Contribution of “complete response to treatment” to survival in patients with unresectable metastatic colorectal cancer: A retrospective analysis

Gulcan Bulut; Merve Guner Oytun; Elvina Almuradova; Mustafa Harman; Ruchan Uslu; Bulent Karabulut

doi:10.1371/journal.pone.0259622

. 2021 Nov 8;16(11):e0259622. doi: 10.1371/journal.pone.0259622

Contribution of “complete response to treatment” to survival in patients with unresectable metastatic colorectal cancer: A retrospective analysis

Gulcan Bulut ^1,^*, Merve Guner Oytun ², Elvina Almuradova ³, Mustafa Harman ⁴, Ruchan Uslu ⁵, Bulent Karabulut ³

Editor: Ludmila Vodickova⁶

PMCID: PMC8575296 PMID: 34748587

Abstract

Background

The aim of the study is to reveal the contribution of complete response (CR) to treatment to overall survival (OS) in patients with unresectable metastatic colorectal cancer. In addition, to evaluate progression-free survival (PFS) in patients who attained CR to treatment and to examine the clinicopathologic features of the patient group with CR.

Methods

This article is a retrospective chart review. Patients diagnosed with metastatic colorectal cancer were divided into two groups. The systemic treatment was compared with the patients who received a full response according to the Response Evaluation Criteria in Solid Tumors (RECIST1.1) and those who did not attain CR (progression partial response and stable response) in terms of both PFS and OS data, and the effect of attaining CR to treatment on prognosis was evaluated.

Results

A total of 222 patients were included in the study. 202 of 222 patients could be evaluated in terms of complete response. All data from their files were tabulated and analyzed retrospectively. The mean age of diagnosis of the study group was 60.13 ± 12.52 years. The total number of patients who attained CR to treatment was 31 (15.3%); 171 (84.6%) patients did not attain CR. Patients who had a CR had longer median PFS times than patients who did not have a CR (15.2 vs. 7.4 months, P<0.001). Patients who had CR had longer median survival times than patients who did not have a CR (39.2 vs. 16.9 months, P<0.001). In subgroup patients who underwent primary surgery, the number of patients who attained CR was statistically higher compared with the number of patients who did not attain CR (p<0.001). Complete response was less common in the presence of liver metastasis and bone metastasis (p = 0.041 and p = 0.046, respectively), had a negative prognostic effect. In other words, 89.1% of patients with liver metastasis, 100.0% of patients with bone metastasis, and 88.7% of those who died did not have a CR to the treatment. According to multivariate analysis, CR to treatment, primary surgery, first-line chemotherapy (combination compared with fluoropyrimidine), and no bone metastasis were found to be predictors for OS.

Conclusion

Providing CR with systemic treatment in patients with unresectable metastatic colorectal cancer (mCRC) contributes to prognosis. The primary resection in our secondary acquisitions from the study, the number of metastatic regions and the combination therapy regimens also contributed to the prognosis.

Introduction

Colorectal cancer (CRC) is the third most diagnosed malignancy in Europe, with an estimated 447,000 new cases diagnosed annually in Europe [1]. CRC is the second most common cause of cancer-related deaths in the Western world; 20% of patients have been found to have metastatic colorectal cancer (mCRC) at diagnosis [1]. Overall survival (OS) for patients with unresectable metastatic colorectal cancer with “best supportive care” (BSC) is 6 months [2]. In studies in the literature, the OS achieved with systemic therapy in patients with mCRC is approximately 2 years [3, 4]. Accordingly, the fact that the comparison parameter is BSC in new randomized studies is unethical and patients with metastatic colorectal cancer are directed to systemic therapy [5, 6]. Increasing OS with the development of biologic agents arouses excitement in clinical practice. Terminology of maximum tumor response revealed by the “First-line therapy for patients with metastatic colorectal cancer” (FIRE-3) study is used in the clinical evaluation of patients in terms of predicting survival. In studies, the depth of response was proven to contribute to OS with the FIRE-3 study [7].

In the literature, it is known that systemic treatment results in patients with mCRC, complete response (CR) is obtained in 10–15% of patients according to RECIST1.1 criteria as known as “Response Evaluation Criteria in Solid Tumors” [8]. RECIST 1.1 is a radiologic common evaluation language developed for clinical studies with a primary endpoint objective response. Although the importance of response depth was demonstrated in the FIRE-3 study, information about patients with CRs is limited [9, 10]. In Turkey, there are no similar studies in the literature.

In our study, it was aimed to compare patients who attained a CR according to RECIST1.1 in the report of radiology and nuclear medicine as a result of systemic treatment with a diagnosis of unresectable mCRC compared with patients who did not attain a CR in terms of clinicopathologic features, treatment regimen, progression-free survival (PFS) and OS data.

Materials and methods

All procedures performed in studies involving human participants were conducted in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki Declaration and ethical standards. (Ege University Clinical Research Ethics Committee approval number: 16–4.4/4).

The files of patients diagnosed with metastatic colorectal cancer who applied to the outpatient clinics of Ege University Medical Oncology Department between January 1st, 2007, and December 31st, 2015, were analyzed retrospectively. And the date of termination of follow up January 1st, 2020. Patients aged over 18 years and diagnosed with metastatic colorectal cancer, regardless of whether they received adjuvant chemotherapy (CT), were included in the study. In other words, both patients with de-novo metastasis and those who developed metastasis after primary tumor resection and adjuvant therapy were included in the study. Patients who underwent metastasectomy at any stage of the treatment, except for biopsies taken for pathologic sampling, patients with another cancer and patients with life-threatening comorbidity were excluded from the study. Age, primary disease region, primary diagnosis date, primary surgery date if the primary tumor is operated, pathologic features of the primary tumor (degree, location of the tumor in the wall of the intestine wall, regional lymph node status = TNM staging), KRAS status, presence of adjuvant treatment, previous primary disease adjuvant treatments (such as primary tumor surgery, adjuvant CT, neo-adjuvant radiotherapy), metastasis history, metastasis regions, first-line and subsequent treatments, start and end dates of treatments, best radiologic response with the treatment applied, last visit date, and date of death if the patient was deceased were saved to the SPSS program.

In addition, the imaging of patients whose radiology evaluations were given in full was reevaluated by the radiology department according to the ’Evaluation Criteria in Solid Tumors’ (RECIST1.1) and CR was confirmed in a single center. Thus, the difference between centers and CR was standardized.

Statistical analysis

Statistical analyses were performed using the IBM SPSS Statistics Version 22 package program. Apart from applying descriptive statistics to the data, the Chi-square test, Student’s t-test, and the Mann-Whitney U test were used in subgroup comparisons, and Kaplan-Meier and Cox regression analyses were used in survival analyses. The statistical limit of significance was accepted as p<0.05. The whole study was a retrospective file data evaluation and no test, examination and/or intervention was performed.

Results

Patient characteristics

A total of 222 patients were included in the study. The mean age of diagnosis of the study group was 60.13 ± 12.52 years. The study group consisted of 134 (60.4%) men and 88 (39.6%) women. The median patient follow-up time was 19.07 (min: 0.3 months-max: 131.6) months. The mean metastasis interval was 5.93 ± 12.81 months. The mean number of metastatic regions was 1.69 ± 0.1. The primary involvement site of the tumor was rectal 82 (37.6%), distal colon 81 (37.2%), proximal colon 44 (20.2%) and transverse colon in 11 (5.0%) patients. Primary surgery was not performed in 80 (40.6%) patients, whereas it was performed in 132 (59.4%) patients. Thus, patients with de novo metastasis comprised 40.6% of the study group. Forty-eight (36.3%) patients received adjuvant therapy with patients with primary surgery. This group might be associated with chemoresistance. Histopathologic diagnosis of the tumor was adeno cancer in 184 (83.6%) patients. In tumor staging, 69 (47.3%) patients were in T3, 48 (32.9%) patients were in T4. Fifty-one (71.8%) patients had lymphovascular invasion (LVI), and 39 (63.2%) patients had perineural invasion (PVI). In terms of KRAS status, 65 (29.5%) patients had mutant-type and 76 (34.5%) patients had wild-type. One hundred forty-two (64.5%) patients had liver metastasis, and 22 (9.9%) patients had bone metastasis. The total number of patients who attained a CR to treatment was 31 (14.6%); 181 (85.4%) patients did not attain a CR. The number of patients with progression was 172 (97.7%). Twenty (9.0%) patients were still alive, 202 (91.0%) patients had died.

Factors associated with attaining complete response

The comparison of clinical and histopathologic findings according to the response to treatment is shown in Table 1. 202 of 222 patients could be evaluated in terms of complete response. The mean age of patients who attained CR was 57.3 ± 12.6 years, and the mean age of patients who did not attain CR was 60.5 ± 12.2 years. This data was not statistically significant (p = 0.192). In patients who underwent primary surgery, the number of patients who attained CR was 28 (21.9%); the number of patients who did not attain CR was 100 (78.1%). In patients who did not undergo primary surgery, the number of patients who attained CR was 3 (3.8%), and the number of patients who did not attain CR was 71 (96.3%). These data were statistically significant (p<0.001). There was a statistically significant difference between patients who attained CR in terms of no liver metastasis, no bone metastasis, and survivor status compared with those who did not attain CR (p = 0.041, p = 0.046, and p<0.001, respectively). In other words, 89.1% of patients with liver metastasis, 100.0% of patients with bone metastasis and 88.7% of those who died did not have a CR to treatment (Table 1).

Table 1. The comparison of clinical and histopathologic findings according to the complete response to treatment.

	Complete Response +		Complete Response -		P
	n = 31 Mean±SD	% Min-max	n = 171 Mean±SD	% Min-max	P
Age at diagnosis	57.3±12.6		60.5±12.2		0.192
Sex					0.731
Male	18	14.0	111	86.0
Female	13	15.7	70	84.3
Metastasis interval (month)	6.5±11.7		5.8±13.2		0.767
Number of metastatic regions	1 (1.09–1.62)		1 (1.60–1.87)		-
Primary region					0.160
Rectum	7	8.9	72	91.1
Distal colon	15	19.0	64	81.0
Proximal colon	6	14.3	36	85.7
Transverse colon	3	30.0	7	70.0
Primary surgery					<0.001
No	3	3.8	71	96.3
Yes	28	21.9	100	78.1
Histology					0.364
Unknown	1	9.1	10	90.9
Adenocarcinoma	25	14.0	153	86.0
Mucinous adenocarcinoma	5	29.4	12	70.6
Signet ring cell adenocarcinoma	0	0.0	3	1.0
Neuroendocrine differentiated adenocarcinoma	0	0.0	3	1.0
Differentiation					0.460
Good	2	18.2	9	81.8
Middle	21	21.6	76	78.4
Poor	1	6.3	15	93.7
Unknown	7	8.0	81	92.0
T stage					-
T1	1	100.0	0	0.0
T2	1	100.0	0	0.0
T3	16	25.0	48	75.0
T4	9	19.1	38	80.9
Tx	0	0.0	26	100.0
LVI					0.303
Yes	13	26.0	37	74.0
No	7	38.9	11	61.1
PNI					0.461
Yes	9	24.3	28	75.7
No	7	33.3	14	66.7
KRAS status					0.759
Unknown
Mutant	10	15.9	53	84.1
Wild type	12	16.0	63	84.0
Metastasis time					0.786
At the time of diagnosis	24	15.3	133	84.7
After adjuvant treatment	7	13.7	44	86.3
Liver metastasis					0.041
No	16	21.3	59	78.7
Yes	15	10.9	122	89.1
Bone metastasis					0.046
No	31	16.2	149	83.8
Yes	0	0.0	22	100.0
Adjuvant therapy					0.609
No	23	14.0	141	86.0
Yes	8	17.0	39	83.0
First-line treatment					0.276
Fluoropyrimidine	1	5.6	17	94.4
Irinotecan	12	19.4	50	80.6
Oxaliplatin	17	13.1	113	86.9
Survival status					<0.001
Survivor	9	52.9	8	47.1
Died	22	11.3	173	88.7

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LVI: Lymphovascular invasion, PNI: Perineural invasion.

When the tumor location subgroup analysis was performed, there was no statistically significant difference between the tumor locations (p = 0.072). The rates of patients with rectum cancer and colon cancer who attained CR was 8.9% and 18.3%, whereas the rates of the same cancers in who did not attain a CR were 91.1% and 81.7%.

Survival and predictors of survival and complete response (CR)

According to the multivariate analysis (logistic regression), the effects of variables on the “CR to treatment” are shown in Table 2. According to the logistic regression analysis, performing primary surgery significantly affects the CR to treatment (p = 0.006, Hazard Ratio HR: 0.168, 95% CI: 0.047–0.594). The effects of the age of diagnosis, liver metastasis, bone metastasis and first-line CT (fluoropyrimidine, irinotecan, and oxaliplatin) parameters on the CR to treatment were not statistically significant.

Table 2. Overall survival analysis based on whether a complete response was attained.

OS	Median (month)	95% C.I.		P
OS	Median (month)	Lower	Upper	P
CR -	16.990	14.702	19.278
CR +	39.230	22.141	56.319	<0.001
Total	19.580	16.646	22.514

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CR: Complete response to treatment, OS: Overall Survival.

OS analysis based on whether CR was attained is shown in Table 2. Patients who had a CR had longer median survival times than patients who did not have a CR (39.2 vs. 16.9 months, P≤0.001) (Fig 1, Table 2).

PFS analysis, based on whether a CR was attained is shown in Table 3. Patients who had a CR had longer median PFS than patients who did not have a CR (15.2 vs. 7.4 months, P<0.001) (Fig 2, Table 3).

Table 3. Progression-free survival analysis based on whether a complete response was attained.

PFS	Median (month)	95% CI		P
PFS	Median (month)	Lower	Upper	P
CR -	7.490	6.088	8.892
CR +	15.240	13.126	17.354	<0.001
Total	8.800	7.422	10.178

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CR: Complete response to treatment, PFS: Progression-free Survival.

According to the univariate analysis (Cox regression analysis), the effect of variables on OS is shown in Table 4. According to the Cox regression analysis, it was found that performing primary surgery contributed to a statistically significant increase in OS (p<0.001, HR: 1.719, 95% CI: 1.282–2.305). It is understood that performing primary surgery increases the OS by 1.719 times. Patients who undergo primary surgery have longer OS than patients with de novo metastasis. The decreases in the number of metastatic regions statistically significantly increased the OS time (p<0.001, HR: 1.375, 95% CI: 1.178–1.604). It is understood that a one-unit increase in the number of metastatic regions reduces OS by 1.375 times. When examining the metastasis sites, two groups were noteworthy. One of these was liver, the most common site of metastasis, and bone metastasis, one of the rare metastatic sites. Having liver metastases significantly reduced OS (p = 0.031, HR: 0.721, 95% CI: 0.535–0.971). Having bone metastases significantly reduced OS (p<0.001, HR: 0.396, 95% CI: 0.250–0.627). It was found that first-line treatment with fluoropyrimidine and a first-line treatment combination with irinotecan significantly increased OS (p = 0.007, p = 0.003, respectively). First-line treatment with combination treatment compared with single-agent fluoropyrimidine was found to increase OS statistically significantly (p = 0.002, HR: 2.196, 95% CI: 1.339–3.600). It was found that attaining a CR to treatment contributed to the most positively statistically significant increase in OS (p<0.001, HR: 2.648, 95% CI: 1.691–4.147) (Table 4).

Table 4. According to the univariate analysis (Cox regression analysis), the effect of variables on overall survival.

	Exp(B)	95.0% CI for Exp(B)		P
	Exp(B)	Lower	Upper	P
Age of diagnosis	1.007	0.995	1.019	0.265
Sex (Male to female)	0.824	0.618	1.100	0.190
Primary region (Rectum)				0.726
Primary region (Distal colon)	0.690	0.367	1.300	0.252
Primary region (Proximal colon)	0.722	0.382	1.365	0.316
Primary region (Transverse colon)	0.724	0.370	1.416	0.345
Primary surgery (performed according to not performed)	1.719	1.282	2.305	<0.001
Histology (Adeno)				0.178
Histology (Mucinous)	0.470	0.149	1.488	0.199
Histology (Signet ring)	0.367	0.106	1.274	0.114
Histology (Neuroendocrine)	1.147	0.231	5.694	0.866
Differentiation (Good)				0.316
Differentiation (Medium)	0.585	0.259	1.323	0.198
Differentiation (Poor)	0.662	0.375	1.171	0.156
T (T1)	0.717	0.097	5.301	0.744
T (T2)	2.483	0.332	18.590	0.376
T (T3)	0.615	0.385	0.981	0.042
T (T4a - T4b)	0.790	0.479	1.302	0.356
The number of LAP excised	1.000	0.988	1.012	0.992
Metastatic LAP number	1.025	0.997	1.054	0.082
LVI (According to the non-existent)	0.729	0.415	1.283	0.273
PNI (According to the non-existent)	0.648	0.358	1.174	0.152
KRAS status (mutant according to Wild)	0.851	0.603	1.202	0.361
Metastasis time (after adjuvant treatment according to the time of diagnosis)	0.990	0.715	1.371	0.952
Disease-free interval	0.996	0.986	1.007	0.470
Decreases in the number metastatic regions	1.375	1.178	1.604	<0.001
Liver metastasis	0.721	0.535	0.971	0.031
Bone metastasis	0.396	0.250	0.627	<0.001
Neoadjuvant therapy (according to the non-existent)	0.898	0.269	2.995	0.861
Adjuvant therapy (according to the non-existent)	1.062	0.757	1.490	0.729
First-line CT (Fluoropyrimidine)^*				0.007
First-line CT (İrinotecan)	2.146	1.296	3.554	0.003
First-line CT (Oxaliplatin)	0.931	0.678	1.279	0.660
First-line CT (Combination with Fluoropyrimidine)	2.196	1.339	3.600	0.002
CR to treatment	2.648	1.691	4.147	<0.001

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CT: Chemotherapy, LVI: Lymphovascular invasion, PNI: Perineural invasion, LAP: Lymphadenopathy, CR: Complete Response to treatment.

* Complete response in the first-line CT (Fluoropyrimidine) group is only one patient. Therefore, other values in the row could not be presented.

According to the multivariate analysis (logistic regression), the effects of variables on OS are shown in Table 5. In the multivariate analysis, CR to treatment (p = 0.002, HR: 2.107, 95% CI: 1.324–3.353); first-line CT (combination compared with single-agent fluoropyrimidine) (p = 0.014, HR: 1.909, 95% CI: 1.140–3.199); performing primary surgery (p = 0.033, HR: 1.406, 95% CI: 1.028–1.924) were found to be positively significantly associated with OS. These parameters prolonged OS and did not cross the line in the HR chart. It is understood that the most positively effective factor on OS is the “CR to treatment” status. Having bone metastases was found to be negatively associated with OS (p = 0.01 HR:0.488 95% CI: 1.140–3.199). Unlike the univariate analysis, decreases in the number of metastatic regions were not found to be significantly associated with OS (p = 0.108, HR: 1.17, 95% CI: 0.996–1.416). And unlike the univariate analysis, having liver metastases was not found to be negatively significantly associated with OS (p = 0.265, HR: 0.830, 95% CI: 0.283–0.840). Only bone metastases shortened OS but did not cross the line on the HR chart (Fig 3, Table 5).

Table 5. According to the multivariate analysis (logistic regression), the effects of variables on overall survival.

	Exp(B)	95.0% CI for Exp(B)		P
	Exp(B)	Lower	Upper	P
Primary surgery (performed according to not performed)	1.406	1.028	1.924	0.033
Liver metastasis	0.830	0.598	1.152	0.265
Bone metastasis	0.488	0.283	0.840	0.010
Decreases in the number metastatic regions	1.170	0.966	1.416	0.108
First-line CT (Combination with Fluoropyrimidine)	1.909	1.140	3.199	0.014
CR to treatment	2.107	1.324	3.353	0.002

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CT: Chemotherapy, CR: Complete Response to treatment.

Discussion

In this retrospective study, we investigated the clinicopathologic features, treatment regimen, OS, and PFS of patients with unresectable mCRC who attained a CR with systemic treatment compared with patients without a CR. It is known that a CR is obtained in 10–15% of patients with metastatic colorectal cancer who receive systemic treatment according to the RECIST1.1 criteria [8]. In our study, similar to the literature, 15.3% of our group of 202 patients attained a CR. Having CR to treatment was found to be associated with OS and PFS. According to the univariate analysis, performing primary surgery, decreased numbers of metastatic regions, liver metastasis, no bone metastasis, first-line CT (fluoropyrimidine), first-line CT (irinotecan), and CR to treatment were found to be associated with OS. However, in the multivariate analysis, primary surgery, first-line CT (combination compare with fluoropyrimidine alone) and CR to treatment were found to be positively associated with OS, and bone metastasis was negatively associated with OS.

CRC is the third most common cancer diagnosed between both sexes with an estimated death rate of 51,020 and an estimated 145,600 new cases for 2019 [11]. Metastatic CRC (mCRC) is an advanced age malignancy that presents at a median age of 67 years [12]. In our study, the mean age of diagnosis of mCRC was 60.13 ± 12.52 years, younger than in the literature. Significantly, OS and PFS number of outliers was significantly lower with increasing age [13]. Contrary to the literature, age was not found to be prognostic for OS and PFS in our study.

mCRC occurs in >50% of cases, the majority of which are inoperable at presentation [14, 15]. In our study, patients with de novo metastasis comprised 40.6% of the study group, slightly less than in the literature. Both patients with de novo metastasis and patients who had primary tumor surgery and received neoadjuvant/adjuvant therapy were included in the study. It was found that performing primary surgery contributed to a statistically significant increase in OS. De novo metastatic colorectal cancer was associated with poor prognosis.

Approximately 60% of patients with CRC will develop liver metastases [16]. Most patients have a recurrence after partial hepatectomy, but approximately 20% are cured [17, 18]. However, the vast majority (80–90%) presents unresectable diseases. In the study of D´Angelica et al. on 49 colorectal cancer patients with unresectable hepatic metastasis was reported that only four patients achieved a CR after CT (oxaliplatin, irinotecan, fluoropyrimidine, and bevacizumab). The median OS was 38 months. The median OS and PFS for all patients were 38 and 13 months. CR was obtained in 10 of 49 patients after primary surgery. The median OS of these patients was 39 months. They reported that primary surgery and treatment with modern systemic CT of colorectal-liver metastasis (CRLM) were associated with long-term survival [19]. In our study, 64.5% of patients with mCRC had liver metastasis. The number of patients with liver metastases and CRs was 15. Similar to the literature, in our study, patients who had a CR had longer median survival times than patients who did not have a CR (39.2 vs. 16.9 months). Patients who had a CR had longer median PFS than patients who did not have a CR (15.2 vs. 7.4 months).

Bone metastasis is a rare consequence of colorectal cancer and is a sign of poor prognosis. Several reports in the literature describe a positive response to double CT, with targeted therapy currently being the standard treatment [20]. In a study by Arslan et al., the authors detected bone metastasis at the 4th month during the treatment of FOLFOX plus bevacizumab for a patient with unresectable mCRC. The patient died 4 months after developing bone metastasis. They stated that bone metastases could be the precursor of short survival [21]. In a study by Nakamura et al., a 51-year-old patient with mCRC with bone metastasis died 16.6 months after the first-line CT treatment [20]. In our study, 22 (9.9%) patients had bone marrow metastases. In terms of bone marrow metastases, there is a statistical significance in patients who attained a CR to treatment compared with those who did not attain a CR. Patients with bone metastasis were not able to attain a CR to treatment. According to the univariate analysis (Cox regression analysis), it was found that the bone metastases significantly reduced the OS (p<0.001, HR: 0.396, 95% CI: 0.250–0.627). In the patient group with bone metastasis, the median OS was 16.990 months, which was quite low. In the multivariate analysis, bone metastasis was found to be significantly associated with OS (p = 0.010, HR: 0.488, 95% CI: 0.283–0.840). None of the patients with bone metastases had a CR to treatment. Bone metastases in metastatic colorectal cancer was also associated with poor prognosis. With bone targeted drugs and radiotherapy methods that can be applied locally to the bone, a complete response may be possible in bone metastasis. Setting new targets could be useful for drug development studies in such patients with poor prognostic subgroups of mCRC.

Treatment of unresectable mCRC is mitigated with systemic antineoplastic therapy aimed at maintaining OS, symptom management, and quality of life [14]. The median survival of patients with advanced colorectal cancer treated with single fluoropyrimidine is approximately 1 year, whereas it is approximately 2 years in those treated with a combination of irinotecan or oxaliplatin with fluoropyrimidine-based CT. As stated in the literature, our patients were receiving fluoropyrimidine, irinotecan, and oxaliplatin treatment as first-line CT. However, it was also found that first-line CT treatment with fluoropyrimidine and irinotecan significantly increased OS, but not first-line CT with oxaliplatin. The combination of new targeted agents (bevacizumab, cetuximab or panitumumab) and CT have extended life expectancy of patients with metastatic colorectal cancer over 30 months and 5-year survival in certain mCRC subsets was reported as 14.2% [14, 15]. In our study, first-line treatment was evaluated regardless of the use of biological agents. Even so, this is what makes our article original; patients who had a CR to treatment had longer median survival times than patients who did not have a CR to treatment (39.2 vs. 16.9 months). Patients who had a CR to treatment had longer median PFS times than patients who did not have a CR (15.2 vs. 7.4 months). CR significantly improved the prognosis. Nevertheless after the long follow-up time, our study reported only 8.2% of patients were alive.

Despite the strengths of the current study, some limitations should be taken into account when considering the results. First, as with any retrospective study, there was a bias inherent in its nature. Second, some studies have identified performance condition as an important prognostic factor in mCRC. However, we did not have access to these data for inclusion in our study. Third, we also did not have information about what treatments the patient received after the first-line treatment in patients who could not achieve CR, maybe sequential systemic treatments could be examined and the incidence of CR could be increased. Fourth, in the subgroup analysis of patients with rectum cancer, the number of patients who received neoadjuvant radio chemotherapy could not be analyzed because there were only six patients. The last limitation, perhaps the most important limitation, is that the study was conducted with rather small number of patients. Future prospective and large database studies should be used to further validate and investigate our results. Interestingly, the CR was an independent predictor of survival for about 40months in OS and for about 15 months in PFS. This series also advises that there could be a higher rate of patients with mCRC attaining CR with raised targets and targeted therapy.

Conclusion

In conclusion, the primary results of our study showed that patients with unresectable mCRC who attained CR had significantly prolonged survival with a permanent response to therapy. The secondary result of our study showed that de novo metastasis or liver metastasis or bone metastasis in patients who did not attain CR was associated with poor prognosis. Finally, the study provides some important results that physicians can use in terms of expected life expectancy when counseling patients who respond completely.

Supporting information

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Data Availability

Data cannot be shared publicly because of local ethics committee decision. Data are available from the Ege University Medical School,Izmir-Turkey Data Access / Ethics Committee (contact via:egetaek@gmail.com) for researchers who meet the criteria for access to confidential data.

Funding Statement

Unfunded studies: The author(s) received no specific funding for this work.

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PLoS One. doi: 10.1371/journal.pone.0259622.r001

Decision Letter 0

Nader Hanna

10 Dec 2020

PONE-D-20-28477

Contribution of “Complete Response to Treatment” to Survival in Patients with Unresectable Metastatic Colorectal Cancer; Retrospective Analysis

PLOS ONE

Dear Dr. Bulut,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

Please submit your revised manuscript by Jan 24 2021 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

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We look forward to receiving your revised manuscript.

Kind regards,

Nader Hanna

Academic Editor

PLOS ONE

Additional Editor Comments:

The manuscript needs through review/edits for the English language and grammar.

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Partly

**********

2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: No

**********

3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: No

**********

4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: No

**********

5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

The authors performed a retrospective review of patients diagnosed with unresectable Stage IV colorectal cancer at a single institution to determine how different treatment strategies affected patient outcomes (overall survival, progression free survival), based on whether patients did or did not attain complete response (CR) to treatment. The authors report that patients who underwent primary surgery had a higher rate of obtaining CR. Patients with liver metastasis and bone metastasis were unlikely to obtain CR. Patients with CR had longer median survival times and progression free survival. Additionally, patients who underwent first line treatment with fluoropyrimidine or irinotecan also increased overall survival, while number of metastatic regions reduced overall survival. While I believe this study and results are interesting and important, the data is presented in somewhat confusing fashion and the conclusions that are drawn are not always clearly presented.

Authors should include in the abstract the type of study this was (a retrospective chart review).

There are multiple places in the manuscript were it is stated p=0.0000. While this may be correct from a rounding standpoint, from a statistical standpoint, I believe it would be more correct to state p<0.001.

What exactly do the authors mean by "primary surgery"? In the Methods section, they state that any patients who underwent metastectomy during treatment were excluded. Does "primary surgery" indicate surgery as the FIRST step in their treatment? Or rather that the patient underwent surgery of their primary tumor? What surgeries did these patients undergo (resection, debulking, diversion) etc, and what were the indications for these operations?

Colon and rectal cancers are grouped together in this analysis, but I do not see any mention of radiation treatment for patients with rectal cancer. Was this not included in their neoadjuvant treatment? It be interesting to see a subgroup analysis of colon vs rectal cancer to ID any difference between the two groups.

In discussing the significant results from Table 2 - the way in which the data are presented is very confusing and the authors extrapolate new percentages within the text (albiet correct percentages based on number of patients with liver/bones mets or those who did not survive) to discuss the significant findings, but these are different than the percentages in Table 2. Would reword this to make the understanding more clear.

In discussing results from Table 6 - the authors interpretation of hazard ratios inconsistently increase or decrease OS (i.e. HR 1.7 for primary surgery increases OS, but HR of 1.375 for met regions DECREASES OS, same for liver vs bone mets). If this is based on how the data was analyzed, it should be described in such a fashion that this is understandable, otherwise, it appears that the results have been interpreted incorrectly.

In discussing results from Table 7 - the authors should discuss the different hazard ratios and how they each affect overall survival. The way that it is written groups all the variables together without describing their affect (i.e. surgery and chemo increase OS, while bone mets decreases overall survival).

In the discussion section, these results are again grouped together without delineating positive or negative association with the multiple variable discussed.

The discussion session includes discussion of mCRC in elderly patients, but it is unclear to me exactly how this relates to the data presented in this study?

What additional therapeutic approaches to metastatic disease are the authors referencing in the last paragraph of the Discussion section?

**********

6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

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Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

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PLoS One. 2021 Nov 8;16(11):e0259622. doi: 10.1371/journal.pone.0259622.r002

Author response to Decision Letter 0

13 Jan 2021

Dear Dr. Editor and Reviewers;

1. The article's titles and figure suggestions were arranged in accordance with PLOS ONE style.

2.The requested correction for ethical approval was rewritten in the first paragraph of the material method section.

3. P-values less than 0.001 was expressed as p < 0.001.

4. The article was edited with a professional scientific editing service. 

 5. the desired correction has been made

  Response to the Reviewers  1. Is the manuscript technically sound, and do the data support the conclusions?  The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Partly

The statistical mistakes , table and explanation part of the study were corrected and correct interpretation was made.

2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: No

This article was received professional support for statistics.The statistics mistake and misinterpretations were corrected and presented.

3. Have the authors made all data underlying the findings in their manuscript fully available? 

Reviewer #1: No

 We've added the maniscpripts statistic data as part of the manuscript or its supporting information, or we've allowed to deposited to a public repository.

4. Is the manuscript presented in an intelligible fashion and written in standard English? 

Reviewer #1: No

The article was edited with a professional scientific editing service.

5. Review Comments to the Author  Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer # 1: There are multiple grammatical and typographical errors throughout the manuscript that make it difficult to easily read. These should be reviewed prior to resubmission to improve readability of manuscript. The authors performed a retrospective review of patients diagnosed with unresectable Stage IV colorectal cancer at a single institution to determine how different treatment strategies affected patient outcomes (overall survival, progression free survival), based on whether patients did or did not attain complete response (CR ) to treatment. The authors report that patients who underwent primary surgery had a higher rate of obtaining CR. Patients with liver metastasis and bone metastasis were unlikely to obtain CR. Patients with CR had longer median survival times and progression free survival. Additionally, patients who underwent first line treatment with fluoropyrimidine or irinotecan also increased overall survival, while number of metastatic regions reduced overall survival. While I believe this study and results are interesting and important, the data is presented in somewhat confusing fashion and the conclusions that are drawn are not always clearly presented. Authors should include in the abstract the type of study this was (a retrospective chart review). There are multiple places in the manuscript were it is stated p = 0.0000. While this may be correct from a rounding standpoint, from a statistical standpoint, I believe it would be more correct to state p <0.001. What exactly do the authors mean by "primary surgery"? In the Methods section, they state that any patients who underwent metastectomy during treatment were excluded. Does "primary surgery" indicate surgery as the FIRST step in their treatment? Or rather that the patient underwent surgery of their primary tumor? What surgeries did these patients undergo (resection, debulking, diversion) etc, and what were the indications for these operations? Colon and rectal cancers are grouped together in this analysis, but I do not see any mention of radiation treatment for patients with rectal cancer. Was this not included in their neoadjuvant treatment? It be interesting to see a subgroup analysis of colon vs rectal cancer to ID any difference between the two groups.

Answers;

The article was editing by David Frances Chapman

The findings and discussion section presented as confusing was rewritten.

‘a retrospective chart review ‘ was added in abstract section

P-values less than 0.001 was expressed as p < 0.001.

Patients who received adjuvant therapy were not excluded in the study, therefore patients who underwent primary tumor resection were included in our study. This was explained in the article more clearly, necessary additions were made. Colon and rectum sub group analyzes were performed in patients and this subgroup analysis was added as a paragraph. But neoadjuvant treatment was not evaluated because only 6 of the rectal cancer patients received neoadjuvant rt. This is our limitation and was added last paragragh.

In discussing the significant results from Table 2 - the way in which the data are presented is very confusing and the authors extrapolate new percentages within the text (albiet correct percentages based on number of patients with liver / bones mets or those who did not survive) to discuss the significant findings, but these are different than the percentages in Table 2. Would reword this to make the understanding more clear

The percentages were rewritten correctly in the article. Mistakes ; It was presented in its corrected form.

In discussing results from Table 6 - Since the p value is accepted as 0.05. in univariate analyzes the number of metastatic regions also both bone met and kc metastasis shortens OS time. But multivariete analises, only bone metastases were found to be statistically significant. While bone negative os contribution was significant in fig 3 according to HR, kc and numbers of metastasis region cut the line, so it was not significant.

In univariate analysis, we realized and corrected our error presented by shortening it with the one without bone metastases and presented it correctly.

……….

How all the data in table 7 affects the OS was added to the article. the explanation was expressed more clearly.

………

Much information given with CRC with elderly patients was removed and restricted to the age paragraph only.

In the discussion section, these results are again grouped together without delineating positive or negative association with the multiple variable discussed. The discussion session includes discussion of mCRC in elderly patients, but it is unclear to me exactly how this relates to the data presented in this study? What additional therapeutic approaches to metastatic disease are the authors referencing in the last paragraph of the Discussion section?

The statistical mistakes , table and explanation part of the study were corrected and correct interpretation was made.Additional therapeutic approaches were actually describing sequential CT. In other words, secondary or third line treatments were not evaluated in this study. It was written into the article in a more descriptive way.

Attachment

Submitted filename: response to reviewers.docx

Click here for additional data file.^{(13.7KB, docx)}

PLoS One. doi: 10.1371/journal.pone.0259622.r003

Decision Letter 1

Ludmila Vodickova

14 Apr 2021

PONE-D-20-28477R1

Contribution of “Complete Response to Treatment” to Survival in Patients with Unresectable Metastatic Colorectal Cancer; A Retrospective Analysis

PLOS ONE

Dear Dr. Bulut,

In agreement with the reviewer the authors did improve the manuscript, however, its presentation and readability remain weak points. Unless the presentation is improved, the manuscript may not be accepted in the present form. I would like to encourage authors to answer all comments and put an effort in improving the language.

Please submit your revised manuscript by May 29 2021 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols.

We look forward to receiving your revised manuscript.

Kind regards,

Ludmila Vodickova, M.D., PhD

Academic Editor

PLOS ONE

Journal Requirements:

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: (No Response)

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

Reviewer #1: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

Reviewer #1: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

Reviewer #1: No

**********

6. Review Comments to the Author

Reviewer #1: Informed consent was obtained from all 222 patients in the study? This is not typical of a retrospective chart review.

There are still multiple grammatical and typographical errors throughout the paper that make it somewhat difficult to read, for example (this does not include all the errors in the article, just a sampling):

Abstract

Background - second sentence is an incomplete sentence

Results - in the sentence discussing primary surgery - what two groups are being compared?

is completion response the same as complete response? Confusing to change the verbiage

Conclusion - mCRC is used without being previously defined in Abstract

Materials and Methods

"if the primary tumor had been operated" is not correct grammar

Abbreviations are used inconsistently throughout the article. If you are using CT to represent chemotherapy, it should be that way through the entire article

Overall, the introductions, methods, and results are much improved (and interesting) from the prior version.

The Discussion, however, remains disorganized and confusing.

The authors include information about novel anti-VEGF, anti-EGFR targeted agents, but these were not included in the study presented and it is confusing how they then tie this to their findings of longer survival times in patients who attained CR. Yes, these new agents are important to include, but I do not understand how this is related to your data?

The paragraph starting with " A total of 20,023 patients" seems completely out of order within the discussion and is not clear what first 24 clinical trials are being referenced?

Then the discussion switches back to talking about chemotherapy again.

I suggest that the authors reorganize the discussion section and ensure that they focus on their findings.

Conclusion

What results can physicians use when counseling patients with CR?

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

PLoS One. 2021 Nov 8;16(11):e0259622. doi: 10.1371/journal.pone.0259622.r004

Author response to Decision Letter 1

1 May 2021

Journal Requirements:

Response th Editor: Wanted changes in references was done.

Reviewer's Responses to Questions

Comments to the Author

Reviewer #1: (No Response)

2. Is the manuscript technically sound, and do the data support the conclusions?

Reviewer #1: Yes

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

4. Have the authors made all data underlying the findings in their manuscript fully available?

Reviewer #1: Yes

4. Have the authors made all data underlying the findings in their manuscript fully available?

Reviewer #1: Yes

5. Is the manuscript presented in an intelligible fashion and written in standard English?

Response the review: the article was editted for standart English

6. Review Comments to the Author

Reviewer #1: Informed consent was obtained from all 222 patients in the study? This is not typical of a retrospective chart review.

Response the reviewer: Informed consent was obtained as it was the request of the university ethics committee. However, this information in the article has been removed to avoid confusion for the reader.

Abstract

Background - second sentence is an incomplete sentence

Response the reviewer: second sentence was completed

Results - in the sentence discussing primary surgery - what two groups are being compared?

is completion response the same as complete response? Confusing to change the verbiage

Response the reviewer: Result section in abstract was re-written according to reviewer recommendation.

Conclusion - mCRC is used without being previously defined in Abstract

Response the reviewer: mCRC was defined in Abstract

Materials and Methods

"if the primary tumor had been operated" is not correct grammar

Response the reviewer: this sentence was written correctly

Abbreviations are used inconsistently throughout the article. If you are using CT to represent chemotherapy, it should be that way through the entire article

Response the reviewer: the abbreviations were written consistently by scanning the entire article.

Overall, the introductions, methods, and results are much improved (and interesting) from the prior version.

Response the reviewer: Thank you very much for your valuable contribution.

The Discussion, however, remains disorganized and confusing.

The paragraph starting with " A total of 20,023 patients" seems completely out of order within the discussion and is not clear what first 24 clinical trials are being referenced?

Then the discussion switches back to talking about chemotherapy again.

I suggest that the authors reorganize the discussion section and ensure that they focus on their findings.

Changed paragraph places so that it can continue within a flow, and focus on our findings

Response the reviewer: Discussion section was re-written. extra information of except findingswas removed. Targeted agents was mentioned only in the times of overall survey in discussion.

Conclusion

What results can physicians use when counseling patients with CR?

Response the reviewer: Wanted changes was done in conclusion.

Attachment

Submitted filename: response to reviewers .docx

Click here for additional data file.^{(12.2KB, docx)}

PLoS One. doi: 10.1371/journal.pone.0259622.r005

Decision Letter 2

Ludmila Vodickova

27 May 2021

PONE-D-20-28477R2

Contribution of “Complete Response to Treatment” to Survival in Patients with Unresectable Metastatic Colorectal Cancer; A Retrospective Analysis

PLOS ONE

Dear Dr. Bulut,

General comments:The authors did a big job in improving the language, the text is now better readible and understandable. Anyway there are still some uncertainties, what the sentence means.Authors referred about metastatic colorectal cancer of two types, liver and bone metastasis. Liver metastasis is the most frequent, opposit is bone metastasis, it is one of rare metastatic site. Is some reason, why authors selected those two types? The authors enrolled 222 patients and evaluated complete response (Yes-No) in 212persons. The percentage for CR group is fitting with 212 persons (e.g. section Results first para, section Discussion, first para). Maybe I would recomend authors to simplify the situation and presented results only from those, who were evaluated from CR point. This is a main aim of the study. In this case Table 1 could be removed. The authors omitted to mention the end of follow up period, the exact date (month/year). Why the authors focused on two distinct group of patients? First, incidentally diagnosed metastatic CRC and second on those with developed metastasis after primary tumor resection? The second group might be associated with chemoresistance or treatment response.128 patients had primary surgery, only 47 had adjuvant chemotherapy, please, add some comment.18 patients had no LVI and 21 patients had no PNI - does it mean that they have only liver or bone metastasis? The study belongs to rather small study, it should be mentioned in the limitation of the study. Particular commentsAbstract:last sentence: ......and the combination therapy regimens... Material and Methodsto add the date of termination of follow up ResultsAs mentioned above, Table 1 could be removed, the text and next table contain all information.Table 3 is also perfectly described in the text and can be omitted. Also because the numbers for Exp(B) in case of bone metastasis are nonsense and numbers in case of fluoropyrimidine are missing.In the text is abbreviation HR, in first appearance maybe should be explained (hazard ratio). Table 6 - there are some empty boxes(cells) in the table, but the significance is calculated. It is confusing. Especially in the case, when is significant result (First line CT(Fluoropyrimidine)). The abbreviation "LAP" is not explain DiscussionFirst paragraph, last sentence....first line CT (combination compare with fluoropyrimidine alone)...Second paragraph: The sentence "Significantly, OS and PFS outliers were lower with increasing age [13]." is not understandable. Does it mean: "OS and PFS number of outliers was significantly lower with increasing age" ?Fourth para, fourth sentence: my suggestion how to reformulate:In the study of D´Angelica et al. on 49 colorectal cancer patients with unresectable hepatic metastasis was reported that only.....Last paraInterestingly, the CR was an independent predictor of survival for about 40months in OS and for about 15 months in PFS. Fig. 1Should be probably "First-line CT (combination with fluoropytimidine)" instead of "First-line CT (combination according to fluoropyrimidine)"

Please submit your revised manuscript by Jul 11 2021 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

We look forward to receiving your revised manuscript.

Kind regards,

Ludmila Vodickova, M.D., PhD

Academic Editor

PLOS ONE

Journal Requirements:

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

Reviewer #2: (No Response)

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

Reviewer #2: No

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #2: N/A

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

Reviewer #2: No

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

Reviewer #2: No

**********

6. Review Comments to the Author

Reviewer #2: I received this manuscript after the first revision. Even though the article has been revised, my feelings are confused. The article focused on determining the complete response in the metastatic CRC. However, everything that the authors studied in their study has long been known, and the conclusions of the study do not contribute much to the already acquired knowledge about the survival of metastatic CRC patients.

The authors stated that CR was less common in the presence of liver metastasis and bone metastasis. My question is: If authors focused on mCRC and no lung or other distant metastasis were observed, what is it outcome of this observation?

It is not clear whether authors focused on sporadic CRC?

What was the end of the study, I mean when the follow up terminated?

Why the authors focused on two distinct group of patients? First, incidentally diagnosed metastatic CRC and second on those with developed metastasis after primary tumor resection? The second group might be associated with chemoresistance or treatment response.

Is it correct the metastasis interval? 5.93±12.81 (Mean ±SD)

The authors stated that there were 20 survivors and median patients follow up was in range 0.3 to almost 132 months. With no defined end of the study, this has no reason to show up.

If I understand correctly, 9% of those patients with no primary surgery reached CR while 42% with no primary surgery did not reach CR. This outcome is clear from Table 2 and further again elaborated in Table 3, 6 and 7. Why it can not be only supplemented by additional text only?

Besides, 128 patients had primary surgery however only 47 had adjuvant therapy. Why? This should be mentioned. What was the median time to develop metastasis in these patients?

Further, 18 patients had no LVI and 21 no PNI, are there really all patients in the study in stage IV?

The main limitation is also relatively small population size that might results many of outcomes as false positives. This should be commented.

Discussion is wordy and not focused on obtained results.

In addition, the article is written in very poor English and the several sentences do not make sense.

The article contains unnecessarily many tables and the following text, which comment on everything that can be found in the table and usually comments on insignificant results. Tables 3, 4 and 5 can be omitted and only stated by additional text as it is already.

**********

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If you choose “no”, your identity will remain anonymous but your review may still be made public.

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Reviewer #2: No

PLoS One. 2021 Nov 8;16(11):e0259622. doi: 10.1371/journal.pone.0259622.r006

Author response to Decision Letter 2

20 Jun 2021

İPONE-D-20-28477 Contribution of “Complete Response to Treatment” to Survival in Patients with Unresectable Metastatic Colorectal Cancer; Retrospective Analysis PLOS ONE  Dear Dr. Editor and Reviewers;

General comments:

Authors referred about metastatic colorectal cancer of two types, liver and bone metastasis. Liver metastasis is the most frequent, opposit is bone metastasis, it is one of rare metastatic site. Is some reason, why authors selected those two types?

1-6 metastatic sites were evaluated and included in the article. however, since these two metastatic sites are very significant, the study focused on these two sites. This comment has been added to the article.

The authors enrolled 222 patients and evaluated complete response (Yes-No) in 212persons. The percentage for CR group is fitting with 212 persons (e.g. section Results first para, section Discussion, first para).

the number of patients is given in the article. Complete response was evaluated only in these 202 patients, as the full data of 202 patients were available.This comment has been added to the article.

Maybe I would recomend authors to simplify the situation and presented results only from those, who were evaluated from CR point. This is a main aim of the study. In this case Table 1 could be removed.

table 1 could be removed.

The authors omitted to mention the end of follow up period, the exact date (month/year).

The end of follow up date (month/year) was added the manuscript

The patient group is metastatic colorectal cancer patients. This group includes patients who have previously been operated and/or received adjuvant therapy.This comment has been added to the article.

128 patients had primary surgery, only 47 had adjuvant chemotherapy, please, add some comment.

80 patients had primary surgery but only 48 patients received adjuvant therapy. This information has also been added to the article.

18 patients had no LVI and 21 patients had no PNI - does it mean that they have only liver or bone metastasis?

Since the initial pathology was evaluated, there was no LVI and PNI from patients who were not metastatic at the time of diagnosis. Added as a comment to the article.

The study belongs to rather small study, it should be mentioned in the limitation of the study.

This knowledge added to the limitations paragraph.

Particular comments

Abstract:

last sentence: ......and the combination therapy regimens…

corrected in the article.

Material and Methods

to add the date of termination of follow up

corrected in the article.

Results

As mentioned above, Table 1 could be removed, the text and next table contain all information.

Table 3 is also perfectly described in the text and can be omitted. Also because the numbers for Exp(B) in case of bone metastasis are nonsense and numbers in case of fluoropyrimidine are missing.

In the text is abbreviation HR, in first appearance maybe should be explained (hazard ratio).

Table 1 and 3 was removed in manuscript

Table 6 - there are some empty boxes(cells) in the table, but the significance is calculated. It is confusing. Especially in the case, when is significant result (First line CT(Fluoropyrimidine)).

The abbreviation "LAP" is not explain

corrected in the article.

Discussion

First paragraph, last sentence.

...first line CT (combination compare with fluoropyrimidine alone)...

Second paragraph: The sentence "Significantly, OS and PFS outliers were lower with increasing age [13]." is not understandable. Does it mean: "OS and PFS number of outliers was significantly lower with increasing age" ?

corrected in the article.

Fourth para, fourth sentence: my suggestion how to reformulate:

In the study of D´Angelica et al. on 49 colorectal cancer patients with unresectable hepatic metastasis was reported that only…..

corrected in the article.

Last para

Interestingly, the CR was an independent predictor of survival for about 40months in OS and for about 15 months in PFS.

corrected in the article.

Fig. 1

Should be probably "First-line CT (combination with fluoropytimidine)" instead of "First-line CT (combination according to fluoropyrimidine)”

corrected in the article.

 Journal Requirements:

Comments to the Author  

Sorry for your comment. There are very few studies on complete response.

I have been waiting for a year for the article to be published in your journal. I'm starting to think I've been lingering for a long time

In this study, all metastatic areas were examined. It was evaluated from 1 to 6 metastatic sites. but there was significant results in both bone and liver. At the same time, the importance of the number of metastatic sites was mentioned in the study.

It is not clear whether authors focused on sporadic CRC? 

Patients who developed both denovo metastatic and follow-up metastases were included in the study.

What was the end of the study, I mean when the follow up terminated?  At the end of the study, patients with complete responses were found to have a long survey.

Why the authors focused on two distinct group of patients?

These are not two different groups, they are all metastatic patients; whether it is metastasis at the time of diagnosis or metastasis develops during follow-up.

First, incidentally diagnosed metastatic CRC and second on those with developed metastasis after primary tumor resection?

The second group might be associated with chemoresistance or treatment response. 

Added as a comment to the article.

Is it correct the metastasis interval? 5.93±12.81 (Mean ±SD) 

This is correct.

The authors stated that there were 20 survivors and median patients follow up was in range 0.3 to almost 132 months. With no defined end of the study, this has no reason to show up. If I understand correctly, 9% of those patients with no primary surgery reached CR while 42% with no primary surgery did not reach CR.

The importance of primary surgery was mentioned in many places in the article.

This outcome is clear from Table 2 and further again elaborated in Table 3, 6 and 7. Why it can not be only supplemented by additional text only?

Table 1 and 3 was removed.

 Besides, 128 patients had primary surgery however only 47 had adjuvant therapy. Why? T his should be mentioned.

Added as a comment to the article.

Further, 18 patients had no LVI and 21 no PNI, are there really all patients in the study in stage IV?

Added as a comment to the article.’ Because only devo metastatic patients were not evaluated’ The main limitation is also relatively small population size that might results many of outcomes as false positives. This should be commented.

Added as a comment to the article.

 Discussion is wordy and not focused on obtained results. In addition, the article is written in very poor English and the several sentences do not make sense. The article contains unnecessarily many tables and the following text, which comment on everything that can be found in the table and usually comments on insignificant results. Tables 3, 4 and 5 can be omitted and only stated by additional text as it is already.

The article’s english was edited

Attachment

Submitted filename: response to reviewers 13.06.docx

Click here for additional data file.^{(14.4KB, docx)}

PLoS One. doi: 10.1371/journal.pone.0259622.r007

Decision Letter 3

Ludmila Vodickova

19 Aug 2021

PONE-D-20-28477R3

Contribution of “Complete Response to Treatment” to Survival in Patients with Unresectable Metastatic Colorectal Cancer; A Retrospective Analysis

PLOS ONE

Dear Dr. Bulut,

The authors did great job in improving the paper, but there are still some very small things to consider and repair:

ABSTRACT:

In addition, to is evaluate progression-free survival…– should be: In addition, to evaluate progression-free survival…

… In subgroup patients with who underwent primary surgery; the number….should be: In subgroup patients who underwent primary surgery, the number…

RESULTS:

The sentence: Because only devo metastatic patients were not evaluated; should be deleted

Twenty (9.0%) patients were still alive, 222 (91.0%) patients had died .- it is some mistake or typing error, this does not correspond with total number of enrolled patients (222=100%).

PFS analysis, based on whether a CR was attained is shown in Table 5

should be . PFS analysis, based on whether a CR was attained is shown in Table 3

Table 4:

there are missing values for Exp(B) and 95%CI in the case of: Primary region (Rectum). Histology (Adeno), Differentiation (Good) – all of them are not significant values, it is not so critical, but there are missing also in the case of First-line CT (Fluoropyrimidine), which are significant P=0.007.

Row with T0 has no sense.

First-line CT (Combination according to Fluoropyrimidine) _ I guess should be: (Combination with Fluoropyrimidine)

Table 5

First-line CT (Combination according to Fluoropyrimidine) _ I think it should be: (Combination with Fluoropyrimidine).

DISCUSSION:

The sentence: However, the vast majority (80-90%) present with unresectable diseases should be:

However, the vast majority (80-90%) presents unresectable diseases

The sentence:

…..whereas it is approximately 2 years in those treated with a combination of irinotecan or oxaliplatin to fluoropyrimidine-based CT.

Should be:… whereas it is approximately 2 years in those treated with a combination of irinotecan or oxaliplatin with fluoropyrimidine-based CT.

FIGURE 3:

First-line CT (Combination according to Fluoropyrimidine) _ should be: Combination with Fluoropyrimidine

Decreases in Number of metastatik lesion

should be: Decreases in Number of metastatic lesions

Please submit your revised manuscript by Oct 03 2021 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

We look forward to receiving your revised manuscript.

Kind regards,

Ludmila Vodickova, M.D., PhD

Academic Editor

PLOS ONE

Journal Requirements:

Please clarify the nature of the informed consent in your Ethics Statement and Methods section. When and how did patients provide their consent? Did patients consent to the medical treatment, and/or did they specifically consent to participate in this study or to have their medical records used in research?

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

PLoS One. 2021 Nov 8;16(11):e0259622. doi: 10.1371/journal.pone.0259622.r008

Author response to Decision Letter 3

25 Aug 2021

Dear Editor,  ABSTRACT:  In addition, to is evaluate progression-free survival…– should be: In addition, to evaluate progression-free survival…  … In subgroup patients with who underwent primary surgery; the number….should be: In subgroup patients who underwent primary surgery, the number…

*the necessary changes was made.

RESULTS:  The sentence: Because only devo metastatic patients were not evaluated; should be deleted

Twenty (9.0%) patients were still alive, 222 (91.0%) patients had died .- it is some mistake or typing error, this does not correspond with total number of enrolled patients (222=100%).

Twenty (9.0%) patients were still alive, 202 (91.0%) patients had died *the necessary changes was made.

PFS analysis, based on whether a CR was attained is shown in Table 5  should be . PFS analysis, based on whether a CR was attained is shown in Table 3 *the necessary changes was made.

Table 4:  there are missing values for Exp(B) and 95%CI in the case of: Primary region (Rectum). Histology (Adeno), Differentiation (Good) – all of them are not significant values, it is not so critical, but there are missing also in the case of First-line CT (Fluoropyrimidine), which are significant P=0.007. Row with T0 has no sense.

Since the number of cases in the sub group is insufficient, the values mentioned in the table cannot be given. The number of patients with a complete response in the first-line CT (Fluoropyrimidine) group is only “1”.

This information has been added as a table description.

The missing values in the table was filled and Row with T0 was deleted

First-line CT (Combination according to Fluoropyrimidine) _ I guess should be: (Combination with Fluoropyrimidine) *the necessary changes was made.

Table 5 First-line CT (Combination according to Fluoropyrimidine) _ I think it should be: (Combination with Fluoropyrimidine). *the necessary changes was made.

DISCUSSION: The sentence: However, the vast majority (80-90%) present with unresectable diseases should be: However, the vast majority (80-90%) presents unresectable diseases *the necessary changes was made.

The sentence: …..whereas it is approximately 2 years in those treated with a combination of irinotecan or oxaliplatin to fluoropyrimidine-based CT.  Should be:… whereas it is approximately 2 years in those treated with a combination of irinotecan or oxaliplatin with fluoropyrimidine-based CT. *the necessary changes was made.

FIGURE 3: First-line CT (Combination according to Fluoropyrimidine) _ should be: Combination with Fluoropyrimidine Decreases in Number of metastatik lesion  should be: Decreases in Number of metastatic lesions

*the necessary changes was made.

Attachment

Submitted filename: response to reviewers 22.08.docx

Click here for additional data file.^{(9.5KB, docx)}

PLoS One. doi: 10.1371/journal.pone.0259622.r009

Decision Letter 4

Ludmila Vodickova

25 Oct 2021

Contribution of “Complete Response to Treatment” to Survival in Patients with Unresectable Metastatic Colorectal Cancer; A Retrospective Analysis

PONE-D-20-28477R4

Dear Dr. Bulut,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.

If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

Ludmila Vodickova, M.D., PhD

Academic Editor

PLOS ONE

PLoS One. doi: 10.1371/journal.pone.0259622.r010

Acceptance letter

Ludmila Vodickova

29 Oct 2021

PONE-D-20-28477R4

Contribution of “Complete Response to Treatment” to Survival in Patients with Unresectable Metastatic Colorectal Cancer: A Retrospective Analysis

Dear Dr. Bulut:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

If we can help with anything else, please email us at plosone@plos.org.

Thank you for submitting your work to PLOS ONE and supporting open access.

Kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Dr. Ludmila Vodickova

Academic Editor

PLOS ONE

Associated Data

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Supplementary Materials

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(DOCX)

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Data Availability Statement

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PERMALINK

Contribution of “complete response to treatment” to survival in patients with unresectable metastatic colorectal cancer: A retrospective analysis

Gulcan Bulut

Merve Guner Oytun

Elvina Almuradova

Mustafa Harman

Ruchan Uslu

Bulent Karabulut

Roles

Abstract

Background

Methods

Results

Conclusion

Introduction

Materials and methods

Statistical analysis

Results

Patient characteristics

Factors associated with attaining complete response

Table 1. The comparison of clinical and histopathologic findings according to the complete response to treatment.

Survival and predictors of survival and complete response (CR)

Table 2. Overall survival analysis based on whether a complete response was attained.

Fig 1. Overall survival analysis based on whether a complete response was attained.

Table 3. Progression-free survival analysis based on whether a complete response was attained.

Fig 2. Progression-free survival analysis based on whether a complete response was attained.

Table 4. According to the univariate analysis (Cox regression analysis), the effect of variables on overall survival.

Table 5. According to the multivariate analysis (logistic regression), the effects of variables on overall survival.

Fig 3. According to the multivariate analysis (logistic regression), the effects of variables on overall survival.

Discussion

Conclusion

Supporting information

Data Availability

Funding Statement

References

Decision Letter 0

Nader Hanna

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Decision Letter 1

Ludmila Vodickova

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Decision Letter 2

Ludmila Vodickova

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Decision Letter 3

Ludmila Vodickova

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Decision Letter 4

Ludmila Vodickova

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Acceptance letter

Ludmila Vodickova

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Associated Data

Supplementary Materials

Data Availability Statement

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