Oncology · Medical Literature
Prioritizing Chemotherapy in Total Neoadjuvant Therapy Improves pCR Rate in Locally Advanced Rectal Cancer in Countries with Limited Radiotherapy Access: A Randomized Controlled Trial.
Abstract
Neoadjuvant chemoradiotherapy (NCRT) for locally advanced rectal cancer (LARC) is frequently delayed in resource-limited settings due to restricted access to radiotherapy. Total neoadjuvant therapy (TNT), which starts with chemotherapy, may offer a practical alternative. This randomized trial compared TNT with the conventional NCRT‑first approach. 202 patients with LARC were randomized to receive either TNT (neoadjuvant chemotherapy followed by NCRT, then surgery) or conventional treatment (NCRT followed by adjuvant chemotherapy and surgery). The primary endpoint was pathological complete response (pCR); treatment-related toxicity and overall survival (OS) were predefined secondary outcomes. A total of 202 patients with LARC (101 per arm) were enrolled and analyzed. The TNT group achieved a significantly higher pCR rate than the conventional group (55.4% vs. 42.57%, p = 0.023). Sphincter preservation, resection margins, and surgical complications were similar between groups. Among treatment-related toxicities, thrombocytopenia was less frequent in the TNT group (5.0% vs. 12.87%, p = 0.048), whereas dysuria was more common (15.8% vs. 5.94%, p = 0.024); other adverse events were comparable. OS remained an exploratory secondary endpoint and did not differ significantly between groups at the time of analysis (p = 0.109). TNT may represent a feasible and well-tolerated treatment strategy, particularly in settings where access to radiotherapy is delayed. The improvement in pCR supports its potential oncologic value; however, survival outcomes remain immature and require confirmation in larger studies with longer follow-up.
Clinical relevance
This RCT addresses a critical gap in the management of locally advanced rectal cancer (LARC) in resource-limited settings, where delayed access to radiotherapy frequently compromises the standard neoadjuvant chemoradiotherapy (NCRT) sequence. By evaluating a chemotherapy-first total neoadjuvant therapy (TNT) strategy, it offers a pragmatic, sequencing-based solution applicable to a large global patient population that cannot reliably access timely radiotherapy. Clinicians practicing in or advising low- and middle-income healthcare systems should be aware of this evidence when designing neoadjuvant pathways for LARC.
Key findings
1. TNT (neoadjuvant chemotherapy → NCRT → surgery) achieved a statistically significantly higher pathological complete response (pCR) rate compared to conventional NCRT-first treatment (55.4% vs. 42.57%; p = 0.023), representing an absolute difference of approximately 12.8 percentage points. 2. Sphincter preservation rates, resection margin status (R0 rates), and surgical complication profiles were similar between the TNT and conventional arms, suggesting no compromise in surgical outcomes with the TNT sequence. 3. Thrombocytopenia was significantly less frequent in the TNT group compared to the conventional group (5.0% vs. 12.87%; p = 0.048), indicating a potentially more favorable hematologic toxicity profile. 4. Dysuria was significantly more common in the TNT group than in the conventional group (15.8% vs. 5.94%; p = 0.024), a clinician-relevant genitourinary adverse event requiring patient counseling and monitoring. 5. All other treatment-related adverse events were comparable between the two arms, supporting the overall tolerability of the TNT sequence. 6. Overall survival (OS) did not differ significantly between groups at the time of analysis (p = 0.109); however, OS was designated an exploratory secondary endpoint and survival data are immature, precluding definitive conclusions on long-term oncologic equivalence or superiority.
Practice implications
In LARC patients facing delayed radiotherapy access — particularly in resource-limited or high-demand healthcare settings — clinicians should consider initiating treatment with systemic chemotherapy first (TNT sequence) rather than deferring all therapy pending radiotherapy availability, as this approach significantly improves pCR rates without worsening surgical outcomes or overall toxicity burden. Patient selection should include those with confirmed LARC who are candidates for both neoadjuvant chemotherapy and subsequent NCRT, with proactive counseling regarding the increased risk of dysuria and close monitoring for genitourinary symptoms throughout the TNT course. Adoption of this strategy into institutional protocols should be considered provisional pending maturation of survival data from this and larger confirmatory trials, as pCR improvement has not yet translated into a demonstrated OS benefit in this dataset.