Advanced stage presentation and its determinant factors among colorectal cancer patients in Amhara regional state Referral Hospitals, Northwest Ethiopia.

INTRODUCTION: Nowadays, the burden of colorectal cancer (CRC) has been increasing in the world, particularly in developing nations. This could be related to the poor prognosis of the disease due to late presentation at diagnosis and poor treatment outcomes. In Ethiopia, studies related to the stage of colorectal cancer at diagnosis and its determinants are limited. Therefore, the study was intended to assess advanced stage presentation and its associated factors among colorectal cancer patients in northwest Ethiopia.
METHODS: An institution-based retrospective study was conducted among 367 CRC patients at two oncologic centers (the University of Gondar and Felege Hiwot comprehensive specialized hospitals) from January 1, 2017, to December 31, 2020. Data were entered into EPi-data 4.2.0.0 and transferred to STATA version 14 statistical software for analysis. Binary logistic regression was used to identify factors associated with the outcome variable. All variables with P-value < 0.2 during bi-variable analysis were considered for multivariable logistic regression. The level of statistical significance was declared at P-value <0.05.
RESULTS: The magnitude of advanced stage presentation of colorectal cancer was 83.1%. Being rural dwellers (Adjusted odds ratio (AOR) = 3.6; 95% CI: 1.8,7.2), not medically insured (AOR = 3.9; 95% CI: 1.9,7.8), patients delay (AOR = 6.5; 95% CI:3.2, 13.3), recurrence of the disease (AOR = 2.3; 95% CI: 1.1,4.7), and no comorbidity illness (AOR = 4.4; 95% CI: 2.1, 9.1) were predictors of advanced stage presentation of CRC.
CONCLUSION: The current study revealed that the advanced-stage presentation of colorectal cancer patients was high. It is recommended that the community shall be aware of the signs and symptoms of the disease using different media, giving more emphasis to the rural community, expanding health insurance, and educating patients about the recurrence chance of the disease. Moreover, expansion of colorectal treatment centers and screening of colorectal cancer should be given emphasis.

Introduction

Colorectal cancer (CRC) is one of the most frequently diagnosed cancers in the world and the second most common oncological cause of death [1]. Its incidence has been gradually increasing, particularly among those who lead a sedentary lifestyle. Moreover, obesity, inactive lifestyle, red meat consumption, alcohol consumption, and tobacco use are considered the pouring factors behind the development of CRC [2].

In all cancer-related deaths among men, 11.2% were owing to CRC and 4.8% of all cancer-related deaths in women were attributed to CRC. Nowadays, it is the most common malignancy representing 13% of all cancers arising in the gastrointestinal tract [2, 3]. In Ethiopia, CRC is the third most prevalent malignancy in the adult populations, and clients often present with late stages of the disease [4]. As to the Addis Ababa cancer registry, CRC is the first in men and fourth in women [5].

Raising awareness of the disease is important to promote healthy lifestyle choices, novel strategies for CRC management, and implementation of global screening programs, which are critical to reducing morbidity and mortality in the future [6]. A significant portion of the CRC survivors had presented with the advanced stage of the disease as reported by different studies conducted around the world [7-10]. Prognosis in CRC is closely related to the disease stage at diagnosis, and patients with early disease may be candidates for curative treatment [7].

Different factors are known to be contributing to the delayed presentation of CRC patients such as; place of residence age of the patients, health insurance, socioeconomic status, screening behavior, health care visit delay, diagnosis delay, shortage of physicians, and accessibility of nearby health facilities [8, 10–15]. Despite studies related to a late-stage presentation of colorectal cancer in different parts of the globe, studies on CRC stage at presentation are limited in Ethiopia, including the study setting. Therefore, the study was aimed at assessing the stage of presentation and its determinant factors among colorectal cancer patients at oncology units in the Amhara region, Northwest Ethiopia.

Materials and methods

Study design, period, and settings

An institution-based cross-sectional study was conducted in two oncologic centers in Northwest Amhara regional state of Ethiopia among CRC patients enrolled from January 1, 2017, to December 31, 2020. The data were collected from April 1-May 1, 2021. The two oncologic centers (University of Gondar Comprehensive Specialized Hospital (UOGCSH) and Felege Hiwot Comprehensive Specialized Hospital (FHCSH) are located in the Amhara region, Northwest parts of Ethiopia. UOGCSH is found in Gondar city (one of the ancient cities in Ethiopia), located about 750 km away from Addis Ababa. Currently, UOGCSH is serving more than five million people whereas FHCSH is located in Bahir Dar town, 552 km away from Addis Ababa.

Study populations

Colorectal cancer patients who had to follow up at UOGCSH and FHCSH from January 1st, 2017 to December 31 2020 were the study populations, and incomplete charts, and charts that were not found during the data collection period were excluded.

Operational definitions

The stage at diagnosis: The eighth edition of the American Joint Committee of Cancer (AJCC) was used for tumor node metastasis (TNM) staging of CRC [16].

Advanced stage: patients diagnosed with the disease stage III and IV

Early-stage: patients diagnosed with the disease stage I and II

Comorbidity illness: is the occurrence of any disease listed in the Charlson comorbidity index other than colorectal cancer at diagnosis [17].

Carcinoembryonic antigen: Tumor markers of gastrointestinal cancers especially colorectal cancer and classified as elevated (≥ 5ng/ml) and not elevated if <5 ng/ml [18].

Time to visit health facilities (symptom duration): Defined as the duration of time from first perceiving of symptom up to health care visit and it is delayed if a patient seeks health care visit more than ninety days after the symptoms of CRC appeared [7, 19].

Time to diagnosis: the duration of time from initial health care visit up to confirmed diagnosis and delayed if it is >30 days [7, 19].

Diagnosis to treatment interval (DTI). The time interval between confirmed CRC diagnoses up to the date of first treatment started and delayed if it is more than 30 days [7, 19].

Sample size determination and procedure

All CRC patients who had to follow up at oncology units of two hospitals from January 1, 2017-December 31, 2020 were included to get an adequate sample size since the total number of CRC patients in both oncology units identified from the registration book was 429 (261 at UOGCSH and 168 FHCRH). Out of 429 identified medical record numbers (MRN), 22 charts were mismatched (registered as CRC in the registration book, but different diagnoses in the chart), 23 were not found during the data collection period, and 17 were incomplete. Finally, 367 study participants were included in the study.

Data collection tools, procedures, and quality

Data were extracted using a pre-tested and structured data abstraction sheet adapted from different kinds of literature [20-26]. The abstraction sheet was developed in English and contains socio-demographic and clinicopathological characteristics of the patients. The data were collected by reviewing medical records. The one-day training was given for data collectors and supervisors on data collection tools and procedures. Two supervisors having master’s degrees in clinical oncology nursing were involved. Data collectors were supervised closely by the supervisors and principal investigator. The completeness of each abstraction sheet was checked by the principal investigator and supervisor on a daily base.

Data processing and analysis

Data were coded, entered, cleaned, and checked by EpiData version 4.6, and analyzed using Stata Version 14.2. Descriptive statistics of different variables were presented using tables, figures, and text. The binary logistic regression model was used to identify independent variables that have associated with the outcome variable (advanced stage presentation). The Hosmer–Lemeshow test was used to test the model fitness of the data and the model fitted with the insignificant p-value. To reduce potential confounders, bi-variable analysis was employed and independent variables with p-value <0.2 were exported to multivariable analysis. Variables with p -values ≤ 0.05 with 95% confidence interval during multivariable binary logistic regression analysis were declared as statistically significant. In addition, the regression analysis technique was used to eliminate the missed data.

Ethical considerations

Ethical clearance was obtained from the Ethical Review Committee of the School of Nursing, college of medicine and health sciences, University of Gondar. An official letter was written to GUCSH and FHCSH for permission and support. The research ethics committee of the school of nursing, University of Gondar waived the requirements for informed consent. All data collected from the chart was kept strictly confidential, anonymous, and used only for the study purpose.

Result

Socio-demographic characteristics of study participants

A total of 367 study participants were involved. The mean age of the participants was 49.2 years and nearly half, 50.7% were in the age groups greater than50 years. More than half (53.0%) were males and 40.0% were from rural. One hundred forty one (38.4%) had health insurance (Table 1).

Table 1

Socio-demographic characteristics of colorectal cancer patients in Northwest Amhara Referral Hospitals (n = 367).

Variables	Categories	Frequency	Percentage (%)
Age in years	<50	181	49.32
	≥50	186	50.68
Sex	Male	193	52.59
	Female	174	47.41
Residence	Urban	148	40.33
	Rural	219	59.67
Marital status	Married	274	74.66
	Unmarried	50	13.62
	Widowed	36	9.81
	Divorced	7	1.91
Health insurance	Yes	141	38.42
	No	226	61.58

Clinico-pathological characteristics of study participants

Nearly57.0% of study participants presented with an elevated level of carcinoembryonic antigen (CEA), and 22.0% had comorbidity illness. Anemia was diagnosed from nearly 27.3% of the patients. The majority (41.1%) of the patients had colon cancer and 83.0% of them had adenocarcinoma. Regarding the delay, 60.2%, 45.5%, and 29.3% of the participants were delayed for symptoms, diagnosis, and treatment respectively (Table 2).

Table 2

Clinicopathological characteristics of study participants (n = 367).

Variables	Categories	Frequency	Percentage (%)
CEA(n = 362)	<5ng/ml	156	43.09
	≥5ng/ml	206	56.91
Comorbidity illness	Yes	80	21.80
	No	287	78.20
Anemic status	Yes	100	27.25
	No	267	72.75
Tumor location	Ano rectal	33	8.99
	Recto sigmoid	17	4.63
	Colon	151	41.14
	Rectal	111	30.25
	Colorectal	55	14.99
Histological type	Adenocarcinoma	305	83.11
	Mucinous cell carcinoma	62	16.89
CRC recurrence	Yes	169	46.05
	No	198	53.95
Symptom duration	< 3months	146	39.78
	≥3 months	221	60.22
Diagnosis duration	≤1 month	200	54.50
	≥1 month	167	45.50
Diagnosis to treatment	≤1 month	244	70.72
	≥1 month	101	29.28

Stage of colorectal cancer at the presentation of patients

The current study revealed that advanced stage presentation of colorectal cancer patients was found to be 83.1% (95% confidence intervals (CIs): 78.9%- 86.6%). Nearly two-thirds (62.9%) were diagnosed with stage IV, and only 12 (3.3%) were diagnosed with stage I (Fig 1).

Fig 1

Distribution of the disease stage on presentation of colorectal cancer patients.

Determinants of advanced-stage presentation of colorectal cancer patients

Both bi-variable and multivariable analysis logistic regression analyses were undertaken. In bi-variable analysis; residence, marital status, insurance status, patient delay, comorbidity illness, disease recurrence, and diagnosis delay were fitted at a p-value<0.2. Whereas, in multivariable analysis; place of residency, insurance status, patient delay, comorbidity illness, and disease recurrence was significantly associated with the outcome variable at a p-value<0.05 using 95% CI.

Patients who were from the rural part of the country were 3.6 times more likely to present with advanced stage than those from urban (AOR = 3.6, 95%CI:1.8–7.2). Patients without insurance coverage are 3.9 times more likely to present with advanced stage than non-insurance users (AOR = 3.9; 95% CI: 1.9–7.8). Similarly, patients who delayed health facilities visits were 6.5 times more likely to be presented with advanced stage than patients who were not delayed (AOR = 6.5;95% CI:3.2–13.3). Moreover, patients with no comorbid illness and with recurrence of CRC disease were 4.4 times (AOR = 4.4; 95%CI: 2.1–9.1) and 2.3 times (AOR = 2.3; 95%CI: 1.1–4.7) more likely presented with advanced stage than those with comorbid illness and without disease recurrences, respectively (Table 3).

Table 3

Determinants of advanced stage presentation among colorectal cancer patients (n = 367).

Variables	Category	Advanced stage		COR(95%CI)	AOR(95%CI)	P-value
		No (%)	Yes (%)
Residence	Urban	42(28.4)	106(71.6)		1	1
	Rural	20(9.1)	199(90.9)	3.9 (2.2–7.0)*	3.6 (1.8–7.2)	<0.001
Marital status	Married	44(16.1)	230(83.9)		1	1
	Unmarried	9(18.0)	41(82.0)	0.8(0.4–1.9)	1.3(0.5–3.5)	0.539
	Widowed	5(13.9)	31(86.1)	1.2(0.4–3.2)	2.4(0.6–8.5)	0.172
	Divorced	4(57.1)	3(42.9)	0.1(0.0–0.6)*	0.2(0.1–1.2)	0.079
Insurance status	Free	38(27.0)	103(73.0)		1	1
	Paid	24(10.6)	202(89.4)	3.1(1.8–5.5)*	3.9(1.9–7.8)	<0.001
Patient delay	Not delayed	45(30.2)	101(69.2)		1	1
	Delayed	17(7.7)	204(92.3)	5.3(2.9–9.8)*	6.5(3.2–13.3)	<0.001
Comorbid illness	Yes	27(33.8)	53(66.0)		1	1
	No	35(12.2)	252(87.8)	3.6(2.1–6.5)*	4.4(2.1–9.1)	<0.001
Disease recurrence	Yes	17(10.1)	152(89.9)	2.6(1.4–4.8)*	2.3(1.1–4.7)	0.023
	No	45(22.7)	153(77.3)		1	1
Diagnosis delay	Not delayed	41(20.5)	159(79.5)		1	1
	Delayed	21(12.6)	146(87.4)	1.8(1.0–3.2)*	1.3(0.6–2.6)	0.416

*P- value <0.2

Discussion

This study aimed to assess the advanced stage presentation and its determinant factors among CRC patients in Northwest Amhara Referral Hospitals. Place of residency, insurance status, patient delay, comorbid illness, and disease recurrence was significantly associated with the advanced stage of the disease. The study revealed that 83.1% of CRC patients presented at an advanced stage of the disease. This is higher than studies conducted in New York at 60.7% [9], Nottingham at 67% [7], and Stanford at 72% [27]. This could be due to differences in socioeconomic status, accessibility of nearby health facilities, health policies of the respected countries, and patient-health care provider rations of the study areas [28, 29].

Rural dwellers presented with a more advanced stage than those from urban. The finding is supported by different studies [16, 30]. This could be due to inaccessibility of health facilities in the rural community, problems of transportation and probably low awareness of the warning signs of the disease as most rural communities in Ethiopia are illiterate [31].

Patients who hadn’t health insurance were presented with advanced stage than those who were insured. This finding is supported by the studies conducted in different countries [8, 11]. The possible justification could be health insurance coverage might solve economic constraints of the patients and visit health care facilities as early as possible if the signs and symptoms of the disease appeared [32, 33].

Patients who delayed visiting a health care facility after the appearance of the first sign/ symptom presented with advanced stage than those who did not. This is supported by studies in Puerto Rico [34], Botswana [35], and Spain [36]. This could be since if patients don’t visit health care facilities and their physicians as early as possible after the sign/symptom, the disease could metastasize and disseminate to different organs [37].

Patients who hadn’t comorbid illness were diagnosed with advanced-stage than those with comorbid illness. This finding is in line with the study conducted in the USA [38], but in contradiction with the literature conducted in different settings [39, 40]. The possible justification could be patients who had comorbidity might visit health care settings more frequently and diagnose with an early stage as another illness [41].

Another contributing factor that caused advanced stage presentation of colorectal cancer patients was a recurrence of the disease. This might be because patients who were diagnosed with colorectal cancer and completed their treatment could not suspect the reoccurrence of the disease despite the presence of signs and symptoms of the disease and causing the delay in their presentation to health care facilities [42]. As such, the government should expand health education regarding CRC symptoms and signs, and options for treatment could increase the early-stage presentation of the disease. As a limitation, the current study didn’t consider the economic status of the study participants which could affect the outcome of the study due to the nature of data collection being a chart review.

Conclusion

The current study revealed that the advanced-stage presentation of colorectal cancer patients was high. Rural residency, no health insurance, delay in health facility visit, absence of comorbidity, and recurrence of the disease significantly increased advanced stage presentation of colorectal cancer. It is recommended that the community shall be aware of the signs and symptoms of the disease using different media, giving more emphasis to the rural community, expanding health insurance, and educating patients about the recurrence rate of the disease. Moreover, expansion of oncology centers, lifestyle modifications, and early screening could be given a great emphasis.

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Reviewer #1: The authors of this study investigated the advanced stage presentation of colorectal cancer (CRC) and the contributing factors in a regional study in Ethiopia. The study is of high importance since reporting results from a lesser investigated country. Although the manuscript is drafted well some comments and amendments need to be considered prior to any decision on this submission.

1. General: a language and grammar revision are necessary on this submission.

2. Abstract, methods: the definition of “advanced stage CRC” should be provided since it is the primary outcome of the study and its criteria is not clear.

3. Abstract, methods: the precise time span pf study is unclear. Authors mentioned year 2021 and als0 2017-2020 as the investigation period. This point needs a revision.

4. Abstract, results: the variables used to generate the adjusted odds ratio (AOR) should be stated for a clearer data presentation.

5. Keywords: the use of keywords should be based on PubMed MeSH database as much as possible and the authors should choose more relevant ones.

6. Introduction: in third line of the first paragraph, the word “oncological” seems to be misspelled as “ontological”.

7. Introduction: this section needs a major revision to replace the short sentences and paragraphs with 3-4 paragraphs with clear storyline and message. Also, adding some information about the epidemiology of CRC in Ethiopia is essential in this section.

8. Methods, Operational definitions: the primary outcome investigated in this study should be highlighted and also the other variables included in the study and the analyses should be categorized in demographic, clinical, and laboratory sub-classes.

9. Methods, Data processing and analysis: details of the regression analysis are inadequate and the statistical analysis need to be explained clearly in this part.

10. Results: the past tense should be used to report the study results.

11. Results and methods: since the prevalence of the advances stage CRC is relatively high in this study, authors should expand the methods section on the pathologic evaluation of the CRC patients in the two referral hospitals mentioned as the data reference.

12. Results, table 3: the variables included in the two-stages regression analysis need to be expanded to all available variables and factors in this database. For example, demographic variables should be added to the adjustment.

13. Discussion: this section needs one paragraph as the policy implications of the findings of this study to benefit the health authorities in Ethiopia.

Reviewer #2: In the present manuscript, the authors aimed to assess stage of presentation and its contributing factors among colorectal cancer patients in Amhara regional state of Ethiopia. It seems that this study is a part of a project which some of other papers have been previously published. Although it is an important subject, in particular for regional policymakers, there are several issues which should be addressed:

General comments:

1- The use of English needs to be improved within the text. Also, typos and grammatical issues should be addressed in the text and tables.

2- The authors have previously published similar studies on other cancers which can be mentioned or discussed in the manuscript:

https://doi.org/10.1186/s13027-021-00371-6

https://doi.org/10.1186/s12885-019-6447-x

#Introduction

1- The first sentence of Introduction is a basic description which is recommended to be omitted since it is clear to the readers of the journal.

2- There are too many paragraphs in the Introduction, so please merge some of them. This section should be written in almost two to three paragraphs in which epidemiology and risk factors of CRC, determinant factors of late stage and preventive measures for CRC, and gap of knowledge and aim of the study should be explained.

3- Reference 2 would be better to be replaced with a more recent article on the epidemiology of cancers or CRC like the followings:

https://doi.org/10.1016/S2468-1253(19)30345-0

https://doi.org/10.3322/caac.21660

#Methods

1- The inclusion and exclusion criteria should be clarified. For example, were individuals with a specific age range or specific stage of CRC excluded? What about effects of comorbidities on inclusion to the study?

2- Please clarify whether the participants received treatment and if yes, how its effects have been adjusted in the analysis.

3- According to STROBE checklist, please mention statistical methods used to control for confounding and explain how missing data were addressed in the "Data processing and analysis" section.

#Results

1- You might want to use a flow diagram to represent the selection of the study participants.

#Discussion

1- It would be better to mention the study design and participants of similar studies in the Discussion and their findings, then compare the results of the present study with them.

2- If applicable, please cite the relevant studies for your justifications for the differences between the results of the present study with previous studies.

3- It would be great to provide the limitations of the present study in the last paragraph of Discussion.

#Minor comments

1- In the Table 3 descriptions, please define the abbreviations used in the table. Also, please clarify the adjustment was performed for what variables in the table and text.

Reviewer #3: Key Message:

This paper aimed to assess the stage of presentation and its contributing factors among colorectal cancer patients in Amhara regional state of Ethiopia in 2017-2020. As a developing country in Africa, Ethiopia needs more consideration from health policies to decrease the burden of diseases. Cancer diagnosis and management are costly procedures that need proper infrastructure and specialized personnel. Therefore, in countries such as Ethiopia, broadly available infrastructures may be lacking, and considering related studies to investigate the ongoing diseases is critical. Consequently, I think the study carries out important messages about the staging of colorectal cancer patients in the study's region and the associated contributing factors. In overall, the paper was written in an acceptable storyline and presented in a reasonable manner. The methods and results parts were in a better situation, and the introduction and the discussion need revisions in this round.

Evidence and examples:

Major issues:

The discussion was mainly a narration and simply a review of the results. The associations of some factors seem to be controversial. In these situations citing enough and proper evidence is highly recommended. Therefore, despite the storyline of the discussion is currently acceptable, it is recommended revising the discussion comprehensively.

In the conclusion part it was just stated: "The current study revealed that advanced stage presentation of colorectal cancer patients was high". But as we can see, the aim of the study was "to assess stage of presentation and its contributing factors among colorectal cancer patients in Amhara regional state of Ethiopia". As we can see, the conclusion lacks findings of contributing factors.

The introduction consisted of some tiny paragraphs. Combining related paragraphs as a whole is highly recommended. The storyline of the introduction should be considered carefully. The introduction may be started from what currently we know (known of evidence) in the first paragraphs, and continued by what we don't know (gap of knowledge) in the next paragraph, and finally completed by what we have done to fill the gap of knowledge and the aim of the study in the last paragraph.

The draft had some grammatical, English fluency and readability issues. Please address these issues by the assistance of an English expert.

Minor issues:

In the introduction in the sentence "CRC incidence has been gradually increasing in the globe, particularly in developing nations who lead sedentary lifestyle." I cannot understand what the authors mean? If you mean developing countries are the leading countries in sedentary lifestyle, I do not agree and if you disagree with me, it is suggested to prove this hypothesis by citing proper evidence.

In the introduction in the sentence "Obesity, inactive lifestyle, red meat consumption, alcohol consumption, and tobacco are considered the pouring factors behind the development of CRC", the "pouring factors" is a vague term and I am not familiar with it.

As this study was partly a descriptive study, it is recommended to add the study period to the aim of the study.

In the methods in the sentence "Carcino embryonic antigen: Tumor markers of gastric cancer especially colorectal cancer and classified as elevated (≥ 5ng/ml) and not elevated if <5 ng/ml", the "gastric cancer" should be revised. Because in medicine, gastric cancer is related to the stomach, and I think here the authors mean gastrointestinal cancers.

In the methods in the sentence "Time to seek health care facility (symptom duration):" as we can see the definition, instead of "time to seek" it is "time to visit" or "time to receive health service" because in the Health Care Access science it is defined that from seeking the healthcare to receiving that also takes considerable time, especially in resource-limited communities.

It is highly recommended to attach the structured data abstraction sheet to the appendix of the paper.

In the methods, please mention the level of education and experience of supervisors.

In the results, it is recommended to report all percentages with one decimal.

At the beginning of the discussion, main findings of the study should be presented. In the current draft, we cannot see enough information for the first paragraph of the discussion. As the authors explained in the introduction, this study was aimed to "assess stage of presentation and its contributing factors among colorectal cancer patients in Amhara regional state of Ethiopia". First, restating the aim of the study in the discussion is not necessary. Second, in the first paragraph of the discussion, the readers are willing to read about which factors are related to the advanced stage of CRC.

In the second paragraph of the discussion starting paragraph with "this" is not suitable. And this paragraph seems to be a continuation of the first paragraph and can be merged into that.

In the discussion, the paragraph started with "Patients who hadn't comorbidity illness were diagnosed with advanced stage than those who had" can be controversial findings. Therefore, it is highly recommended to discuss this issue carefully and cite more studies.

In the discussion in the sentence "Another contributing factor that caused delayed presentation of colorectal cancer patients was recurrence of the disease". The "delayed presentation" is vague and can be assumed as "advanced stage presentation" or "delay of receiving treatment".

**********

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Reviewer #1: Yes: Sina Azadnajafabad, MD, MPH

Reviewer #2: No

Reviewer #3: Yes: Mohammad-Mahdi Rashidi

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1 Jun 2022

01/06/2022

Dear Academic Editor,

PLOS ONE

Subject: Submission of revised manuscript entitled as “Advanced stage presentation and its determinant factors among colorectal cancer patients in Northwest Amhara Regional State Referral Hospitals of Ethiopia (PONE-D-22-07229).

Dear,Negar Rezaei M.D., Ph.D, thank you for your email enclosing the Editorial member’s and the reviewer’s comments. We have carefully revised the manuscript and incorporated their comments accordingly. Our responses are given in point-by-point response below.

We hope the revised version is suitable for publication and look forward to hearing from you in due courses.

Sincerely

Mulugeta Wassie.

University of Gondar, College of Medicine and health Sciences, School of Nursing, Department of Medical Nursing.

Point by point responses to Editorial Board Member’s and Reviewers’ comments

Academic Editor

1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming.

Authors’ response: Thank you very much for your constructive suggestions and comments. We have tried to abide with the PLOS ONE style requirements

2. Please provide additional details regarding participant consent. In the ethics statement in the Methods and online submission information, please ensure that you have specified (1) whether consent was informed and (2) what type you obtained (for instance, written or verbal, and if verbal, how it was documented and witnessed). If your study included minors, state whether you obtained consent from parents or guardians. If the need for consent was waived by the ethics committee, please include this information.

If you are reporting a retrospective study of medical records or archived samples, please ensure that you have discussed whether all data were fully anonymized before you accessed them and/or whether the IRB or ethics committee waived the requirement for informed consent. If patients provided informed written consent to have data from their medical records used in research, please include this information.

Authors’ response: Thank you very much for your constructive suggestions. We have used a retrospective study of medical records and we have discussed it in ethics statement of the manuscript as all data were fully anonymized. The research ethics committee of school of nursing, University of Gondar waived the requirements for informed consent.

3. We note that you have indicated that data from this study are available upon request. PLOS only allows data to be available upon request if there are legal or ethical restrictions on sharing data publicly. For more information on unacceptable data access restrictions, please see http://journals.plos.org/plosone/s/data-availability#loc-unacceptable-data-access-restrictions.

In your revised cover letter, please address the following prompts:

a) If there are ethical or legal restrictions on sharing a de-identified data set, please explain them in detail (e.g., data contain potentially sensitive information, data are owned by a third-party organization, etc.) and who has imposed them (e.g., an ethics committee). Please also provide contact information for a data access committee, ethics committee, or other institutional body to which data requests may be sent.

b) If there are no restrictions, please upload the minimal anonymized data set necessary to replicate your study findings as either Supporting Information files or to a stable, public repository and provide us with the relevant URLs, DOIs, or accession numbers. For a list of acceptable repositories, please see http://journals.plos.org/plosone/s/data-availability#loc-recommended-repositories.

Authors’ response: Thank you very much for your suggestions. We have updated the data availability statement and we uploaded the minimal data used to extract the report in the form of excel in “supplementary files” section.

********************

Reviewer #1:

The authors of this study investigated the advanced stage presentation of colorectal cancer (CRC) and the contributing factors in a regional study in Ethiopia. The study is of high importance since reporting results from a lesser investigated country. Although the manuscript is drafted well some comments and amendments need to be considered prior to any decision on this submission.

1. General: a language and grammar revision is necessary on this submission.

Authors’ response: Thank you very much for your review and constructive comments provided. We have tried to revise the whole manuscript to address the language and grammatical errors.

2. Abstract, methods: the definition of “advanced stage CRC” should be provided since it is the primary outcome of the study and its criteria is not clear.

Authors’ response: Thank you very much for your constructive comments. The authors have tried to address the comments in the manuscript.

3. Abstract, methods: the precise time span of study is unclear. Authors mentioned year 2021 and also 2017-2020 as the investigation period. This point needs a revision.

Authors’ response: Thank you very much for your constructive comments. Sorry for the unclarity. “April 1-May 1, 2021” was the actual data collection period and “2017-2020” was the period of patients’ registration(admission) in the each respective hospitals as this study is retrospective chart review study. We also tried to clear it in the abstract section of the document.

4. Abstract, results: the variables used to generate the adjusted odds ratio (AOR) should be stated for a clearer data presentation.

Authors’ response: Thank you very much for your constructive comments. We have stated the variables used to generate AOR in the abstract section as per the comment.

5. Keywords: the use of keywords should be based on PubMed MeSH database as much as possible and the authors should choose more relevant ones.

Authors’ response: Thank you very much for your constructive comments. We have tried to use MeSH database to select the Keywords and modified in the manuscript accordingly.

6. Introduction: in third line of the first paragraph, the word “oncological” seems to be misspelled as “ontological”.

Authors’ response: Thank you very much for your critical review. We have corrected it in the main document

7. Introduction: this section needs a major revision to replace the short sentences and paragraphs with 3-4 paragraphs with clear storyline and message. Also, adding some information about the epidemiology of CRC in Ethiopia is essential in this section.

Authors’ response: Thank you very much for your constructive comments. We have tried to address the comments and suggestions in the manuscript.

8. Methods, Operational definitions: the primary outcome investigated in this study should be highlighted and also the other variables included in the study and the analyses should be categorized in demographic, clinical, and laboratory sub-classes.

Authors’ response: Thank you very much for your constructive comments. We have tried to address the comments and suggestions in the manuscript.

9. Methods, Data processing and analysis: details of the regression analysis are inadequate and the statistical analysis needs to be explained clearly in this part.

Authors’ response: Thank you very much for your comments. The authors have tried to explain more about the regression analysis in the revised manuscript.

10. Results: the past tense should be used to report the study results.

Authors’ response: Thank you very much for your comments. We have rewritten in the form of past tense

11. Results and methods: since the prevalence of the advances stage CRC is relatively high in this study, authors should expand the methods section on the pathologic evaluation of the CRC patients in the two referral hospitals mentioned as the data reference.

Authors’ response: Thank you very much for your comments. The authors have tried to assess the pathological evaluation of CRC and presented it in the result section like histological type of disease, CEA level …..

12. Results, table 3: the variables included in the two-stage regression analysis need to be expanded to all available variables and factors in this database. For example, demographic variables should be added to the adjustment.

Authors’ response: Thank you very much for your comments. Firs, the authors have employed bivariable (all independent variables individually regressed against the dependent variable) regression analysis to identify the potential confounders. And those variables with p-value <0.2 were identified and included in the two stage regression (multivariable analysis) and variables with a p-value<0.05 were declared as significantly affected the outcome variable. It shows that all available variables including socio demographic variables were included step by step (from bi variable to multi variable) analysis.

13. Discussion: this section needs one paragraph as the policy implications of the findings of this study to benefit the health authorities in Ethiopia.

Authors’ response: Thank you very much for your comments. We have added one paragraph on the implication of the findings with recommendations

***************************

Reviewer #2:

In the present manuscript, the authors aimed to assess stage of presentation and its contributing factors among colorectal cancer patients in Amhara regional state of Ethiopia. It seems that this study is a part of a project which some of other papers have been previously published. Although it is an important subject, in particular for regional policymakers, there are several issues which should be addressed:

General comments:

1- The use of English needs to be improved within the text. Also, typos and grammatical issues should be addressed in the text and tables.

Authors’ response: Thank you very much for your comments. We have tried to improve the grammar and typos of the manuscript in the main document.

2- The authors have previously published similar studies on other cancers which can be mentioned or discussed in the manuscript:

https://doi.org/10.1186/s13027-021-00371-6, https://doi.org/10.1186/s12885-019-6447-x

Authors’ response: Thank you very much for your comments. As you have mentioned, the publications (https://doi.org/10.1186/s13027-021-00371-6, https://doi.org/10.1186/s12885-019-6447-x ) are the publications of the primary author of this manuscript. However, these articles are conducted among CERVICAL CANCER patients who haven’t any similarity of the current study. Due to dissimilarity of the study population and the malignancy type, the authors intentionally left to discuss these articles with the current manuscript. Also there is no space to discuss or include such articles in the current document.

#Introduction

1- The first sentence of Introduction is a basic description which is recommended to be omitted since it is clear to the readers of the journal.

Authors’ response: Thank you very much for your comments. We have omitted the first sentence of the introduction.

2- There are too many paragraphs in the Introduction, so please merge some of them. This section should be written in almost two to three paragraphs in which epidemiology and risk factors of CRC, determinant factors of late stage and preventive measures for CRC, and gap of knowledge and aim of the study should be explained.

Authors’ response: Thank you very much for your suggestion and comments. We have merged those fragmented paragraphs and added some other important information in the main document.

3- Reference 2 would be better to be replaced with a more recent article on the epidemiology of cancers or CRC like the followings:

https://doi.org/10.1016/S2468-1253(19)30345-0, https://doi.org/10.3322/caac.21660

Authors’ response: Thank you very much for cooperation and suggestion. We have incorporated the recent articles with their references as per your suggestion in the main document.

#Methods

1- The inclusion and exclusion criteria should be clarified. For example, were individuals with a specific age range or specific stage of CRC excluded? What about effects of comorbidities on inclusion to the study?

Authors’ response: Thank you very much for your comments. Patients with age groups less than 15 were excluded in the current study since patients with this age group are treated in pediatric oncology ward and the occurrence of CRC in this age group is very rare. It has been included in the revised manuscript. But there was no any exclusion for patients with specific stage or with comorbidity. Comorbidity was one of the “independent variables” and there is no any reason to exclude those patients with comorbidity. If we were studying mortality of CRC, patients with comorbid illness could be excluded. But, currently we are studying about STAGE. We think, treating comorbidity as an explanatory variable weather it affected early or late presentation of the patients is enough.

2- Please clarify whether the participants received treatment and if yes, how its effects have been adjusted in the analysis.

Authors’ response: Thank you very much for your concern. We think treatment has no any effect for the current study as it is about the BASELINE PRESENTATION STAGE. Furthermore, since we are investigating baseline presentation, all patients did not get any treatment and it is default.

3- According to STROBE checklist, please mention statistical methods used to control for confounding and explain how missing data were addressed in the "Data processing and analysis" section.

Authors’ response: Thank you very much for your comments and suggestions.

The Hosmer–Lemeshow test was used to test the model fitness of the data and binary logistic regression model has fitted with insignificant p-value (p-value >0.05). Bi-variable analysis was used to reduce confounding variables. Variables with p-value less than 0.2 in bivariable analysis were included in multivariable analysis.

Regarding the treating of missing data, regression analysis technique was used to systematically eliminate the missed data. Regression analysis technique uses the lowest sample size in the subgroup analysis. In fact there was insignificant missing value in our dataset. It appears only in one variable subgroup (CEA with n=362) out of the total (376).

#Results

1- You might want to use a flow diagram to represent the selection of the study participants.

Authors’ response: Thank you very much for your suggestion. The authors believe that it is not appropriate to put the flow diagram to represent the selection of the study participants in the RESULT section. If it is much important to use a flow diagram, we can put it in the methods and material section of the main manuscript.

#Discussion

1- It would be better to mention the study design and participants of similar studies in the Discussion and their findings, then compare the results of the present study with them.

Authors’ response: Thank you very much for your suggestions and comments. It has been addressed as per the comments in the main document.

2- If applicable, please cite the relevant studies for your justifications for the differences between the results of the present study with previous studies.

Authors’ response: Thank you very much for your suggestions and comments. We have tried to cite the relevant studies to strengthen the justifications of similarities and dissimilarities with the current study.

3- It would be great to provide the limitations of the present study in the last paragraph of Discussion.

Authors’ response: Thank you very much for your suggestions and comments. We have provided the limitations of the current study in the specified space.

#Minor comments

1- In the Table 3 descriptions, please define the abbreviations used in the table. Also, please clarify the adjustment was performed for what variables in the table and text.

Authors’ response: Thank you very much for your suggestions and comments. We have tried to address the comments as per the suggestions and the comments.

Reviewer #3:

Key Message:

This paper aimed to assess the stage of presentation and its contributing factors among colorectal cancer patients in Amhara regional state of Ethiopia in 2017-2020. As a developing country in Africa, Ethiopia needs more consideration from health policies to decrease the burden of diseases. Cancer diagnosis and management are costly procedures that need proper infrastructure and specialized personnel. Therefore, in countries such as Ethiopia, broadly available infrastructures may be lacking, and considering related studies to investigate the ongoing diseases is critical. Consequently, I think the study carries out important messages about the staging of colorectal cancer patients in the study's region and the associated contributing factors. In overall, the paper was written in an acceptable storyline and presented in a reasonable manner. The methods and results parts were in a better situation, and the introduction and the discussion need revisions in this round.

Evidence and examples:

Major issues:

The discussion was mainly a narration and simply a review of the results. The associations of some factors seem to be controversial. In these situations citing enough and proper evidence is highly recommended. Therefore, despite the storyline of the discussion is currently acceptable, it is recommended revising the discussion comprehensively.

Authors’ response: Thank you very much for your suggestions and comments. The authors have tried to revise the discussion section of the manuscript as per the comments.

****

In the conclusion part it was just stated: "The current study revealed that advanced stage presentation of colorectal cancer patients was high". But as we can see, the aim of the study was "to assess stage of presentation and its contributing factors among colorectal cancer patients in Amhara regional state of Ethiopia". As we can see, the conclusion lacks findings of contributing factors.

Authors’ response: Thank you very much for your comments. We have included the contributing factors in the conclusion of the revised manuscript.

****

The introduction consisted of some tiny paragraphs. Combining related paragraphs as a whole is highly recommended. The storyline of the introduction should be considered carefully. The introduction may be started from what currently we know (known of evidence) in the first paragraphs, and continued by what we don't know (gap of knowledge) in the next paragraph, and finally completed by what we have done to fill the gap of knowledge and the aim of the study in the last paragraph.

Authors’ response: Thank you very much for your suggestions and comments. We have revised the introduction section of the revised manuscript rigorously.

****

The draft had some grammatical, English fluency and readability issues. Please address these issues by the assistance of an English expert.

Authors’ response: Thank you very much for your suggestions and comments. We have tried to address the raised issues in the revised manuscript.

****

Minor issues:

In the introduction in the sentence "CRC incidence has been gradually increasing in the globe, particularly in developing nations who lead sedentary lifestyle." I cannot understand what the authors mean? If you mean developing countries are the leading countries in sedentary lifestyle, I do not agree and if you disagree with me, it is suggested to prove this hypothesis by citing proper evidence.

Authors’ response: Thank you very much for your suggestions. In this sentence the authors have wanted to pass the information “those individuals leading sedentary life are more prone to develop CRC even they are living in developing nations as compared to those who don’t have sedentary life style”. Nowadays, sedentary life style (using vehicles even for very short distance, long time sitting in the office, absence of regular physical activities….) in developing nations becomes more common than before. But it is not mean that developing nations lead more sedentary lifestyle than developed nations. We have tried to modify the sentence in the revised manuscript.

****

In the introduction in the sentence "Obesity, inactive lifestyle, red meat consumption, alcohol consumption, and tobacco are considered the pouring factors behind the development of CRC", the "pouring factors" is a vague term and I am not familiar with it.

Authors’ response: Thank you very much for your concern. Sorry for the inconvenience. “Pouring factors” in this sentence is to mean “the driving factors”.

****

As this study was partly a descriptive study, it is recommended to add the study period to the aim of the study.

Authors’ response: Thank you very much for your suggestions. We have added the study period in the revised manuscript

****

In the methods in the sentence "Carcino embryonic antigen: Tumor markers of gastric cancer especially colorectal cancer and classified as elevated (≥ 5ng/ml) and not elevated if <5 ng/ml", the "gastric cancer" should be revised. Because in medicine, gastric cancer is related to the stomach, and I think here the authors mean gastrointestinal cancers.

Authors’ response: Thank you very much for your critical review and comments. We have changed the word “gastric cancer” to “gastrointestinal cancers” in the revised manuscript.

****

In the methods in the sentence "Time to seek health care facility (symptom duration):" as we can see the definition, instead of "time to seek" it is "time to visit" or "time to receive health service" because in the Health Care Access science it is defined that from seeking the healthcare to receiving that also takes considerable time, especially in resource-limited communities. It is highly recommended to attach the structured data abstraction sheet to the appendix of the paper.

Authors’ response: Thank you very much for your comment. We really appreciate your critical and professional review of the document. As per the comment we have changed “Time to seek health care facility” by "time to visit health facilities".

Regarding the “data abstract sheet”, the journal manuscript preparation style doesn’t allow attaching it as an appendix and there is no space to attach the abstract sheet in the manuscript tracking system of the journal. Rather, the journal needs ‘the dataset’ in which the report is extracted from and we have attached the dataset as the supplementary file.

****

In the methods, please mention the level of education and experience of supervisors.

Authors’ response: Thank you very much for your suggestion. We have mentioned the level of education and experience of supervisors.

****

In the results, it is recommended to report all percentages with one decimal.

Authors’ response: Thank you very much for your suggestion. We have tried to revise the result section as per the comment.

****

At the beginning of the discussion, main findings of the study should be presented. In the current draft, we cannot see enough information for the first paragraph of the discussion. As the authors explained in the introduction, this study was aimed to "assess stage of presentation and its contributing factors among colorectal cancer patients in Amhara regional state of Ethiopia". First, restating the aim of the study in the discussion is not necessary. Second, in the first paragraph of the discussion, the readers are willing to read about which factors are related to the advanced stage of CRC.

Authors’ response: Thank you very much for your comments. Dear reviewer, some scholars agree with your idea about the introduction paragraph of the discussion. On the other side, there are also some scholars strongly recommend to introduce the aim of the study in the first section of the discussion. If it violates scholarly writing style, we can remove it, but now we leave as it is. Regarding the contributing factors, we have added variables that affected the outcome variable in the recommended place.

****

In the second paragraph of the discussion starting paragraph with "this" is not suitable. And this paragraph seems to be a continuation of the first paragraph and can be merged into that.

Authors’ response: Thank you very much for your comments. We have merged it as per the comment.

****

In the discussion, the paragraph started with "Patients who hadn't comorbidity illness were diagnosed with advanced stage than those who had" can be controversial findings. Therefore, it is highly recommended to discuss this issue carefully and cite more studies.

Authors’ response: Thank you very much for your comments: As you mentioned, it seems controversial. But the reality seems true. Patients with comorbidity might have frequent contact with health care professionals for the reason other than CRC. This frequent contact could help the patients and health care professionals to detect the early signs and symptoms of the CRC. Therefore, this might help the patients with comorbid illness to be diagnosed at the early stage of the disease than those who haven’t. This is also supported by different literatures (Zafar SY, Abernethy AP, Abbott DH, Grambow SC, Marcello JE, Herndon JE 2nd, Rowe KL, Kolimaga JT, Zullig LL, Patwardhan MB, Provenzale DT. Comorbidity, age, race and stage at diagnosis in colorectal cancer: a retrospective, parallel analysis of two health systems. BMC Cancer. 2008 Nov 25;8:345. doi: 10.1186/1471-2407-8-345. PMID: 19032772; PMCID: PMC2613913.)

****

In the discussion in the sentence "Another contributing factor that caused delayed presentation of colorectal cancer patients was recurrence of the disease". The "delayed presentation" is vague and can be assumed as "advanced stage presentation" or "delay of receiving treatment"

Authors’ response: Thank you very much for your comments. As per your comment, we have changed the "delayed presentation" to "advanced stage presentation".

Submitted filename: Response to Reviewers.docx

Click here for additional data file.

17 Jun 2022

23 Jul 2022

Manuscript ID: PONE-D-22-07229R1

Topic: Advanced stage presentation and its determinant factors among colorectal cancer patients in Northwest Amhara Regional State Referral Hospitals of Ethiopia

Dear Editors and reviewers;

We sincerely appreciate the valuable comments and suggestions from the reviewers and editors side. The suggestions and comments have been closely followed and revisions have been made accordingly. The following are the questions extracted from the reviewers’ comments along with our summarized responses. Thank you very much for your constructive comments. We tried to inculcate your comments and questions as described below. The changes are attached with. Much correction has been made through the document.

Editor comments

Editor’s comment #01: There is a questionable difference between the manuscript-mentioned study period and the dates available in the datasheet.

Author’s response:

Thank you very much for your constructive comments: Your concern is quite right. Sorry for the inconvenience. But there is a difference in Ethiopian calendar (E.C) and Gregorian calendar (G.C). On the dataset, time of study participants enrollment was by Ethiopian calendar since the data is registered in E.C. But the time in the manuscript was written by G.C. By adding 8 years (from January to August) on 2009 E.C equals with 2017 in G.C and adding 7 years (from September to December) on 2013 E.C equals 2020 G.C. This 8 and 7 years difference is due to the new year of January and September in G.C and E.C respectively. During analysis we changed Ethiopian calendar to Gregorian calendar. Kindly understand it in such a manner.

Editor’s comment #02: A native language edit of manuscript is recommended.

Author’s response: Thank you very much for the comment: sure! The manuscript has been reviewed by different personnel and many editorial and grammatical issues have been addressed.

Reviewer #01

Reviewer 1 comments and suggestion #01: The authors tried to address my comments and suggestions in this revision and I can say they were successful to some extent. Most of the scientific comments have been addressed. One major issue still remains that is the several grammatical and typo errors and the poor language of this manuscript. The prepared draft needs a revision by a native editor or English expert and the language and structure of manuscript should be revised in this regard, otherwise it may jeopardize the efforts of the authors.

Author’s response:

Thank you very much for your critical comments for the improvement of the manuscript. The manuscript has been reviewed by different personnel and many editorial and grammatical issues have been addressed.

Reviewer #02

Reviewer 2 comments and suggestion #01: Thank you for implementing the comments. Manuscript will require thorough proofreading to meet the required standards of language.

Author’s response: Thank you very much for your critical comments for the improvement of the manuscript. The manuscript has been reviewed by different personnel and many editorial and grammatical issues have been addressed.

Reviewer #03

Reviewer 3 comments and suggestion #01: In this manuscript, the authors aimed to assess stage of presentation and its contributing factors among colorectal cancer patients in Amhara regional state of Ethiopia. The manuscript was reviewed once in the previous round and revised by the authors. I reviewed previous comments and authors' responses, and most of them were adequate. Just to mention some English fluency issues still were in the manuscript. A copyediting by an expert is recommended. As the academic editor requested uploading the minimal anonym zed dataset, the authors uploaded the minimal data used to extract the report in the form of a datasheet in the supplements. As I reviewed the datasheet two issues raised some questions. First, the number of participants was 367 in the datasheet, which was also mentioned in the last sentence of the "Sample size determination and procedure" subheading in "Materials and Methods", but as we can see in all other parts of the manuscript the total number of participants was reported 376. Another issue is that in the "Study design, Period, and settings" part, it was mentioned that "patients enrolled from January 1, 2017, to December 31, 2020", but in the datasheet, "Date_of_last_visit" is from 2009 to 2013. As it seems from this evidence the participants' recruitments were not from 2017 to 2020. I would like to receive the authors' response in this regard.

Author’s response:

Thank you very much for your critical comments. The manuscript has been reviewed by different personnel and many editorial and grammatical issues have been addressed. You are right about the sample size difference but this is due to type errors, the exact number of sample size is 367.

The other concern that you raise is about enrollments of study participants:

Your concern is quite right. Sorry for the inconvenience. But there is a difference in Ethiopian calendar (E.C) and Gregorian calendar (G.C). On the datasheet time of study participants enrollment was by Ethiopian calendar since the data is registered in E.C. But the time in the manuscript was written by G.C. By adding 8 years (from January to August) on 2009 E.C equals with 2017 in G.C and adding 7 years (from September to December) on 2013 E.C equals 2020 G.C. This 8 and 7 years difference is due to the new year of January and September in G.C and E.C respectively. During analysis we changed Ethiopian calendar to Gregorian calendar. Kindly understand it in such a manner.

Submitted filename: Response to reviewers comment.docx

Click here for additional data file.

4 Aug 2022

10 Aug 2022

10/08/2022

Dear Academic Editor,

PLOS ONE

Subject: Submission of revised manuscript entitled as “Advanced stage presentation and its determinant factors among colorectal cancer patients in Northwest Amhara Regional State Referral Hospitals of Ethiopia (PONE-D-22-07229R2).

Dear, Negar Rezaei, M.D., Ph.D, thank you for your email enclosing the Editorial member’s and the reviewer’s comments. We have carefully revised the manuscript and incorporated their comments accordingly. Our responses are given in point-by-point response below.

We hope the revised version is suitable for publication and look forward to hearing from you in due courses.

Sincerely

Mulugeta Wassie.

Point by point responses to Editorial Board Member’s and Reviewers’ comments

Editor comments

Editor’s comment #01: Please consider the reviewer 3 comments

Authors’ response: Thank very much for your suggestions. We have incorporated all the comments raised by reviewer 3 in the manuscript

Reviewers’ comments:

Reviewer #1: No comments.

Reviewer #2: No comments.

Reviewer #3:

�  Please add the confidence interval (CI) measurement definition to the analysis section of the methods.

Authors’ response: Thank you very much for your constructive comment. We have added the confidence interval (CI) measurement definition in the manuscript on the analysis section.

�  Some percentages were presented without decimals, some with one decimal, and some with two decimals. To maintain consistency, I suggest presenting all the percentages with one decimal.

Authors’ response: Thank you very much for your constructive comments. We have tried to make consistent all decimals throughout the document using one decimal.

�  Line 151: Please correct "One hundred fourth one".

Authors’ response: Thank you very much for your constructive comment. We have corrected it in the manuscript.

�  Line 166, suggested format: "83.1% (95 % confidence intervals (CIs): 78.9%, 86.6%)".

Authors’ response: Thank you very much for your constructive comment. We have corrected it as your suggestion.

�  Until line 177, you used "," as a separator between confidence intervals, but after line 177 "-" was used instead. Please keep the consistency.

Authors’ response: Thank you very much for your critical constructive comment. We have used "-" throughout the document to make consistency.

Submitted filename: Response to reviewers comment .docx

Click here for additional data file.

15 Aug 2022

Advanced stage presentation and its determinant factors among colorectal cancer patients in Amhara Regional State Referral Hospitals, Northwest Ethiopia

PONE-D-22-07229R3

Dear Dr. Wassie,

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.

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Kind regards,

Negar Rezaei, M.D., Ph.D.,

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

24 Aug 2022

PONE-D-22-07229R3

Advanced stage presentation and its determinant factors among colorectal cancer patients in Amhara Regional State Referral Hospitals, Northwest Ethiopia

Dear Dr. Wassie:

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.

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