What is the response percentage following Total Neoadjuvant Therapy (TNT) for rectal cancer?

Response Rates Following Total Neoadjuvant Therapy for Rectal Cancer

Total neoadjuvant therapy (TNT) achieves pathologic complete response (pCR) rates of approximately 22-26% when surgical specimens are examined, with clinical complete response (cCR) or near-complete response rates reaching 71-76% depending on the chemotherapy sequencing strategy. 1

Pathologic Complete Response Rates

The most robust data from the 2024 ASCO guidelines demonstrate that TNT significantly improves pCR rates compared to standard neoadjuvant chemoradiation alone:

• TNT achieves pCR rates of 21.8-22.7% in randomized controlled trials when patients undergo surgery 1
• Standard chemoradiation (CRT) alone achieves pCR rates of only 12.3-13.8% 1
• TNT provides a 74% relative improvement in pCR rates compared to CRT (RR 1.74,95% CI 1.45-2.10) 1

The OPRA trial specifically showed that combined pCR plus sustained clinical complete response rates were:

• 71% in the induction chemotherapy group (chemotherapy before chemoradiation) 1
• 76% in the consolidation chemotherapy group (chemotherapy after chemoradiation) 1

Clinical Complete Response Rates

Clinical complete response rates are substantially lower than the combined response metrics and show important discordance with pathologic findings:

• The STELLAR trial reported cCR rates of only 11.1% with TNT versus 4.4% with CRT alone 1
• The CONVERT trial showed even lower cCR rates of 0.6-1.5% 1
• This discordance highlights the difficulty of detecting complete response preoperatively, as cCR rates are generally much lower than pCR rates in randomized trials 1

Downstaging and Overall Response

Beyond complete response, TNT produces substantial tumor downstaging:

• 50-60% of patients experience tumor downstaging following neoadjuvant therapy 1
• Approximately 18-26% of patients achieve pCR when examining surgical specimens after neoadjuvant CRT 1
• Historical rates with radiation alone were below 10%, which increased to 15-30% with chemoradiation, and now reach 22-26% with TNT 1, 2

Factors Affecting Response Rates

Several tumor and treatment characteristics predict higher response rates:

• Low rectal tumors show improved complete response rates (OR 1.5,95% CI 1.03-2.4, p=0.04) 3
• Absence of extramural vascular invasion (EMVI) predicts better response (OR 2.2,95% CI 1.1-5.6, p=0.01) 3
• Well-differentiated tumors (G1-G2) are more likely to respond than poorly differentiated tumors 4
• T2 tumors achieve higher cCR rates (28%) compared to more advanced stages 1
• Tumors <4 cm in diameter show better response rates (14% cCR) 1

Organ Preservation Outcomes

For patients pursuing nonoperative management after achieving clinical complete response:

• TME-free survival at 3 years was 41-53% depending on chemotherapy sequencing 1
• 2-year local regrowth rate is 15.7% (95% CI 11.6-20.1) with nonoperative management protocols 1
• 95.4% of patients with regrowth successfully receive salvage therapy (95% CI 89.6-99.3) 1

Critical Caveats

Important limitations in interpreting response rates:

• MRI and endoscopy cannot reliably distinguish complete responders preoperatively, with MRI showing only 64% overall accuracy for response assessment 5
• Lymph node metastases persist in a subset of patients even with apparent primary tumor complete response 1
• The definition of complete response matters: pCR plus sustained cCR yields much higher rates (71-76%) than pCR alone (22-26%) 1
• Response rates vary significantly by TNT regimen, with consolidation chemotherapy (after CRT) showing slightly higher combined response rates than induction chemotherapy 1

The overall complete response rate of 37% reported in recent cohorts includes both pathologic complete response after surgery (22.7%) and sustained clinical complete response under watch-and-wait surveillance (77.4% of those selected) 3