The Organ Preservation in Patients with Rectal Adenocarcinoma (OPRA) trial demonstrated that the watch-and-wait strategy is safe for patients with stage 2 and stage 3 rectal cancers that achieve a clinical complete response (CCR) or near-complete clinical response (NCR) to total neoadjuvant therapy (TNT). (1)
A new analysis of OPRA trial data, published recently in JAMA Network Open, has reported outcome probabilities stratified by clinical tumor response. The three-year probability of rectum preservation was 77% for patients with CCR and 40% for patients with NCR. Clinical tumor response grade was associated with all survival outcomes, including disease-free survival (DFS), local recurrence-free survival, distant metastasis-free survival, and overall survival. (2)
“Most OPRA trial participants with a CCR and a significant proportion of those with an NCR avoided surgical removal and had good survival outcomes,” said colorectal surgeon Julio Garcia-Aguilar, MD, PhD, Chief of the Colorectal Service and the Benno C. Schmidt Chair in Surgical Oncology at MSK and senior author of the analysis. “Our three-tier grading schema will be useful for counseling patients on their optimal treatment plan, based on how their tumors respond to neoadjuvant therapy.”
The Dilemma: Watch-and-Wait or Total Mesorectal Excision?
The watch-and-wait strategy is predicated on the assumption that no viable cancer cells remain in the bowel wall or regional lymph nodes of patients who achieve a CCR after TNT. However, a CCR does not always represent complete tumor elimination, as some patients develop tumor regrowth during surveillance. While most regrowth cases are salvageable with total mesorectal excision (TME), concerns remain about the potential for tumor spread. (3) (4) (5) (6)
Clinical response is assessed at a fixed interval after TNT using digital rectal examination, endoscopy, and magnetic resonance imaging (MRI). However, the time it takes to achieve a CCR can vary, with some evidence suggesting delayed assessment after TNT increases response rates. (7) (8) (9) Further, assessing responses too early and applying strict response criteria may deprive patients with an NCR of the benefits of organ preservation. (10) (11) (12) (13)
The OPRA Trial
Dr. Garcia-Aguilar was the principal investigator of the OPRA trial (NCT02008656), a multicenter phase 2 randomized study in which patients with stage 2 or stage 3 rectal cancer received total neoadjuvant therapy. Patients were randomized to induction chemotherapy followed by chemoradiation or chemoradiation followed by consolidation chemotherapy.
To maximize patient eligibility for organ preservation, Dr. Garcia-Aguilar and colleagues devised a three-tier grading schema for stratifying clinical tumor response after TNT: CCR, NCR, and incomplete clinical response (ICR) as follows:
Three-Tier Schema for Grading Rectal Tumor Response to Neoadjuvant Therapy (2)
| CCR | NCR | ICR | |
|---|---|---|---|
| Endoscopy | Flat white scar | Irregular mucosa | Visible tumor |
| Telangiectasia | Small nodules | ||
| No ulceration or nodularity | Minor mucosal abnormality | ||
| Superficial ulceration | |||
| Mild persisting erythema | |||
| DRE | Normal | Smooth induration | Palpable tumor nodule |
| Minor mucosal abnormality |
Terms: clinical complete response (CCR), near-complete clinical response (NCR), incomplete clinical response (ICR), digital rectal examination (DRE).
The investigators assessed tumor response at eight weeks (± four weeks) after TNT by digital rectal examination and flexible endoscopy and classified the responses. MRI was also performed at restaging before or after flexible sigmoidoscopy. TME was recommended to all patients with an ICR grade after TNT. (2)
Patients who pursued a watch-and-wait strategy were followed at frequent intervals with digital rectal examination, flexible sigmoidoscopy, MRI, carcinoembryonic antigen testing, and CT imaging as previously described. (15) The median follow-up for patients who pursued organ preservation was four years. (1)
Over the entire cohort of 324 patients, organ preservation was achievable in half of the patients with rectal cancer treated with TNT, with no detriment to survival compared with historical controls treated with standard chemoradiotherapy, TME, and postoperative chemotherapy. (1)
Organ Preservation and Survival Outcomes by Clinical Response to Neoadjuvant Therapy
The secondary analysis assessed organ preservation and survival outcomes by clinical response grade.
Among 304 evaluable patients, 125 had a CCR, 114 had an NCR, and 65 had an ICR. Age, sex, tumor distance from the anal verge, pathological tumor classification, and clinical nodal classification were similar among tumor response grades. (2)
The three-year organ preservation rates were: (2)
- 47% for the entire cohort,
- 77% for the CCR group, and
- 40% for the NCR group (p < 0.001).
The risk of local regrowth at two years was: (2)
- 20% for the CCR group, and
- 49% for the NCR group.
Disease-free survival rates at three years were: (2)
- 74% for the entire cohort,
- 88% for the CCR group,
- 69% for the NCR group, and
- 56% for the ICR group.
Advancing Outcomes for Patients with Rectal Cancer
Dr. Garcia-Aguilar and colleagues noted in the paper that clinical response grades in the OPRA trial were based on surgeons’ assessments of endoscopic and digital rectal examinations at restaging. As the study protocol recommended prioritizing endoscopic assessment over MRI, the researchers did not evaluate the contribution of MRI. (2)
“While these results are instructive for patient counseling, further work is required to improve diagnostic accuracy. Combining endoscopic imaging and MRI and exploring new tools, such as artificial intelligence and narrow band imaging, may improve the optimal identification of patients most likely to achieve organ preservation,” said Dr. Garcia-Aguilar. “Many thanks to the hundreds of patients, investigators, and support staff across 12 institutions who made the OPRA trial possible.”
Learn more about MSK clinical trials for patients with rectal cancer. Read more about how MSK advances are helping more patients with rectal cancer avoid surgery.
The study was funded in part by National Cancer Institute grants RO1CA182551, P30CA008748, and T32CA009501. Access disclosures for Dr. Garcia-Aguilar.