Endoscopic assessment of rectal cancer response after neoadjuvant chemoradiotherapy: A narrative literature review

Table 1 Characteristics of the included studies

Ref.	Year	Number of patients	Stage	Type of neoadjuvant treatment	Time of endoscopic assessment	Endoscopic modality used	Time of surgery	Definition of ECR	pCR	ECR	Accuracy of pCR prediction
Lim et al[15]	2010-2015	87	T3/T4 and/or N+	5 × 5 1.8 Gy + 5.4 Gy boost + ChT (5FU, capecitabine or FOLFOX)	1-2 weeks prior to surgery	N/A	6-8 weeks after CRT	A flat whitish or reddish scar ulcer, or a flat active/healing stage ulcer with regular edges surrounded by normal mucosa; disappearance of the neoplastic pit pattern without magnification; and disappearance of the neoplastic nodule or stenosis	21.7%	17.9%	88.7%
Chino et al[12]	2013-2015	79	T3/T4 and/or N+	Neoadjuvant chemoradiotherapy (oral fluoracil + 50.4 Gy), long course 59%, induction chemo (mFOLFOX + bevacizumab) + nCRT for cT4, cN2 or MRF (+) or positive lateral lymph nodes (41%)	48 days after CRT	WL-C, white light conventional endoscopy; ME, magnifying endoscopy under crystal violet staining	1-3 days after endoscopy	WL-C: Linear scar/flat scar, completely closed ulcer, no white moss, no protruded nodule. ME: Regenerated pits uniformly arranged, hyper-cellular pits. Wall extension by insufflation: Normal extension	21.5%	12.6%	85% for ME
Bengulescu et al[16]	2015-2017	43	Stage II/III rectal adenocarcinoma	Long course chemoradiotherapy (5FU + RT 504 Gy in 28 fractions)	N/A	N/A	6-8 weeks after nCRT	Endoscopy good grade (complete response or good response): Erythema; telangectasia; clean ulcer at the base; no elevation	N/A	67%	N/A
Wang et al[17]	2014-2021	214	LARC	Neoadjuvant chemoradiotherapy not otherwise specified	6–16 weeks after the completion of NT	Classic endoscopy (Olympus, Tokyo, Japan). ResNet-18 and DenseNet-121 deep learning algorithms		Good response; scarring (flat and white fibrosis with vasculopathy); erythema (erosion with peripheral erythematous mucosal changes)	23.8%	N/A	Manual method 75%, DenseNet-121: 72.6%, ResNet-18: 71.6%
Ishioka et al[14]	2012-2017	61	Stage II/II rectal cancer with poor features: MRF < 1 mm, cT4, positive lateral lymph nodes, mesorectal N2 disease and/or tumor requiring abdominoperineal resection	Neoadjuvant chemotherapy (folinic acid, fluorouracil, oxaliplatin + bevacizumab) followed by 50.4 Gy radiotherapy with concurrent S-1	Median 43 days after end of radiotherapy	White-light endoscopy and chromoendoscopy with indigo carmine dye, followed by magnifying NBI	Median 47 days after end of radiotherapy	Complete response (all 5): White light endoscopy: Ulcer completely closed and linear or flat shape of scar; no residual protruded nodules; preservation of rectal wall distention by insufflation. NBI: Regular or regenerated surface pattern; invisible or isolated vessel pattern (orderly network of micro vessels comprised of thin-caliber vessels)	31.1%	11.4%	70.5% with conventional white-light endoscopy, 75.4% white-light endoscopy + NBI
Kawai et al[18]	2007-2015	198 (186 radical surgery)	Low rectal cancer or T3/4 or N (+)	50.4 Gy with concurrent fluorouracil	3-8 weeks after end of CRT	Colonoscopy	6-8 weeks after end of CRT	Changes in the marginal tumor swelling, classified as almost no change, less than half according to pre-CRT measures, and almost flattened; changes in central ulceration, assessed according to whether reepithelialization of the ulcer was present; a cancer-negative biopsy result	12.8% in surgery group, 16.7% estimation in the watch-and-wait group	22.3% in radical surgery group, 50% in watchful waiting	Flattened marginal swelling 69.7%. Ulcer reepithelization 81.2%. Cancer negative biopsy 66.4%
Van Der Sande et al[19]	2012-2015	161 (87 surgery, 74 watch and wait)	cT1-2: 21.7%, cT3: 73.3%, cT4: 5%, cNo: 25.5%, cN1: 28.6%, cN2: 46%	Long course CRT or short course RT + interval	9 weeks after end of radiotherapy median (8-12 weeks)	White light imaging flexible sigmoidoscopy, 3 readers (2 surgeons, 1 gastroenterologist)	18 weeks interval between endoscopy and surgery	A flat scar; a small flat ulcer (< 1 cm); a large flat ulcer; ulcer with an irregular border; an adenomatous mass; tumorous mass	16%	42.8% (20.3% in surgery, 79.7% in watch and wait)	AUC 0.84, 0.80, 0.84 for complete response prediction for each of the 3 readers
Haak et al[13]	2012-2015	226	cT1-2: 22%, cT3: 71%, cT4: 7%, cNo: 24%, cN1: 28%, cN2: 48%	Long course CRT or short course RT + interval	10 weeks, median: 8-15 weeks	White light imaging flexible endoscopy (EPK-I video processor, Pentax Medical Netherlands, Uithoorn, the Netherlands) + deep learning	5 weeks, median: 2-10 weeks, between endoscopy and surgery	N/A	10.6%	48%	67%-75% for different convolutional neural network models including endoscopic images and clinical variables
Felder et al[20]	N/A survey	41+17 endoscopic pictures	N/A	Neoadjuvant treatment not otherwise specified	N/A	Two cross-sectional surveys, each containing endoscopic photos of rectal cancers treated with NT. The first survey assessed reproducibility of eight endoscopic criteria using 41 unique endoscopic photos. The second survey included endoscopic pairs of pre-neoadjuvant and post-neoadjuvant treatment photos of 17 patients	N/A	Flat and white scar; telangiectasias; absence of ulceration; absence of nodularity; small mucosal nodules or minor mucosal abnormality; superficial ulceration; mild persisting erythema of the scar; and visible tumor	N/A	N/A	89%
Williams et al[9]	2014-2020	263	cT1-2: 12.6%, cT3: 75.6%, cT4: 11.8%, cN (+): 63.7%	TNT (INCT-CRT or CRT-CNCT)	8 ± 4 weeks after TNT completion	Flexible sigmoidoscopy	N/A	Flat scar; telangiectasia; ulcer; nodularity; mucosal irregularity; mild erythema of the scar; visible tumor	N/A	42.5%	N/A
Williams et al[10]	2012-2020	288	Stage II/III	TNT (INCT-CRT or CRT-CNCT)	47 days median time from end of TNT	White-light flexible endoscopy with an Olympus scope (model CF-Q160S). Convolutional Neural Network using ResNet-50	N/A	Flat white scar; telangiectasias; no ulceration; no nodularity	N/A	N/A	AUC 0.99 for training set, AUC 0.98 for main test, AUC 0.92 for local regrowth
Chen et al[21]	2013-2021	1000	T3-4 and / or N (+)	Long course radiotherapy 50 Gy or short course radiotherapy 25 Gy. Concurrent chemotherapy oral/intravenous 5FU or combined with oxaliplatin/irinotecan	6-8 weeks after NT	White-light endoscopy with endoscopy-based Deep Convolutional Neural Network with a ResNeSt-50 variant	6-12 weeks after NT	N/A	21.9%	N/A	94.21% for training set, 92.13% for validation set, 87.14% for independent set
Sohn et al[22]	2004-2013	425	cT3-4 and/or N (+)	nCRT (45 Gy + 5.4 Gy boost + 5FU/Leucovorin or capecitabine or tegafur/uracil)	Immediately before surgery	White-light endoscopy	6-8 weeks after nCRT	E-GR: Scarring (the flat and white mucosa with fibrotic changes); telangiectasia (scarring surrounded by small blood vessels); erythema (scarring or erosion with peripheral erythematous mucosal changes)	10.8%	11.1%	N/A
Han et al[23]	2004-2013	481	cT3-4	nCRT (45 Gy + 5.4 Gy boost + 5FU/Leucovorin or capecitabine or capecitabine + irinotecan or tegafur/uracil)	6-8 weeks after nCRT	White-light endoscopy	6-8 weeks after nCRT	E-GR: Scarring (the flat and white mucosa with fibrotic changes); telangiectasia (scarring surrounded by small blood vessels); erythema (scarring or erosion with peripheral erythematous mucosal changes)	11%	N/A	Pathologic good response: ≤ ypT1, positive predictive value of 0.65, negative predictive value of 0.885
Thompson et al[11]	2012-2017	109	LARC	TNT [ChT (FOLFOX or CAPEOX) + long-course chemoradiotherapy with concurrent 5FU or capecitabine]	6 weeks after TNT and subsequent follow up visits (3 total selected including first visit)	White-light endoscopy with convolutional neural network VGG-19	Watch and wait	N/A	N/A	N/A	Training set AUROC 0.83, testing set AUROC 0.83

AUC: Area under the curve; AUROC: Area under the receiver operator curve; CRT: Chemoradiotherapy; ECR: Endoscopic complete response; E-GR: Endoscopic good response; LARC: Locally advanced rectal cancer; ME: Magnifying endoscopy; MRF: Magnetic resonance fingerprinting; NBI: Narrow-band imaging; nCRT: Neoadjuvant chemoradiotherapy; NT: Neoadjuvant therapy; N/A: Not applicable; RT: Radiotherapy; TNT: Total neoadjuvant treatment; 5FU: 5-fluorouracil.

Table 2 Quality assessment of studies using Quality Assessment of Diagnostic Accuracy Studies-2

Ref.	Risk of bias				Applicability concerns
	Patient selection	Index test	Reference standard	Flow and timing	Patient selection	Index test	Reference standard
Lim et al[15]	High risk	Low risk	Low risk	Low risk	Low risk	Low risk	Low risk
Chino et al[12]	High risk	Unclear risk	Unclear risk	Low risk	High risk	High risk	Unclear risk
Bengulescu et al[16]	High risk	Low risk	Low risk	Low risk	Low risk	Low risk	Low risk
Wang et al[17]	High risk	Low risk	Unclear risk	Low risk	Low risk	Low risk	Unclear risk
Ishioka et al[14]	High risk	Low risk	Low risk	Low risk	Low risk	Low risk	Low risk
Kawai et al[18]	High risk	Unclear risk	Low risk	Low risk	Low risk	High risk	Low risk
Van Der Sande et al[19]	High risk	Low risk	Low risk	Low risk	Low risk	Low risk	Low risk
Haak et al[13]	High risk	Low risk	Low risk	Low risk	Low risk	Low risk	Low risk
Felder et al[20]	High risk	Unclear risk	Low risk	High risk	Low risk	Unclear risk	Low risk
Williams et al[9]	High risk	Low risk	Unclear risk	High risk	Low risk	Unclear risk	Unclear risk
Williams et al[10]	High risk	Unclear risk	Unclear risk	High risk	Low risk	Unclear risk	Unclear risk
Chen et al[21]	High risk	Unclear risk	Unclear risk	Low risk	Low risk	High risk	Unclear risk
Sohn et al[22]	High risk	Unclear risk	Low risk	Low risk	Low risk	Low risk	Low risk
Han et al[23]	High risk	Low risk	Unclear risk	Low risk	Low risk	Low risk	Unclear risk
Thompson et al[11]	High risk	High risk	High risk	High risk	Low risk	High risk	High risk