OPRA
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Clinical Question
Does total neoadjuvant therapy (TNT) and a selective watch-and-wait (WW) approach achieve comparable disease-free survival (DFS) compared to standard resection-based treatment?
Bottom Line
Organ preservation was achieved in 46% of patients with locally advanced rectal adenocarcinoma using TNT and a selective WW approach without compromising disease-free survival compared to historic controls. Treatment initiation with chemoradiotherapy followed by consolidation chemotherapy (CRT-CNCT) demonstrated higher organ preservation rates than induction chemotherapy followed by chemoradiotherapy (INCT-CRT).
Major Points
The OPRA trial randomized patients with stage II and III rectal cancer to either induction chemoradiotherapy with consolidation chemotherapy (CRT-CNCT) or induction chemotherapy followed by chemoradiotherapy (INCT-CRT). Patients with a complete or near-complete clinical response were managed with WW, while incomplete responses underwent TME. The trial demonstrated equivalent disease-free survival, overall survival, and distant metastasis free survival. INCT-CRT demonstrated superior rates of organ preservation (53% vs. 41%) and lower rates of tumor regrowth (27% vs. 40%).
Guidelines
- NCCN guidelines Version 4.2024: "In those patients who achieve a complete clinical response with no evidence of residual disease on digital rectal examination (DRE), rectal MRI, and direct endoscopic evaluation, a “watch and wait,” nonoperative (chemotherapy and/or RT) management approach may be considered in centers with experienced multidisciplinary teams.
The degree to which risk of local and/or distant failure may be increased relative to standard surgical resection has not yet been adequately characterized. Decisions for nonoperative management (NOM) should involve a careful discussion with the patient of their risk tolerance"
- NCCN guidelines for watch and wait protocol:
- DRE and proctoscopy every 3-4 months for 2 years, then every 6 months/3 years
- MRI rectum every 6 months for at least 3 years
- 2023 ASCRS Clinical Practice Guidelines Managment of Rectal Cancer Supplement
- Following neoadjuvant therapy, patients should be assessed to determine response to treatment at 8-12 weeks
https://fascrs.org/ascrs/media/files/2023-Rectal-Cancer-Supplement.pdf
Design
- Phase II, non-blinded, randomized, multicenter trial
- N=324 patients with stage II or III rectal adenocarcinoma
- Setting: 18 institutions in the United States
- Enrollment: 2014-2020
- Follow-up: Median 3 years
- Primary endpoint: 3-year disease-free survival
- Secondary endpoints: TME-free survival, adverse events, and local/distant recurrence rates
- Analysis: Intention-to-treat, Kaplan-Meier survival estimates, and multivariable Cox regression
Population
Inclusion Criteria
- Age >18 years
- Clinical Stage II (T3-4, N0) or III (any T, N1-2)
- Clinical staging for rectal adenocarcinoma by MRI rectal cancer protocol, CT chest abdomen pelvis, and colonoscopy
- No distant metastasis or prior pelvic irradiation
- Adequate organ function and ECOG performance status ≤1
Exclusion Criteria
- Recurrent rectal cancer
- Distant metastasis
- Prior pelvic radiation
- Incomplete staging or prior treatments disrupting TNT protocols
- History of other malignancies within 5 years
Baseline Characteristics
- Median age: 59 years
- Clinical T stage: T3 (78%), T4 (13%)
- Clinical nodal status: N-positive (71%)
Interventions
- INCT-CRT group: Induction chemotherapy (mFOLFOX6 or CAPEOX) followed by chemoradiotherapy
- CRT-CNCT group: Chemoradiotherapy followed by consolidation chemotherapy (mFOLFOX6 or CAPEOX)
- Radiotherapy: 4,500-5,600 cGy with concurrent capecitabine or infusional fluorouracil
- Restaging with MRI, endoscopy, CT chest abdomen pelvis, and physical within 8 weeks of completing TNT to assess response
- Patients with a complete or near complete response were offered watch and wait
- Watch and wait protocol consisted of digital rectal examination and flexible sigmoidoscopy every 4 months for the first 2 years from the time of assessment of response, and every 6 months for the following 3 years
- Rectal MRI was performed every 6 months for the first 2 years and yearly for the following 3 years
- Patients with an incomplete response were recommended for total mesorectal excision
- Patients with lack of complete response or those with evidence of endoscopic regrowth were recommended for TME
Outcomes
Primary Outcome
- 3-year disease-free survival
- Disease-free survival defined as lack of locoregional regrowth, distant metastasis, new colorectal primary, or death from any cause
- 76% (both groups, p=NS)
Secondary Outcomes
- Organ preservation (TME-free survival)
- 41% (64/158) for INCT-CRT vs. 53% (87/166) for CRT-CNCT, p=0.01
- Local recurrence-free survival
- 94% (both groups)
- Distant metastasis-free survival
- 84% (132/158) for INCT-CRT vs. 82% (136/166) for CRT-CNCT
Adverse Events
- Grade ≥3 adverse events during TNT
- 41% (64/158) for INCT-CRT vs. 34% (57/166) for CRT-CNCT
Criticisms
- Lack of a control arm with standard CRT and TME limits direct comparison to standard therapy.
- Follow-up duration may be insufficient to assess long-term oncologic outcomes.
- Higher organ preservation rate with CRT-CNCT may reflect differences in regrowth, not initial response rates.
Funding
- Supported by grants from the National Cancer Institute (R01CA182551, P30CA008748)