Neoadjuvant Chemotherapy, Excision, and Observation for Early Rectal Cancer: The Phase II NEO Trial (CCTG CO.28) Primary End Point Results

Author(s): Hagen F. Kennecke, MD, MHA¹;Chris J. O’Callaghan, PhD, DVM, MSc²;Jonathan M. Loree, MD, MS³;Hussein Moloo, MD, MPH⁴;Rebecca Auer, MD, MSc⁴;Derek J. Jonker, MD⁴;Manoj Raval, MD, MSc⁵;Reilly Musselman, MD⁴;Grace Ma, MD⁶;Antonio Caycedo-Marulanda, MD⁶;Vlad V. Simianu, MD⁷;Sunil Patel, MD²;Lacey D. Pitre, MD⁸;Ramzi Helewa, MD, MSc⁹;Vallerie L. Gordon, MD¹⁰;Katerina Neumann, MSc, PhD, MD¹¹;Halla Nimeiri, MD¹²;Max Sherry, MSc, MBA²;Dongsheng Tu, PhD²;and Carl J. Brown, MD, MSc⁵

Source: DOI: 10.1200/JCO.22.00184 Journal of Clinical Oncology 41, no. 2 (January 10, 2023) 233-242.

Dr. Anjan Patel's Thoughts

Nice study showing a non-radiation approach to node-negative, earlier stage, low-lying rectal cancer, using FOLFOX/CAPEOX x 3 months followed by local excision for those with downstaging to T0/T1 disease. 79% of patients achieved organ preservation, and 2-year locoregional RFS was 90%. A good option for those who are not good candidates for radiation yet still want to avoid an APR-type surgery.

PURPOSE

Organ-sparing therapy for early-stage I/IIA rectal cancer is intended to avoid functional disturbances or a permanent ostomy associated with total mesorectal excision (TME). The objective of this phase II trial was to determine the outcomes and organ-sparing rate of patients with early-stage rectal cancer treated with neoadjuvant chemotherapy followed by transanal excision surgery (TES).

METHODS

This phase II trial included patients with clinical T1-T3abN0 low- or mid-rectal adenocarcinoma eligible for endoscopic resection who were treated with 3 months of chemotherapy (modified folinic acid–fluorouracil-oxaliplatin 6 or capecitabine-oxaliplatin). Those with evidence of response proceeded to transanal endoscopic surgery 2-6 weeks later. The primary end point was protocol-specified organ preservation rate, defined as the proportion of patients with tumor downstaging to ypT0/T1N0/X and who avoided radical surgery.

RESULTS

Of 58 patients enrolled, all commenced chemotherapy and 56 proceeded to surgery. A total of 33/58 patients had tumor downstaging to ypT0/1N0/X on the surgery specimen, resulting in an intention-to-treat protocol-specified organ preservation rate of 57% (90% CI, 45 to 68). Of 23 remaining patients recommended for TME surgery on the basis of protocol requirements, 13 declined and elected to proceed directly to observation resulting in 79% (90% CI, 69 to 88) achieving organ preservation. The remaining 10/23 patients proceeded to recommended TME of whom seven had no histopathologic residual disease. The 1-year and 2-year locoregional relapse-free survival was, respectively, 98% (95% CI, 86 to 100) and 90% (95% CI, 58 to 98), and there were no distant recurrences or deaths. Minimal change in quality of life and rectal function scores was observed.

CONCLUSION

Three months of induction chemotherapy may successfully downstage a significant proportion of patients with early-stage rectal cancer, allowing well-tolerated organ-preserving surgery.

Author Affiliations

¹Providence Cancer Institute and Earle A Chiles Research Institute, Portland, OR;²Canadian Cancer Trials Group, Queen’s University, Kingston, ON, Canada;³BC Cancer, Vancouver, BC, Canada;⁴The Ottawa Hospital Research Institute, Ottawa, ON, Canada;⁵Providence-St. Paul’s Hospital, Vancouver, BC, Canada;⁶Health Sciences North, Sudbury, ON, Canada;⁷Virginia Mason Cancer Institute, Seattle, WA;⁸Juravinski Cancer Center, Hamilton, ON, Canada;⁹University of Manitoba, Winnipeg, MB, Canada;¹⁰CancerCare Manitoba, Winnipeg, MB, Canada;¹¹Nova Scotia Health, Halifax, NS, Canada;¹²Foundation Medicine, Cambridge, MA

Long-Term Results of Organ Preservation in Patients With Rectal Adenocarcinoma Treated With Total Neoadjuvant Therapy: The Randomized Phase II OPRA Trial

There is hope for organ preservation in rectal preservation. I believe the good news is that waiting is not as harmful. Those who underwent surgery after regrowth almost had the same disease-free survival (DFS) as those who had surgery after treatment because of incomplete response. The use of CtDNA (not analyzed in the trial) may play an even a bigger role where you may not have to wait for clinical regrowth to have the surgery, but of course more trials are needed to see if this will have clinical benefit. (Is the positive or rising CtDNA enough reason to have surgery vs imaging recurrence?)
Still, this is an exciting new era that will see change in treating early-stage colorectal cancer, recall the immunotherapy results in patients who were MMR deficient.

Prospective Correlation of Magnetic Resonance Tumor Regression Grade With Pathologic Outcomes in Total Neoadjuvant Therapy for Rectal Adenocarcinoma

Tumor regression grade defined as the ratio between fibrosis and residual tumor, is routinely used to assess response to therapy and demonstrated to be an important predictor of patient’s outcome. In the era of TNT (total Neoadjuvant Therapy) this will help assess response to avoid surgery. It will be nice to add MRD testing in the blood as another tool.

Preoperative Treatment of Locally Advanced Rectal Cancer

Paradigm shift in rectal cancer therapy? Some may not need surgery, now some may not need radiotherapy.

PD-1 Blockade in Mismatch Repair–Deficient, Locally Advanced Rectal Cancer

Very impressive results that may change treatment-paradigm. However, number of patients treated, and duration of follow-up are significant issues here for early adoption.