Table 2.

Studies evaluating the watch and wait protocol

Study	Patients (n)	Neoadjuvant therapy		Details	Outcomes/endpoints
		Radiation	Chemotherapy
Prospective
Habr-Gama et al[24] (Brazil)	69	54 Gy radiation (45-Gy delivered as 3-field approach with daily doses of 1.8 Gy on weekdays to pelvis, followed by 9-Gy boost to the primary tumor and perirectal tissue)	3 cycles of 5-FU (450 mg/m2) bolus and a fixed dose of 50 mg leucovorin for 3 consecutive days every 3 wk. After completion of radiation, patients received 3 additional identical cycles of chemotherapy every 3 mo	Assessment after CRT: 10 wk; assessment for sustained cCR: From 10 wk to 12 mo after CRT; patients with local recurrences after sustained cCR classified as LR	3-yr OS for patients with initial cCR = 3-yr DFS for patients with initial cCR = 72%
Lambregts et al[25] and Maas et al[26] (Netherlands)	21	28 fractions of 1.8 Gy = 50.4 Gy	IV oxaliplatin and capecitabine	Assessment after CRT: 6-8 wk; evaluation for cCR: MRI and endoscopy; operative management with CRT and resection (control group): 20 patients with pCR after surgery	Nonoperative management group; 1 patient developed LR and had surgery as salvage treatment; 20 patients are alive without disease; no difference in 2-yr DFS and OS between the watch and wait and the CRT and resection groups
Smith et al[27] (United States)	32	External beam radiation over 5-6 wk, median dose 50.4 Gy (range 45-56 Gy)	5-FU or capecitabine	Assessment after CRT: 4-10 wk; evaluation for cCR: DRE, endoscopy ± biopsy; evaluation for cCR at 1-yr: DRE, flexible sigmoidoscopy every 3 mo; evaluation for cCR subsequent years: DRE, flexible sigmoidoscopy every 4-6 mo; operative management (control group): 256 patients, 57 (22%) with pCR; median follow up: 28 mo	Nonoperative management group had a higher rate of LR (21% vs 0%, P = 0.001): 6 recurred locally (median 11 mo), 3 had concurrent DR; 2-yr DR (8% vs 2%, P = 0.30), DFS (88% vs 98%, P = 0.27), and OS (97% vs 100%, P = 0.56) were similar for nonoperative management and rectal resection/pCR groups
Dalton et al[28] (United Kingdom)	12	45 Gy in 25 fractions over 5 wk	Concurrent capecitabine	Assessment after CRT: 8 wk; evaluation for cCR: MRI complemented with EUA/biopsy and PET/CT if tumor regression is suspected; cCR patients are followed with repeat EUA at 3 mo and 12 mo, and 6-monthly PET/CT and MRI; median follow up 25.5 mo	cCR in 12/49 (24.4%); 6/12 patients with cCR without evidence of disease

LR: Local recurrence; DR: Distant recurrence; DFS: Disease-free survival; OS: Overall survival; Gy: Gray; CRT: Chemoradiation therapy; DRE: Digital rectal examination; EUA: Examination under anesthesia; 5-FU: 5-fluorouracil; cCR: Clinical complete response; pCR: Pathological complete response; PET/CT: Positron emission test/computerized tomography; MRI: Magnetic resonance imaging.