Top Line: It’s that time of year again. Let’s jump into important results from ASCO 2023.
The Study: PROSPECT was a large phase 3 that compared neoadjuvant chemoradiation and neoadjuvant FOLFOX chemotherapy with selective use of chemoradiation in 1128 patients with locally advanced rectal cancer. Eligible patients had T2, node positive disease or T3 disease regardless of node positivity. They also had to be eligible for sphincter sparing surgery. Low-lying tumors, T4 tumors, those with ≥4 nodes >1cm, and tumors within 3 mm of the radial margin were ineligible. In other words, PROSPECT specifically excluded patients at high risk of locoregional recurrence as pelvic radiation is most beneficial in these patients. The median tumor distance from the anal verge was 8 cm, >20% were >10 cm from the anal verge, and roughly 15% were within 5cm of the anal verge. A numerically higher proportion of patients in the CRT arm had T3N+ disease (57% v 50%). In the CRT arm, patients received 50.4 Gy in 28 fractions with concurrent 5-FU or capecitabine. In the FOLFOX arm, patients received 6 cycles of FOLFOX, and if the primary tumor decreased by <20%, they were treated with additional neoadjuvant CRT, which was required for 9% of the FOLFOX patients. Surgical outcomes were similar with an R0 resection rate of 91.2% for CRT and 90.4% for FOLFOX and a pathologic complete response rate of 24.3% for CRT and 21.9% for FOLFOX. The primary endpoint of 5-year DFS was non-inferior for FOLFOX compared to CRT (80.8% v 78.6%). There was no difference in 5-year OS (89.5% v 90.2%). The rate of local recurrence at 5 years was <2% in each group. Neoadjuvant FOLFOX had almost twice the rate of grade 3 or higher adverse events (41% v 22.8%). In other words, FOLFOX achieved non-inferior outcomes at the cost of increased toxicity. Finally, how do the results of PROSPECT fit into evolving paradigms like total neoadjuvant therapy and non-operative management? Because FOLFOX wasn’t better than CRT in PROSPECT, one could presume TNT might be superior to FOLFOX as was the case with CRT. PROSPECT provides options for the subset of patients with low risk features of locoregional recurrence who aren’t receiving TNT.
TBL: In the PROSPECT trial, neoadjuvant FOLFOX resulted in similar survival and disease control outcomes with worse grade 3+ toxicity compared to chemoradiation for select rectal cancer patients without low-lying tumors and without high risk features. | Schrag, N Engl J Med 2023
The Study: PROSPECT was a large phase 3 that compared neoadjuvant chemoradiation and neoadjuvant FOLFOX chemotherapy with selective use of chemoradiation in 1128 patients with locally advanced rectal cancer. Eligible patients had T2, node positive disease or T3 disease regardless of node positivity. They also had to be eligible for sphincter sparing surgery. Low-lying tumors, T4 tumors, those with ≥4 nodes >1cm, and tumors within 3 mm of the radial margin were ineligible. In other words, PROSPECT specifically excluded patients at high risk of locoregional recurrence as pelvic radiation is most beneficial in these patients. The median tumor distance from the anal verge was 8 cm, >20% were >10 cm from the anal verge, and roughly 15% were within 5cm of the anal verge. A numerically higher proportion of patients in the CRT arm had T3N+ disease (57% v 50%). In the CRT arm, patients received 50.4 Gy in 28 fractions with concurrent 5-FU or capecitabine. In the FOLFOX arm, patients received 6 cycles of FOLFOX, and if the primary tumor decreased by <20%, they were treated with additional neoadjuvant CRT, which was required for 9% of the FOLFOX patients. Surgical outcomes were similar with an R0 resection rate of 91.2% for CRT and 90.4% for FOLFOX and a pathologic complete response rate of 24.3% for CRT and 21.9% for FOLFOX. The primary endpoint of 5-year DFS was non-inferior for FOLFOX compared to CRT (80.8% v 78.6%). There was no difference in 5-year OS (89.5% v 90.2%). The rate of local recurrence at 5 years was <2% in each group. Neoadjuvant FOLFOX had almost twice the rate of grade 3 or higher adverse events (41% v 22.8%). In other words, FOLFOX achieved non-inferior outcomes at the cost of increased toxicity. Finally, how do the results of PROSPECT fit into evolving paradigms like total neoadjuvant therapy and non-operative management? Because FOLFOX wasn’t better than CRT in PROSPECT, one could presume TNT might be superior to FOLFOX as was the case with CRT. PROSPECT provides options for the subset of patients with low risk features of locoregional recurrence who aren’t receiving TNT.
TBL: In the PROSPECT trial, neoadjuvant FOLFOX resulted in similar survival and disease control outcomes with worse grade 3+ toxicity compared to chemoradiation for select rectal cancer patients without low-lying tumors and without high risk features. | Schrag, N Engl J Med 2023