Among patients with stage II or stage III rectal adenocarcinoma, organ preservation is achievable in up to half of patients who undergo total neoadjuvant chemotherapy (TNT), according to the results from a new randomized phase 2 trial.
The study included 324 patients from 18 centers who were randomized into one of two groups: induction chemotherapy followed by chemoradiotherapy (INCT-CRT) or chemoradiotherapy followed by consolidation chemotherapy (CRT-CNCT). Patients in both groups then underwent either total mesorectal excision (TME) or a watch-and-wait strategy, depending on tumor response.
“What the study shows is that the order of the chemo and the radiation dose doesn’t affect survival, but it seems to affect the probability of preserving the rectum. That data is consistent with other studies that have compared head-to-head chemotherapy followed by radiation versus radiation followed by chemotherapy. In addition, the survival rate for this study is no different from other prospective studies that included patients with similar-stage tumors selected by MRI. So the data suggest that you can probably avoid surgery in half of the patients with locally advanced rectal cancer and still achieve similar survival compared to patients treated with more conventional neoadjuvant treatments and mandatory surgery,” said lead author Julio Garcia-Aguilar, MD, PhD, in an interview.
“It is a significant shift in the treatment paradigm, that can potentially benefit half of the 50,000 rectal cancer patients diagnosed every year in the United States,” said Dr. Garcia-Aguilar, chief of colorectal surgery at Memorial Sloan Kettering Cancer Center, New York.
The study was published online in the Journal of Clinical Oncology.
Neoadjuvant CRT, TME, and adjuvant chemotherapy is an effective treatment strategy for locally advanced rectal adenocarcinoma, but the regimen can cause bowel, urinary, and sexual dysfunction. The majority of adverse effects from the therapy can be traced to surgery. In addition, some patients with distal rectal cancer often require a permanent colostomy.
TNT is a newer approach that delivers chemotherapy plus radiotherapy before surgery. It is designed to improve treatment compliance and eradicate micrometastases in advance of surgery.
After a median follow-up of 3 years, disease-free survival (76% in both groups) was similar to historical controls (75%). Both groups had similar rates of local recurrence-free survival (94% each) and distant metastasis–free survival (84% for INCT-CRT and 82% for CRT-CNCT).
Following TNT, 26% of patients were recommended for TME, including 28% in the INCT-CRT group and 24% in the CRT-CNCT group, and the rest offered watchful-waiting. Forty percent of those in the INCT-CRT group and 27% in the CRT-CNCT group who went on to watchful waiting had tumor regrowth. Of these combined 75 patients, 67 underwent successful salvage surgery.
In the intention-to-treat analysis, 53% of patients had a preserved rectum at 3 years (95% confidence interval, 45%-62%) in the CRT-CNCT group versus 41% in the INCT-CRT group (95% CI, 33%-50%; P = .01).
The new results reinforce other results and should contribute to shifting clinical practice, according to Dr. Garcia-Aguilar. “I think what we have learned is that rectal cancers respond to chemotherapy and radiation at a higher rate that we thought previously, but that the response takes time. That’s something that we use currently in an adaptive way to modify the treatment as we observe the tumor response,” he said.
The slow regrowth means that patients can be closely monitored without undue risk, but such an approach demands buy-in from the patient. “The patient needs to be compliant with a close surveillance protocol, because otherwise it can be a disaster. I think that’s really part of the message,” Dr. Garcia-Aguilar said.
Dr. Garcia-Aguilar has an ownership interest in Intuitive Surgical and has advised or consulted for Medtronic, Intuitive Surgical, and Johnson & Johnson.