Intentional Watch and Wait or Organ Preservation Surgery Following Neoadjuvant Chemoradiotherapy Plus Consolidation CAPEOX for MRI-defined Low-risk Rectal Cancer: Findings From a Prospective Phase 2 Trial (PKUCH-R01 Trial, NCT02860234)

Abstract

Objective: To assess the efficacy and safety of intentional watch and wait (W&W) and organ preservation surgery following neoadjuvant chemoradiotherapy plus consolidation CAPEOX in magnetic resonance imaging (MRI)-defined low-risk rectal cancer.

Background: Clinical T2/early T3 rectal cancers can achieve high yield pathological complete response (ypCR) rates after chemoradiotherapy; thus, an intentional W&W or organ preservation strategy for good clinical responders in these subgroups can be further tested.

Methods: This prospective, single-arm, phase 2 trial enrolled patients with low-risk MRI prestaged rectal cancers, who concurrently received chemoradiation, followed by four 3-weekly cycles of CAPEOX regimen. Following reassessment, clinical complete response (cCR) or near-cCR patients underwent W&W/organ preservation surgery; the primary endpoint was a 3-year organ preservation rate.

Results: Of the 64 participants, 58 completed treatment, with 6.4% and 33.9% grade 3 to 4 toxicities in the radiotherapy and consolidation CAPEOX phases, respectively, during a median 39.5-month follow-up. Initial cCR, and non-cCR occurred in 33, 13, and 18 patients, respectively. Of the 31 cCR and 7 near-cCR cases managed by W&W, local regrowth occurred in 7; of these, 6 received salvage surgery. The estimated 2-year local regrowth rates were 12.9% [95% confidence interval (CI): 1.1%-24.7%] in cCR and 42.9% (95% CI: 6.2%-79.6%) in near-cCR cases, respectively. Eight patients received local excision, including 2 with regrowth salvage. Lung metastases occurred in 3 patients and multiple metastasis occurred in 1 patient; no local recurrence occurred. The estimated 3-year organ preservation rate was 67.2% (95% CI: 55.6%-78.8%). The estimated 3-year cancer-specific survival, non-regrowth disease-free survival, and stoma-free survival were 96.6% (95% CI: 92.1%-100%), 92.2% (95% CI: 85.5%-98.9%), and 82.7% (95% CI: 73.5%-91.9%), respectively.

Conclusions: Chemoradiotherapy plus consolidation CAPEOX for MRI-defined low-risk rectal cancer can lead to high rates of organ preservation through intentional W&W or local excision. The oncologic safety of this strategy should be further tested.

Trial registration: ClinicalTrials.gov NCT02860234.

FIGURE 1

Overall consort flow diagram to show patient recruitment, initial response, tailored treatment, and organ preservation.

FIGURE 2

Typical images of baseline MRI, restaging MRI, and endoscopic features of patients with different responses, assessed by Memorial Sloan-Kettering Cancer Center criteria through MDT discussion at Peking University Cancer Hospital. A1–A3: One cCR case treated with W&W, without regrowth; A1, baseline mrT3a tumor; A2, minimal hypointense fibrosis confined in the rectal wall by restaging MRI; A3, typical endoscopic view of cCR with significant flat/whitening mucosa and telangiectasia. B1–B3: One near-cCR case treated with W&W, without regrowth; B1, baseline mrT3a tumor; B2, mostly full-thickness hypointense fibrosis confined in the rectal wall by restaging MRI; B3, typical endoscopic view of near-cCR with minor mucosal abnormality and mild erythema. C1–C3: One non-cCR case treated with LAR; C1, baseline mrT3a tumor; C2, intermediate signal in fibrosis beyond the rectal wall; C3, macroscopic view of palpable ulcerative lesion in rectum specimen. D1–D3: One near-cCR case treated with LE, without local recurrence; D1, baseline mrT3b tumor; D2, mostly hypointense signal in fibrosis, slightly beyond the rectal wall; C3, macroscopic view of the specimen after pyramid LE with partial mesorectum. Pathology revealed ypT2 tumor with negative radial and deep margins. E1–E3: One cCR case with regrowth treated with LE without local recurrence; E1, baseline mrT2 tumor; E2, MRI features of regrowth, intermediate signal in fibrosis confined in the rectal wall; E3, endoscopic view of regrowth (by narrow-band imaging), visible intraluminal lesion with positive biopsy. Pathology revealed ypT2 tumor with negative radial and deep margins.

FIGURE 3

The KM curve of local regrowth in cCR/near-cCR cases following W&W. The estimated 2-year local regrowth rates were 12.9% (95% CI: 1.1%–24.7%) in cCR, 42.9% (95% CI: 6.2%–79.6%) in near-cCR cases, and 18.4% (95% CI: 6.1%–30.7%) in cCR/near-cCR cases.

FIGURE 4

The KM curves of TME-free survival, NR-DFS, and stoma-free survival. The estimated 3-year OPR is 67.2% (95% CI: 55.6%–78.8%), NR-DFS is 92.2% (95% CI: 85.5%–98.9%), and stoma-free survival is 82.7% (95% CI: 73.5%–91.9%).