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==Bottom Line== | ==Bottom Line== | ||
Organ preservation was achieved in nearly half of patients with locally advanced rectal adenocarcinoma using TNT and a selective WW approach without compromising | Organ preservation was achieved in nearly half of patients with locally advanced rectal adenocarcinoma using TNT and a selective WW approach without compromising disease-free survival. Delivering chemoradiotherapy followed by consolidation chemotherapy (CRT-CNCT) led to higher organ preservation rates than induction chemotherapy followed by chemoradiotherapy (INCT-CRT). | ||
==Major Points== | ==Major Points== | ||
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* 324 patients with stage II-III rectal adenocarcinoma were randomized to INCT-CRT or CRT-CNCT and treated with TNT (systemic chemotherapy and chemoradiotherapy). | * 324 patients with stage II-III rectal adenocarcinoma were randomized to INCT-CRT or CRT-CNCT and treated with TNT (systemic chemotherapy and chemoradiotherapy). | ||
* Patients were restaged after TNT; those with a complete or near-complete clinical response were managed with WW, while others underwent TME. | * Patients were restaged after TNT; those with a complete or near-complete clinical response were managed with WW, while others underwent TME. | ||
* Primary endpoint: 3-year | * Primary endpoint: 3-year disease-free survival. Secondary endpoints: TME-free survival, local recurrence-free survival, and distant metastasis-free survival. | ||
* At 3 years, | * At 3 years, disease-free survival was 76% in both INCT-CRT and CRT-CNCT groups, comparable to historical controls. | ||
* Organ preservation rates were 41% for INCT-CRT and 53% for CRT-CNCT (p=0.01). | * Organ preservation rates were 41% (64/158) for INCT-CRT and 53% (87/166) for CRT-CNCT (p=0.01). | ||
==Guidelines== | ==Guidelines== | ||
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==Design== | ==Design== | ||
* Phase II, randomized, multicenter trial | * Phase II, non-blinded, randomized, multicenter trial | ||
* N=324 patients with stage II or III rectal adenocarcinoma | * N=324 patients with stage II or III rectal adenocarcinoma | ||
* Setting: 18 institutions in the United States | * Setting: 18 institutions in the United States | ||
* Enrollment: 2014-2020 | * Enrollment: 2014-2020 | ||
* Follow-up: Median 3 years | * Follow-up: Median 3 years | ||
* Primary endpoint: 3-year | * Primary endpoint: 3-year disease-free survival | ||
* Secondary endpoints: TME-free survival, adverse events, and local/distant recurrence rates | * Secondary endpoints: TME-free survival, adverse events, and local/distant recurrence rates | ||
* Analysis: Intention-to-treat, Kaplan-Meier survival estimates, and multivariable Cox regression | * Analysis: Intention-to-treat, Kaplan-Meier survival estimates, and multivariable Cox regression | ||
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===Inclusion Criteria=== | ===Inclusion Criteria=== | ||
* Age >18 years | * Age >18 years | ||
* Stage II (T3-4, N0) or III (any T, N1-2) rectal adenocarcinoma | * 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 | * No distant metastasis or prior pelvic irradiation | ||
* Adequate organ function and ECOG performance status ≤1 | * Adequate organ function and ECOG performance status ≤1 | ||
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===Exclusion Criteria=== | ===Exclusion Criteria=== | ||
* Recurrent rectal cancer | * Recurrent rectal cancer | ||
* Distant metastasis | |||
* Prior pelvic radiation | |||
* Incomplete staging or prior treatments disrupting TNT protocols | * Incomplete staging or prior treatments disrupting TNT protocols | ||
* History of other malignancies within 5 years | * History of other malignancies within 5 years | ||
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* **CRT-CNCT group**: Chemoradiotherapy followed by consolidation chemotherapy (mFOLFOX6 or CAPEOX) | * **CRT-CNCT group**: Chemoradiotherapy followed by consolidation chemotherapy (mFOLFOX6 or CAPEOX) | ||
* Radiotherapy: 4,500-5,600 cGy with concurrent capecitabine or infusional fluorouracil | * Radiotherapy: 4,500-5,600 cGy with concurrent capecitabine or infusional fluorouracil | ||
* Restaging with MRI, endoscopy, and physical | * 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== | ==Outcomes== | ||
===Primary Outcome=== | ===Primary Outcome=== | ||
* 3-year | * 3-year disease-free survival: 76% (both groups, p=NS) | ||
**Disease-free survival defined as lack of locoregional regrowth, distant metastasis, new colorectal primary, or death from any cause | |||
===Secondary Outcomes=== | ===Secondary Outcomes=== | ||
* Organ preservation (TME-free survival): 41% (INCT-CRT | * 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) | * Local recurrence-free survival: 94% (both groups) | ||
* Distant metastasis-free survival: 84% (INCT-CRT | * Distant metastasis-free survival: 84% (132/158) for INCT-CRT vs. 82% (136/166) for CRT-CNCT | ||
===Adverse Events=== | ===Adverse Events=== | ||
* Grade ≥3 adverse events during TNT: 41% (INCT-CRT | * Grade ≥3 adverse events during TNT: 41% (64/158) for INCT-CRT vs. 34% (57/166) for CRT-CNCT | ||
==Criticisms== | ==Criticisms== | ||