The goal of Specific Aim 1 is to evaluate 3-year RFS in patients managed with INCT or CNCT, CRT and selective NOM, compared with standard historical controls treated with CRT and TME followed by ACT. We hypothesize that 85 % of patients with LARC treated with TNT and selective NOM will be alive and free of disease at 3 years. The 3-year disease-free survival (DFS) for similar patients (stage II/III LARC within 6 cm from the anal verge) treated according to the standard of care (CRT, TME, and ACT) is 75 % . In this trial, each arm is designed as a single-stage study that discriminates between 3-year DFS rates of 75 % (historical control) and 85 % (study groups). Using the approach proposed by Lawless (1982) , for 80 % power, a type I error of 5 %, and a one-sided test, we will require 101 patients per arm, accrued over a 4-year period, with an additional 3 years of follow-up. With a sample size of 101 patients, we will consider the trial worthy of further study if the 3-year DFS rate exceeds .82 (the upper critical value). We anticipate about 10 % loss to follow-up, and will recruit an additional 10 patients per arm to account for this. Patient accrual is expected to take 4 years, with approximately 5 patients accrued per month.
The goal of Specific Aim 2 is to compare outcomes in patients treated on the two arms of this study, with respect to rates of organ preservation, compliance with the neoadjuvant protocol, and adverse events. If both arms meet the endpoint in Specific Aim 1, we plan to use NOM rate to determine the more promising regimen using a “pick the winner” strategy. We will calculate the proportion of patients treated with NOM who are alive and free of disease 3 years following the start of the study. We will require at least 20 NOM patients in each arm to employ the following strategy: If there is a difference of 5 NOM patients between arms, the arm with more NOM patients will be deemed the winner. With 101 patients in each arm, 20 % NOM in patients treated with INCT and 30 % in patients treated with CNCT, we will have an 83 % probability of selecting CNCT, a 1 % probability of selecting INCT, and a 16 % probability of considering the study inconclusive. In addition, we will calculate therapy compliance using the following measures: number of days RT was held, the number of RT delays of ? 1 week, the number of dose delays and number of dose reductions in INCT and CNCT. We will also calculate the rate of grade 3 or higher adverse events and surgical complications in each treatment arm.
The primary endpoint of QoL will be assessed using the EQ-5D index, an overall measure of QoL and health ranging from 0 (worst health) to 1 (best health)parison will be done using the two-sample t-test
In regard to Specific Aim 3, we will measure patient-reported functional outcomes and QoL in patients with LARC treated with NOM, compared to patients treated with TME. In secondary analyses we will use a paired t-test to compare the EQ-5D index, measured at 1 year, in patients with durable NOM vs. TME. The differences in EQ-5D index from 1 year to 3 years will also be compared in patients with durable NOM vs. TME, using an ANCOVA model.
This will be the first study investigating the diagnostic performance of conventional and DW-MRI in LARC patients treated with TNT
The goal of Specific Aim 4 is to investigate the diagnostic performance of conventional MRI and DW-MRI in identifying LARC patients treated with TNT who will benefit from NOM. Therefore, this aim will GetItOn opiniГіn com be considered exploratory.