In a phase II trial reported in the Journal of Clinical Oncology, Garcia-Aguilar et al found that total neoadjuvant therapy followed by a watch-and-wait strategy vs total mesorectal excision based on response allowed for organ preservation in approximately half of patients with rectal adenocarcinoma.
Study Details
The U.S. multicenter trial included 324 eligible patients with stage II or III disease. They were randomly assigned between April 2014 and March 2020 to receive either induction chemotherapy followed by chemoradiotherapy (INCT-CRT; n = 158) or chemoradiotherapy followed by consolidation chemotherapy (CRT-CNCT; n = 166) and either total mesorectal excision or watch-and-wait on the basis of tumor response. Patients in both groups received 4 months of infusional fluorouracil, leucovorin, and oxaliplatin or capecitabine/oxaliplatin and 5,000 to 5,600 cGy of radiation combined with either continuous-infusion fluorouracil or capecitabine during radiotherapy.
Patients with a clinical complete response or near-complete response were offered participation in a standardized watch-and-wait protocol consisting of digital rectal examination and flexible sigmoidoscopy every 4 months for the first 2 years from time of assessment of response and every 6 months for the following 3 years. Rectal magnetic resonance imaging was to be performed every 6 months for the first 2 years and annually for the following 3 years.
The trial was designed as two stand-alone studies with disease-free survival as the primary endpoint for both groups. Comparison was made with historical data indicating 75% 3-year disease-free survival among similar patients treated with a standard approach of chemoradiation followed by total mesorectal excision and adjuvant chemotherapy.
Key Findings
Median follow-up for patients who were alive and event-free at the time of analysis was 3 years (interquartile range = 1.84–4.06 years).
Among 304 patients restaged at the end of total neoadjuvant therapy, 28% in the INCT-CRT group and 24% in the CRT-CNCT group had total mesorectal excision recommended; 71% and 76% were offered watch-and-wait. Among 225 patients who entered the watch-and-wait protocol, 40% in the INCT-CRT group and 27% in the CRT-CNCT group developed tumor regrowth during follow-up. All patients diagnosed with tumor regrowth were recommended for total mesorectal excision.
For the intention-to-treat organ preservation analysis, patients who had local excision, refused total mesorectal excision, or had total mesorectal excision withheld because of distant progression were all censored as having total mesorectal excision. On this basis, total mesorectal excision–free survival at 3 years was 41% (95% confidence interval [CI] = 33%–50%) in the INCT-CRT group and 53% (95% CI = 45%–62%) in the CRT-CNCT group. The proportions of patients who actually had their rectums preserved were 47% (95% CI = 39%–56%) and 60% (95% CI = 52%–68%).
Disease-free survival at 3 years was 76% (95% CI = 69%–84%) in the INCT-CRT group and 76% (95% CI = 69%–83%) in the CRT-CNCT group (P = .98), consistent with the historical 3-year disease-free survival rate of 75% observed with standard chemoradiation followed by total mesorectal excision and adjuvant chemotherapy.
No differences were found between the INCT-CRT group and the CRT-CNCT group in 3-year local recurrence–free survival (94%, 95% CI = 89%–99%, vs 94%, 95% CI = 90%–98%; P = .78), distant metastasis–free survival (84%, 95% CI = 77%–91%, vs 82%, 95% CI = 75%–89%; P = .67), or overall survival (15 vs 12 deaths, P = .39).
Patients who underwent total mesorectal excision after restaging (total of 17 disease-free survival events) and patients who underwent total mesorectal excision after regrowth (total of 16 events) had similar disease-free survival rates (P = .50).
The investigators concluded, “Organ preservation is achievable in half of the patients with rectal cancer treated with total neoadjuvant therapy, without an apparent detriment in survival, compared with historical controls treated with chemoradiotherapy, total mesorectal excision, and postoperative chemotherapy.”
Julio Garcia-Aguilar, MD, PhD, of the Colorectal Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, is the corresponding author for the Journal of Clinical Oncology article.
Disclosure: The study was supported by grants from the National Cancer Institute. For full disclosures of the study authors, visit ascopubs.org.
