Impact of Salvage Surgery following Colonic Endoscopic Polypectomy for Patients with Invasive Neoplasia

Round 1

Reviewer 1 Report

Thanks for giving me the possibility to review this paper. The paper address a very interesting aspect in the treatment of early phases of colo-rectal cancer. The presentation arises some dubts. 

The main is related to the staging of the patients who underwent endoscopic treatment. It is hard to understand why cN+ patients did not receive ET + surgery. It can be related to clinical factors, as well as for M1 patients. I should expect to consider only cN0, cM0 patients and consider clinical nodal and distant metastases as exclusion criteria. 

Another unclear aspect is related to tumor deposits. Tumor deposits are defined as  foci of carcinoma separated from the main lesion and identified in pericolonic or perirectal fat or the adjacent mesentery. In TNM Ed 7 and 8 tumor deposits are classified as N1c, and they can be diagnosed only with pathological examination of a surgical specimen. Probably the term is used with a different meaning. 

Author Response

Thanks for giving me the possibility to review this paper. The paper addresses a very interesting aspect in the treatment of early phases of colo-rectal cancer. The presentation arises some dubts.

-The main is related to the staging of the patients who underwent endoscopic treatment. It is hard to understand why cN+ patients did not receive ET + surgery. It can be related to clinical factors, as well as for M1 patients. I should expect to consider only cN0, cM0 patients and consider clinical nodal and distant metastases as exclusion criteria.

Response: Thanks for the constructive suggestion. We totally understand the concern of the reviewer. After our careful consideration, we still insisted that the patients with N+ or M+ should be included in the study, the reasons are listed below:

1. The staging of lymph nodes(LNs)/Metastasis(M) herein is either clinical stage or pathological stage. That means the N stage and M stage were diagnosed or corrected after surgery. Therefore, TNM stage was potentially modified after the intervention. If we exclude those patients with N+ and M+, while some of them may be diagnosed as N0/M0 before surgery. This will artificially increase the selection bias.
2. According to the experience of our institution, a systematic check for the status of lymph node and distant metastasis may not be a routine for the patients with invasive polyps in some hospitals. For some extents, the N/M staging might not be so accurate that to differentiate the patients with lymph node or distal metastasis. For example, those patients with N+ or M+ may fail to be diagnosed because a systematic CT scan (including full abdominal and chest CT) wasn’t applied.
3. One of the goals in this manuscript is to explore the predictive factors of lymphovascular metastasis. If we exclude those patients with N+ and M+, the goal regarding the predictive factor of lymphovascular metastasis can’t be achieved.

PS:  According to the common sense, those patients with Tis or T1(without deep submucosa invasion >1000μm) are not supposed to develop lymph nodes or distal metastasis. But many cases with T1 stage in our study developed N+ (22/2309, 0.9528%) or M+ (37/2309, 1.6024%). To our knowledge, this may be the clinical reasons, such as the presence of residual tumor, or the quality of pathological tissue is too low (even missing) to accurately evaluate the staging, especially for the endoscopic resected tissue. We should objectively treat this phenomenon, and the problem of residual tumor in clinics did surely exist.

-Another unclear aspect is related to tumor deposits. Tumor deposits are defined as foci of carcinoma separated from the main lesion and identified in pericolonic or perirectal fat or the adjacent mesentery. In TNM Ed 7 and 8 tumor deposits are classified as N1c, and they can be diagnosed only with pathological examination of a surgical specimen. Probably the term is used with a different meaning.

Response: Thanks for your professional advice. We have to admit these mistakes. And the wrong expression (tumor deposits) was replaced by residual tumor. 

Reviewer 2 Report

The manuscript is interesting and overall well written.
However there are some critical issues that need to be further stressed:

- the classification of T1 is not differentiated in relation to the infiltration state of the sub-mucosa. I strongly recommend developing the topic by re-evaluating the specimens and inserting this data into the statistical analysis;

- both the endoscopic procedure and surgery have a risk of morbidity and mortality that have not been reported or taken into account in assessing the overall prognosis. The benefits of cancer-related survival may be lost in the complications of major colic resections...

Author Response

The manuscript is interesting and overall well written. However there are some critical issues that need to be further stressed:

- the classification of T1 is not differentiated in relation to the infiltration state of the sub-mucosa. I strongly recommend developing the topic by re-evaluating the specimens and inserting this data into the statistical analysis;

Response: Thanks for your constructive point.  The status of sub-mucosa invasion could potentially influence our outcomes. However, the depth of submucosa invasion (SID) can’t be obtained. Therefore, only the status of submucosa invasion was included in our modified version. As suggested, the corresponding analysis has been added in the manuscript:

Figure 2. Kaplan-Meier cancer-specific survival plots in patients underwent endoscopic removal of invasive neoplasia. (A) All patients; (B) Patients with intramucosal carcinoma (Tis); (C) Patients with submucosal carcinoma (T1). (D) Patients with or without submucosa invasion; (Page 6, line 139)

 

Table 1. Baseline Characteristics before and after propensity-score matching analysis. (Page 4, line 131)

Characteristics	Before PSM				After PSM
	Overall	ET only	ET+Surg	p-value	Overall	ET only	ET+Surg	p-value
N	5805	1214	4591		2428	1214	1214
Sex (%)
Female	2410 (41.5)	485 (40.0)	1925 (41.9)	0.226	989 (40.7)	485 (40.0)	504 (41.5)	0.457
Male	3395 (58.5)	729 (60.0)	2666 (58.1)		1439 (59.3)	729 (60.0)	710 (58.5)
Age (mean (SD))	63.41 (12.05)	64.08 (11.97)	63.23 (12.06)	0.03	64.21 (11.87)	64.08 (11.97)	64.35 (11.76)	0.573
Grade (%)
Well differentiated; Grade I	793 (13.7)	157 (12.9)	636 (13.9)	0.556	315 (13.0)	157 (12.9)	158 (13.0)	0.453
Moderately differentiated; Grade II	1457 (25.1)	290 (23.9)	1167 (25.4)		566 (23.3)	290 (23.9)	276 (22.7)
Poorly differentiated; Grade III	121 (2.1)	25 (2.1)	96 (2.1)		51 (2.1)	25 (2.1)	26 (2.1)
Undifferentiated; anaplastic; Grade IV	72 (1.2)	18 (1.5)	54 (1.2)		27 (1.1)	18 (1.5)	9 (0.7)
Unknown	3362 (57.9)	724 (59.6)	2638 (57.5)		1469 (60.5)	724 (59.6)	745 (61.4)
Histology type (%)
Adenocarcinoma	5654 (97.4)	1176 (96.9)	4478 (97.5)	0.092	2361 (97.2)	1176 (96.9)	1185 (97.6)	0.733
Mucinous adenocarcinoma	23 (0.4)	5 (0.4)	18 (0.4)		7 (0.3)	5 (0.4)	2 (0.2)
Neuroendocrine carcinoma	16 (0.3)	8 (0.7)	8 (0.2)		15 (0.6)	8 (0.7)	7 (0.6)
Signet ring cell carcinoma	4 (0.1)	2 (0.2)	2 (0.0)		4 (0.2)	2 (0.2)	2 (0.2)
Squamous cell carcinoma	4 (0.1)	1 (0.1)	3 (0.1)		1 (0.0)	1 (0.1)	0 (0.0)
Multiply histology types	2 (0.0)	0 (0.0)	2 (0.0)		0 (0.0)	0 (0.0)	0 (0.0)
Unknown	102 (1.8)	22 (1.8)	80 (1.7)		40 (1.6)	22 (1.8)	18 (1.5)
Localization (%)
Right colon	1282 (22.1)	276 (22.7)	1006 (21.9)	0.804	545 (22.4)	276 (22.7)	269 (22.2)	0.678
Left colon	4407 (75.9)	915 (75.4)	3492 (76.1)		1842 (75.9)	915 (75.4)	927 (76.4)
Rectum	116 (2.0)	23 (1.9)	93 (2.0)		41 (1.7)	23 (1.9)	18 (1.5)
T stage (%)
Tis	3496 (60.2)	760 (62.6)	2736 (59.6)	0.061	1497 (61.7)	760 (62.6)	737 (60.7)	0.358
T1	2309 (39.8)	454 (37.4)	1855 (40.4)		931 (38.3)	454 (37.4)	477 (39.3)
T1, Submucosa invasion positive	1062(18.3)	203(16.7)	859(18.7)		402(16.6)	203 (16.7)	199 (16.4)
T1, Submucosa invasion negative	1186(20.4)	227(18.7)	959(20.9)		494(20.3)	227 (18.7)	267 (22.0)
Polyp size (%)
<10mm	1315 (22.7)	260 (21.4)	1055 (23.0)	0.009	519 (21.4)	260 (21.4)	259 (21.3)	0.466
10-19mm	404 (7.0)	65 (5.4)	339 (7.4)		121 (5.0)	65 (5.4)	56 (4.6)
20-29mm	197 (3.4)	40 (3.3)	157 (3.4)		77 (3.2)	40 (3.3)	37 (3.0)
30-39mm	81 (1.4)	19 (1.6)	62 (1.4)		27 (1.1)	19 (1.6)	8 (0.7)
40-49mm	26 (0.4)	4 (0.3)	22 (0.5)		8 (0.3)	4 (0.3)	4 (0.3)
50-mm	31 (0.5)	13 (1.1)	18 (0.4)		27 (1.1)	13 (1.1)	14 (1.2)
Unknown	3751 (64.6)	813 (67.0)	2938 (64.0)		1649 (67.9)	813 (67.0)	836 (68.9)

 

 

Variable	ET only group		ET + surgery group		p-value
	5-year CSS rate	95%CI	5-year CSS rate	95%CI
Overall	0.958	0.946-0.970	0.974	0.964-0.983	0.017
T stage
Tis stage	0.979	0.968-0.990	0.988	0.981-0.996	0.093
T1 stage	0.921	0.894-0.948	0.950	0.929-0.971	0.047
Submucosa invasion
T1, Submucosa invasion positive	0.947	0.913-0.981	0.950	0.918-0.907	0.552
T1, Submucosa invasion negative	0.924	0.888-0.960	0.949	0.920-0.978	0.949
Polyp size
<10 mm	0.983	0.966-1.000	0.971	0.950-0.992	0.610
10-19 mm	0.976	0.931-1.000	0.960	0.906-1.000	0.770
≥20 mm	0.882	0.808-0.962	0.948	0.893-1.000	0.200

Table 2. 5-year Cancer-specific survival for different treatment modalities among patients with endoscopic removal of invasive neoplasia. (Page 7, line 165)

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Table 3. Univariate Cox regression analysis. (Page 8, line 178)

Variable		Hazard ratio	Lower 95% CI	P value
Overall	ET alone	Reference
	ET + Surgery	0.61	0.40 - 0.92	0.018
T stage
Tis	ET alone	Reference
	ET + Surgery	0.54	0.26 - 1.12	0.099
T1	ET alone	Reference
	ET + Surgery	0.61	0.37 - 1.00	0.050
Submucosa invasion
T1, Submucosa invasion positive	ET alone	Reference
	ET + Surgery	0.72	0.32 – 1.64	0.435
T1, Submucosa invasion negative	ET alone	Reference
	ET + Surgery	0.71	0.36 - 1.40	0.322
Polyp size
<10 mm	ET alone	Reference
	ET + Surgery	1.32	0.46 - 3.81	0.607
10-19 mm	ET alone	Reference
	ET + Surgery	0.76	0.13 - 4.60	0.766
20- mm	ET alone	Reference
	ET + Surgery	0.20	0.02 - 1.76	0.146

 

 

 

 

 

Table 4. The migration of lymph nodes and distant tissue/organ among the entire patients with endoscopic polypectomy. (Page 9, line 195)

		N stage						M stage
	Subgroup	Overall	N0	Probability	N1+N2	Probability	P value	Overall	M0	Probability	M1	Probability	P value
n		5805	5783	99.6210%	22	0.3790%		5805	5768	99.3626%	37	0.6374%
T stage	Tis	3496	3496	100.0000%	0	0.0000%	<0.001	3496	3496	100.0000%	0	0.0000%	<0.001
	T1	2309	2287	99.0472%	22	0.9528%		2309	2272	98.3976%	37	1.6024%
T1, Submucosa invasion	Submucosa positive	402	400	99.5025%	2	0.4975%	0.289	402	400	99.5025%	2	0.4975%	0.041
	Submucosa negative	494	490	99.1903%	4	0.8097%		494	482	97.5709%	12	2.4291%
Polyp size in mm	<10	1315	1313	99.8479%	2	0.1521%	<0.001	1315	1314	99.9240%	1	0.0760%	<0.001
	10-19	404	403	99.7525%	1	0.2475%		404	400	99.0099%	4	0.9901%
	20-29	197	195	98.9848%	2	1.0152%		197	194	98.4772%	3	1.5228%
	30-39	81	78	96.2963%	3	3.7037%		81	78	96.2963%	3	3.7037%
	40-49	26	25	96.1538%	1	3.8462%		26	25	96.1538%	1	3.8462%
	>50	31	28	90.3226%	3	9.6774%		31	28	90.3226%	3	9.6774%
Localization	Unknown	3751	3741	99.7334%	10	0.2666%		3751	3729	99.4135%	22	0.5865%
	Right colon	1282	1275	99.4540%	7	0.5460%	0.047	1282	1267	98.8300%	15	1.1700%	<0.001
	Left colon	4407	4394	99.7050%	13	0.2950%		4407	4388	99.5689%	19	0.4311%
	Rectum	116	114	98.2759%	2	1.7241%		116	113	97.4138%	3	2.5862%
CEA	Negative	424	420	99.0566%	4	0.9434%	<0.001	424	421	99.2925%	3	0.7075%	<0.001
	Positive	120	112	93.3333%	8	6.6667%		120	95	79.1667%	25	20.8333%
	Unknown	5261	5251	99.8099%	10	0.1901%		5261	5252	99.8289%	9	0.1711%

- both the endoscopic procedure and surgery have a risk of morbidity and mortality that have not been reported or taken into account in assessing the overall prognosis. The benefits of cancer-related survival may be lost in the complications of major colic resections...

Repsonse: Thanks for your constructive advices. In order to evaluate other complication reasons that could contribute to the survival analysis. The overall survival analysis were performed, as shown in supplementary Figure S 1 and S2.

Supplementary Figure S1. Kaplan-Meier overall survival plots in patients underwent endoscopic removal of invasive neoplasia. (A) All patients; (B) Patients with intramucosal carcinoma (Tis); (C) Patients with submucosal carcinoma (T1). (D) Patients with or without submucosa invasion;

 

 

Supplementary Figure S2. Kaplan-Meier overall survival plots in patients underwent endoscopic removal of invasive neoplasia. (A) Invasive polyp size less than 10 mm; (B) Invasive polyp size between 10 mm and 20 mm; (C) Invasive polyp size larger than 20 mm.

Round 2

Reviewer 2 Report

The Authors adequately satisfied the review for submucosal involvement.

Possible complications after surgical or endoscopic resection should instead be discussed in the main text and not only in the supplementary materials.

Author Response

Dear Reviewer, thanks for this remark. We inserted the follwoing paragraph into the discussion part: "In summary possible complications after endoscopic resection are the misidentification of the T stage and polyp size, and periprocedural complications as bleeding and perforation. Complications after surgical resection of Tis and T1 malignancies are the over-extended operation with subsequent functional impairments and possible long-time complications of the hospital stay and the operation mode like surgical side infections or incisional hernia."