERT is a randomized, open-label, multicenter, Phase III study, designed to address this clinical gap by focusing specifically on patients with LARC and uninvolved mesorectal fascia (MRF), a subgroup with a more favorable risk profile for local recurrence. This study enrolled 663 patients, of whom 589 received protocol-directed therapy. Enrolled patients had LARC within 12 cm from the anal verge. Patients were assigned to receive either Neoadjuvant chemotherapy (nCT) with 4 cycles of CAPOX chemotherapy alone (N=300), or nCRT which was standard CRT with Capecitabine concurrently (N=289). The Primary end point was 3-year LocoRegional Recurrence-Free Survival (LRRFS). Secondary end points included 3-year Disease-Free survival (DFS), 3-year Overall Survival (OS), and Safety.
At a median follow-up of 48 months, both treatment strategies achieved excellent local control.
- 3-year LRRFS: 96.3% (nCT) vs 97.4% (nCRT)
- 3-year DFS: 89.2% vs 87.9%
- 3-year OS: 95.0% vs 94.1%
Although the study did not formally meet its predefined noninferiority margin, this was largely driven by unexpectedly low recurrence rates in both arms, reflecting advances in surgical technique and perioperative care.
Toxicity and Quality of Life: A Key Differentiator
nCT was associated with a significantly lower incidence of long-term grade 2–4 adverse events (16.0% vs 26.3%) and reduced rates of proctitis.
These findings highlight a critical trade-off: while oncologic outcomes appear comparable in selected patients, radiotherapy contributes substantially to long-term morbidity, further supporting a treatment de-escalation strategy in appropriately selected patients.
From a survivorship perspective, avoiding radiation may:
- Reduce chronic bowel dysfunction and low anterior resection syndrome–like symptoms
- Lower the risk of radiation dermatitis and pelvic fibrosis
- Potentially decrease the risk of secondary malignancies
- Preserve fertility and ovarian function in younger patients
Potential candidates for nCT alone:
- MRF-negative tumors
- cT2–T3 disease without extensive nodal burden
- Patients prioritizing quality of life and toxicity reduction
Patients who likely still require radiotherapy:
- MRF-involved disease
- T4b tumors
- High-risk nodal disease
Exploratory findings also suggest caution in:
- Tumors located <5 cm from the anal verge, where local control may be more challenging
Taking a risk-adapted Approach:
- High-risk disease → TNT including radiotherapy
- Intermediate-risk → selective radiotherapy strategies
- Lower-risk (MRF-negative) → potential chemotherapy-alone approaches
Limitations and Future Directions
Several considerations remain:
- Open-label design and modified intention-to-treat population
- Lack of molecular stratification (e.g., mismatch repair status)
- Rapidly evolving standards, including immunotherapy for dMMR disease
Future studies will need to integrate molecular profiling, imaging, and patient preferences to refine treatment selection further.
Clinical Takeaways
- nCT with CAPOX achieved comparable DFS and OS to nCRT in MRF-negative LARC
- Noninferiority was not formally met, but outcomes were influenced by very low recurrence rates
- Significantly reduced long-term toxicity supports a de-escalation approach
- Findings are consistent with NCCN and ASCO guidance supporting selective omission of radiotherapy in carefully chosen patients
Conclusion: Toward a More Individualized Treatment Paradigm
The CONVERT trial adds important prospective evidence supporting the selective omission of radiotherapy in LARC. While not practice-changing in isolation, it strengthens a growing movement toward precision-based, risk-adapted care, balancing oncologic efficacy with long-term quality of life. As guidelines continue to evolve, the challenge will be to identify the right patient for the right treatment intensity, ensuring optimal outcomes without unnecessary toxicity.
Neoadjuvant Chemotherapy With CAPOX Versus Chemoradiation for Locally Advanced Rectal Cancer With Uninvolved Mesorectal Fascia (CONVERT): Final Results of a Phase III Trial. Mei W-J, Wang X-Z, Zhang X, et al. J Clin Oncol. 2026;44: 970-980.
