Prevalence and determinants of late-stage presentation among cervical cancer patients, a systematic review and meta-analysis.

BACKGROUND: An estimated 570,000 women were diagnosed with cervical cancer worldwide, and about 311,000 women died from the disease. Cervical cancer is possibly the most curable human cancer; if detected at the precancerous stage. Additionally, early diagnosis and management other factors are essential to decrease mortality rate among those patients. So this review was aimed to identify the prevalence and determinants of late-stage presentation among cervical cancer patients.
METHODS: A systematic search had carried out on PubMed, EMBASE, MEDLINE, Cochrane, Scopus, Web of Science CINAHL, and manually on Google Scholar. This meta-analysis follows the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The modified Newcastle-Ottawa Scale (NOS) was used to assess the quality of each study. A meta-analysis was done using a random-effects method using the STATA™ Version 14 software. RESULT: Twenty-five studies from 3 world regions with 53,233 participants were enrolled in this meta-analysis. The overall estimated global pooled prevalence of late-stage presentation among cervical cancer patients with a random-effects model was 60.66% (95% CI: 56.27, 65.06). The subgroup analysis revealed that the prevalence of late-stage presentation was 62.60% in Africa, 69.30% in Asia, 46.51% in Europe, and 50.16% in North America. Educational status (p = 0.031) and place of residence (p = 0.004) are determinants of late-stage presentation.
CONCLUSION: The results of this meta-analysis indicated that the prevalence of late-stage presentation of cervical cancer is substantially high. Place of residence and educational status were significantly associated with late-stage presentation. Health care organizations should work on early screening, management, and on increasing community awareness to minimize late stage at presentation among those patients.

Introduction

World Health Organization (WHO) reports that cervical cancer is the fourth most common cancer in women. An estimated 570, 000 women were diagnosed with cervical cancer worldwide from them around 311, 000 women died from the disease in 2018. Cervical cancer is possibly the foremost curable human cancer, if detected at the precancerous stage [1]. The challenge is that 80% of women in the developing countries seek treatment after they have developed signs and symptoms [2].

Presentation of cervical cancer in a sophisticated stage of disease is the outcome of multiple complex factors including availability of health services for screening, diagnosis, and other cultural and social issues [3]. Reports showed late stage at diagnosis is correlated with lower survival rates in cervical cancer patients [4-6].

Advanced cervical cancer is one among of the main causes of cancer related mortality in women because of poor access to appropriate management especially, in low- and medium income countries. One amongst the foremost important prognostic factors for cervical cancer is how early the disease is detected and how far it’s spread. Recently, delay in diagnosis and treatment continues to be the leading obstacle to overcome in the fight to cure cancer [7-9].

Several studies worldwide have investigated the factors related to delayed diagnosis and disparities in its fatality rate in different racial, geographic and socio-economic groups [10-13]; is also knowledge on pooled determinants of delays for this cancer may be useful in establishing comprehensive preventative strategies.

The concept of delayed diagnosis of cervical cancer is categorized in four components including patient delay, health care provider delay, referral delay and system delay. In most countries of the globe, especially in developing countries patients and health care providers delay have more crucial role [14-16].

In Africa, high incidence of cervical cancer has been reported at rates exceeding 50 per 100,000 populations [17]. In sub-Saharan Africa, cervical cancer is the second commonest cause of cancer morbidity and the leading reason for a mortality over 577,000 deaths annually; the same is true in Eastern Africa [18].

Quick scale-up of immunization and double lifetime uterine cervix screening in the world could prevent up to 13.4 million malignancies over the long run half century [19, 20]. Additionally, early diagnosis and managing other factors will decrease mortality and also the prevalence among those patients [21]. So, this systematic review and meta-analysis aimed is to identify pooled prevalence and determinants of late-stage presentation among cervical cancer patients.

To determine pooled prevalence of late stage presentation among cervical cancer patient

To identify determinants of late stage presentation among cervical cancer patient

Methods

Inclusion and exclusion criteria

This systematic review and meta-analysis included all types of studies conducted in different regions of the world which reports the prevalence and determinants of late-stage presentation among cervical cancer patients, regardless of women’s age until July, 17, 2021; whereas, studies which were not fully accessed in which an attempt was made to contact the corresponding author and studies with methodological problems were excluded.

Information sources, search strategy, and study selection

The studies were retrieved through manual and electronic searches. The databases systematically searched were; PubMed, Scopus, Web of Science, institutional repositories, Academic Search Premier, and manually from reference lists of the previous study. Electronic database searching followed by reference lists search used to identify studies; then exported into EndNote version 7.0 to remove duplicates. Screening of titles and abstracts was done by authors independently. The Cochrane acronym POCC, which stands for population, Condition, and Context, was used to decide on all keywords. The keywords used were, “cervical cancer patient, cervical cancer cases, Late-stage presentation, late diagnosis, delayed diagnosis, advanced disease, early diagnosis, delayed presentation, late tumor stage, prolonged time to diagnosis, delayed care seeking, cancer presentation, delayed access to care, stage of diagnosis, delayed treatment initiation, patient delay, delays in diagnosis, stage at diagnosis, advanced disease at presentation, late-stage cervical cancer, and advanced stage at diagnosis. Finally, this meta-analysis was reported under the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement 2020 guidelines [22]. We registered the protocol on Prospero (ID: CRD42021284177).

Data collection process and data items

Data extraction was done by both authors (TT and MT) independently by using a data extraction format prepared in a Microsoft Excel 2013 spreadsheet. The extracted data were: the Author’s name, publication year, country, design, sample size, the prevalence of late-stage presentation, and associated factors with their odds ratio.

The outcome of the review

The primary outcome of this review was the prevalence of late-stage presentation. The second outcome of this review was determinants of late-stage presentation with their odds ratio.

Quality assessment

The modified Newcastle-Ottawa Scale (NOS) for cross-sectional studies was used to assess the quality of studies [23]. Studies that scored five and more on the NOS were included [24]. Any disagreement while data extractions were resolved through discussion.

Publication bias and heterogeneity

Funnel plot and Egger’s test had used to assess publication bias. A p-value< 0.05 had used to declare the statistical significance of publication bias. I2-statics were computed to assess heterogeneity among reported prevalence I2 test statistics had used to check the heterogeneity of studies. In which if, < 50 declared as low, 50–75% as moderate, and > 75% as having high heterogeneity [25].

Data synthesis and analysis

A random-effects meta-analysis model was used to estimate the Der Simonian and Laird’s pooled effect to show heterogeneity. Subgroup analysis was conducted to adjust random variation between point estimates of original study and investigate how failure fluctuates across subgroup participants. Outlier within the included articles was checked using sensitivity analysis. Publication bias across studies was assessed using funnel plot and egger’s regression test, at P < 0.05 to indicate publication bias. Forest plot format was used to present the point prevalence and 95% CIs. In this plot, the weight of study indicated by the size of each box, while each crossed line referred to 95% confidence interval. For the secondary outcomes, odds ratio was used to determine the association between late stage presentation and associated factors. STATA™ V14 software was used to carry out the all Meta-analysis.

Results

Study selection

Initially, a total of 64,059 studies had retrieved from the databases and manual searching. From this, 33,547 duplicates were found and removed. The rest, 35,771 articles’ were screened by their titles and abstracts. Then 29,835 were irrelevant and removed. Finally, 81 full-text articles were assessed for eligibility, and then due to failure to report the outcome of interest 56, articles were excluded. Finally, a total of 25 studies was fulfilled the inclusion criteria and enrolled in the study. The detailed retrieval process is shown in (Fig 1).

Fig 1

PRISMA flowchart diagram of the study selection.

Study characteristics

The 25 studies [26-50] included 53,233 participants. Most of the included studies were cross-sectional studies and the sample size ranged from 50 [33] to 13624 [50]. Most studies were conducted in Ethiopia. Among the included studies, prevalence of late stage presentation among cervical cancer patients were ranged from 28 [42] to 89.1 [32] (Table 1).

Table 1

Characteristics of the included studies in the systematic review and meta-analysis.

Authors Name	Publication Year	Study area	Study design	Sample size	Prevalence (95% CI)
Wassie M, Fentie B.	2021	Ethiopia	Cross-sectional	1057	56.8(53.81–59.78)
Mlange R, et al.	2016	Tanzania	Cross-sectional	202	63.9(57.27–70.52)
Dunyo P	2018	Ethiopia	Cross-sectional	157	65.97(58.55–73.38)
Ndlovu N	2003	Zimbabwe	Cross-sectional	108	80(72.45–87.54)
Ibrahim A, et al.	2011	Sudan	Cohort	197	72(65.72–78.27)
Gyenwali D, et al.	2013	Nepal	Cross-sectional	110	80.9(73.55–88.24)
Behnamfar F, Azadehrah M	2015	Iran	Cross-sectional	55	89.1(80.86–97.33)
Dereje N, et al.	2020	Ethiopia	Cross-sectional	50	60.4(46.84–73.95)
Zeleke S, et al.	2021	Ethiopia	Cross-sectional	410	86.3(82.97–89.62)
Begoihn M, et al.	2019	Ethiopia	Cohort	1575	55.2(52.74–57.65)
Tanturovski D, et al.	2013	Macedonia	Cross-sectional	107	72(63.49–80.50)
Ouasmani F et al.	2016	Morocco	Cross-sectional	401	39.9(35.10–44.69)
Panda J, et al.	2020	India	Cross-sectional	122	39.3(30.63–47.96)
Berraho M, et al.	2012	Morocco	Cross-sectional	200	54.5(47.59–61.40)
Frida KM, et al.	2017	Kenya	Cross-sectional	152	53.9(45.97–61.82)
Kaku M, et al.	2008	India	Cross-sectional	473	50.4(45.89–54.90)
Lim AW, et al.	2014	England	Cross-sectional	128	28(20.22–35.77)
Ferrante JM, et al.	2000	USA	Cross-sectional	852	45.3(41.95–48.64)
Friebel-Klingner TM, et al.	2021	Botswana	Cross-sectional	984	44.7(41.59–47.80)
Mwaka AD, et al.	2016	Uganda	Cross-sectional	149	65(57.34–72.65)
El Ibrahimi S, Pinheiro PS.	2017	USA	Cross-sectional	31425	59(58.45–59.54)
Senapati R,	2016	India	Cross-sectional	246	78.04(72.86–83.21)
Tiwari V, et al.	2015	India	Cross-sectional	300	77.87(73.17–82.56)
Nassali MN, et al.	2018	Botswana	Cross-sectional	149	55.1(47.11–63.08)
Saghari S, et al.	2015	USA	Cross-sectional	13624	46(45.16–46.83)

Meta-analysis

Based on this study, the overall estimated pooled prevalence of late-stage presentation among cervical cancer patients with a random-effects model was 60.66% (95% CI: 56.27, 65.06) with a heterogeneity index (I2) of 98.4% (p = 0.000) (Fig 2).

Fig 2

Forest plot showing pooled global prevalence of late stage presentation among cervical cancer patient.

To adjust, the reported heterogeneity of the study (I2 = 98.4%), the subgroup analysis based on the world region had done; accordingly, the prevalence of late-stage presentation among cervical cancer patients was found 62.60% in Africa, 69.30% in Asia, 46.51% in Europe, and 50.16% in North America (Fig 3).

Fig 3

Subgroup analysis of global late stage presentation among cervical cancer patients.

Meta-regression was conducted to identify the source of heterogeneity by using sample size and year of publication as a covariate; the result showed there is no effect of sample size and year of publication on heterogeneity between studies (Table 2). A publication bias was assessed using funnel plot and objectively by Egger test at a 5% significant level. A funnel plot showed asymmetrical distribution evidencing publication bias, and the Egger tests were not statistically significant with a p-value = 0.623 (Fig 4).

Table 2

Meta-regression analysis of factors affecting between-study heterogeneity on prevalence of late-stage presentation.

Heterogeneity source	Coefficients	Std. Err.	P-value
Sample size	0.0000892	.0.0017334	0.959
Year of publication	0.0231892	2.083469	0.991

Fig 4

Funnel plot to test the publication bias in 25 studies with 95% confidence limits.

Sensitivity analysis had carried out by removing studies step by step to evaluate the effect of a single study on the overall effect estimate but, removing of a single study wouldn’t have a significant influence on pooled prevalence. Additionally, there is no study away from the lower and upper limit of confidence interval (Fig 5).

Fig 5

Sensitivity analysis of pooled prevalence of late stage presentation for each study being removed one at a time.

Determinants of late stage presentation

Five variables were extracted to identify determinants of late-stage presentation among cervical cancer patients. Of those, two variables (educational status and place of residence) had identified as significant factors (Table 3).

Table 3

Determinants of late-stage presentation among cervical cancer patients.

Determinants	Comparison	No of studies	Sample size	OR(95%CI)	P -value	I2 (%)	Heterogeneity test (p value)	Egger’s test (P -value)
Educational status	No formal education Vs primary and above	7	1014	0.39(0.17–0.91)	0.031	85.4	< 0.001	0.413
Age of the patient	< 50 years old Vs > = 50 years old	3	14833	1.91(0.94–3.90)	0.073	96.0	< 0.001	0.681
Marital status	Married Vs others	6	15735	1.433(0.86–2.37)	0.162	92.3	< 0.001	0.760
Place of residence	Urban Vs Rural	5	4814	2.87(1.38–5.93)	0.004	94.9	< 0.001	0.200
Screening history	Yes vs No	4	1194	2.31(0.91–5.85)	0.077	72.2	0.013	0.374

Accordingly, those patients educated primary and above were 61% less likely to have the late presentation of cervical cancer than those with no formal education (OR: 0.39(95%CI 0.17–0.19), p = 0.031, I2: 85.4%, the heterogeneity test (p< 0.001).

Those patient who came from the rural area were 2.87 times more likely to have a late presentation of cervical cancer than who come from urban areas (OR: 2.87(95%CI 1.38–5.93), p = 0.004, I2: 94.9%, the heterogeneity test (p< 0.001).

Discussion

A study showed the fate of patients after proved diagnosis of cervical cancer was 98% of the patients’ consent to further medical care, and around 27% finally had a hysterectomy [51]. The figure is one indication of the worse effect of cervical cancer.

According to this Meta-analysis, the overall estimated pooled prevalence of late-stage presentation among cervical cancer patients with a random-effects model was 60.66% (95% CI: 56.27, 65.06) with a heterogeneity index (I2) of 98.4% (p = 0.000). The increased prevalence of late stage presentation of this preventable and curable cancer puts a patient at higher risk of death [52]. The subgroup analysis showed that the prevalence of late-stage presentation among cervical cancer patients was 62.60% in Africa, 69.30 in Asia, 46.51% in Europe, and 50.16% in North America. The highest prevalence in low-medium income countries might be due to poor urbanization level, demographic, and low socio-economic characteristics of the study participants. This systematic review and meta-analysis also identified pooled determinants of late presentation among cervical cancer patients. Among the extracted factors’ educational status and place of residence are significantly associated.

There is an association between educational level and late-stage presentation. This study t also indicated, patients educated primary and above were 61% less likely to have the late stage presentation of cervical cancer than those with no formal education (OR: 0.39(95%CI 0.17–0.19). Different studies showed that low educational level is a risk factor and determinant of health-seeking behavior among patients [53, 54]. Those patient who came from the rural area were 2.87 times more likely to have a late -stage presentation of cervical cancer than who come from urban areas (OR: 2.87(95%CI 1.38–5.93). Place of residence determines health care service utilization, and in advance, it’s related to premature mortality [55, 56] secondary to delayed presentation and poor health care seeking behavior.

Conclusion

The results of this meta-analysis indicated that the prevalence of late-stage presentation of cervical cancer is substantially high. Place of residence and educational status were significantly associated with late-stage presentation. Health care organizations should work on early screening, management, and on increasing community awareness to minimize late stage at presentation among those patients.

Limitation of the study

This systematic review and meta-analysis presented up-to-date evidence on the prevalence of late-stage presentation and determinants of cervical cancer; it might have faced the following limitations. First, the lack of studies from three regions of the world may affect the generalizability of the finding. Secondly, we have faced difficulties comparing our findings due to the lack of regional and worldwide systematic reviews and meta-analyses.

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9 Feb 2022

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Reviewer #1: 1.The topic is not novel enough, there is no important clinical value.

2.The meta-analysis unreported preliminary design analysis.

3.Literature Searches and Search terms are incomplete. To ensure a high recall rate, otherwise it will affect the reliability and authenticity of the conclusions of Meta analysis. Please attach search terms that were used in each database as supplement for Data source and search strategies in the manuscript. Please provide details search terms in supplementary documents. Please attach syntax used in each database as supplementary.

4.There is still a considerable heterogeneity as in your limitation. Researchers can perform a subgroup analysis or Meta-regression analysis.

Reviewer #2: Thank you for the opportunity to review this paper. This is an interesting topic but there so many issues that need to be addressed. First, the language is very poor. The authors need a support from a native English language writer or seek the journal’s language editing service. Second, the study objectives and methodology were poorly written. They stated under “outcome measure” that the primary measure was “prevalence” while the secondary measure was “determinants” but the title of this paper was “determinants”. So many missing information and not adhering to PRISMA guideline. Also not registered in PROSPERO. Results and tables were poorly presented. The authors should seek support from a librarian or an expert in systematic review to review this interesting paper. Below are a few comments. I could not present all errors I found in the paper due to its fundamental flaws.

Abstract:

1. The authors need to specify that they also want to estimate the prevalence and not only the determinants.

2. Several descriptive and grammatical errors. Please have a review of the choice of word. Example first sentence in the results

“From 64,059 obtained studies, 25 studies from 3 world regions involving 53,233 participants enrolled in this meta-analysis.”

Also in the conclusion:

“…..Therefore health care organizations should work on early screening and treatment, as well as increasing community awareness to minimize premature death among those patients is essential” needs to be rephrased. The use of the term “therefore” doesn’t fit in.

Also see the Introduction section:

“Several studies worldwide have investigated the factors associated with delayed diagnosis of the cancer and disparities in its mortality rate in different racial, geographic and socio-economic groups [10-13]. However knowledge of delays for this cancer could be useful in establishing comprehensive preventative strategies.” The use of However is a problem here.

Please check other through out this paper. I found so many disconnect and wrong use of coordinating and subordinating conjunctions.

Introduction

1. I would move this statement forward to the first or second paragraph:

“In Africa, high incidences of cervical cancer are reported at rates exceeding 50 per 100,000 populations [17]. In sub-Saharan Africa, cervical cancer is the second commonest cancer morbidity and the leading cause of mortality with over 577,000 deaths annually; furthermore, in Eastern Africa it is the number one commonest cancer in women [18].”

2. “Other factors were scattered studied so, this systematic

review and meta-analysis aimed is to identify pooled determinants of late-stage presentation among cervical cancer patients”???.

This sentence is not clear.

3. Authors need to align their study objectives to the study title.

Methods

1. The methodology of this review was poorly written. The authors claim to follow the PRISMA guideline, but I could not verify this in the methodology.

2. Looks like this systematic review was not registered in PROSPERO

3. “…The databases used were EMBASE, MEDLINE, Cochrane, Scopus, Web of Science,

CINAHL, and manually on Google Scholar.” This should be under information sources.

4. “Both funnel plot and Egger’s test had used to assess publication bias. A p-value< 0.05 had used to declare the statistical significance of publication bias. Also, I2 test statistics had used to check the heterogeneity of studies. I2 test statistics of < 50, 50–75% and > 75% was declared as low, moderate and high heterogeneity respectively [25]”.

So many errors here and there and poorly written. The authors could not clearly describe their analytical approach and the reasons for what they did.

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3 Mar 2022

REVIEWER COMMENTS

Determinants of late-stage presentation among cervical cancer patients, a systematic review and Meta-analysis Thank you for the opportunity to review this paper. This is an interesting topic but there so many issues that need to be addressed. First, the language is very poor. The authors need a support from a native English language writer or seek the journal’s language editing service. Second, the study objectives and methodology were poorly written. They stated under “outcome measure” that the primary measure was “prevalence” while the secondary measure was “determinants” but the title of this paper was “determinants”. So many missing information and not adhering to PRISMA guideline. Also not registered in PROSPERO. Results and tables were poorly presented. The authors should seek support from a librarian or an expert in systematic review to review this interesting paper. Below are a few comments. I could not present all errors I found in the paper due to its fundamental flaws. Abstract: The authors need to specify that they also want to estimate the prevalence and not only the determinants. Response – corrected Several descriptive and grammatical errors. Please have a review of the choice of word. Example first sentence in the results “From 64,059 obtained studies, 25 studies from 3 world regions involving 53,233 participants enrolled in this meta-analysis.”Also in the conclusion: “…..Therefore health care organizations should work on early screening and treatment, as well as increasing community awareness to minimize premature death among those patients is essential” needs to be rephrased. The use of the term “therefore” doesn’t fit in.Also see the Introduction section: “Several studies worldwide have investigated the factors associated with delayed diagnosis of the cancer and disparities in its mortality rate in different racial, geographic and socio-economic groups [10-13]. However knowledge of delays for this cancer could be useful in establishing comprehensive preventative strategies.” The use of However is a problem here. Please check other through out this paper. I found so many disconnect and wrong use of coordinating and subordinating conjunctions. Response – corrected IntroductionI would move this statement forward to the first or second paragraph: “In Africa, high incidences of cervical cancer are reported at rates exceeding 50 per 100,000 populations [17]. In sub-Saharan Africa, cervical cancer is the second commonest cancer morbidity and the leading cause of mortality with over 577,000 deaths annually; furthermore, in Eastern Africa it is the number one commonest cancer in women [18].” Response – corrected “Other factors were scattered studied so, this systematicreview and meta-analysis aimed is to identify pooled determinants of late-stage presentation among cervical cancer patients”???.This sentence is not clear. Response – corrected Authors need to align their study objectives to the study title. Response – corrected MethodsThe methodology of this review was poorly written. The authors claim to follow the PRISMA guideline, but I could not verify this in the methodology.Response – corrected and followed updated PRISMA guideline Looks like this systematic review was not registered in PROSPEROResponse – corrected and registration ID was mentioned“…The databases used were EMBASE, MEDLINE, Cochrane, Scopus, Web of Science,CINAHL, and manually on Google Scholar.” This should be under information sources.Response – corrected “Both funnel plot and Egger’s test had used to assess publication bias. A p-value< 0.05 had used to declare the statistical significance of publication bias. Also, I2 test statistics had used to check the heterogeneity of studies. I2 test statistics of < 50, 50–75% and > 75% was declared as low, moderate and high heterogeneity respectively [25]”. So many errors here and there and poorly written. The authors could not clearly describe their analytical approach and the reasons for what they did. Response – corrected

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12 Apr 2022

Prevalence and determinants of late-stage presentation among cervical cancer patients, a systematic review and Meta-analysis

PONE-D-21-23859R1

Dear Dr. Tiwabwork Tekalign,

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.

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Obinna Ikechukwu Ekwunife, PhD

Academic Editor

PLOS ONE

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Reviewer #1: All comments have been addressed

Reviewer #2: All comments have been addressed

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Reviewer #1: Partly

Reviewer #2: Yes

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Reviewer #1: I Don't Know

Reviewer #2: Yes

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Reviewer #1: Yes

Reviewer #2: Yes

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Reviewer #1: Yes

Reviewer #2: Yes

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Reviewer #1: (No Response)

Reviewer #2: My concerns have been addressed. I have no further comments. The figures may need editing for qauality.

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Reviewer #1: No

Reviewer #2: No

18 Apr 2022

PONE-D-21-23859R1

Prevalence and determinants of late-stage presentation among cervical cancer patients, a systematic review and Meta-analysis

Dear Dr. Tekalign:

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.

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Kind regards,

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on behalf of

Dr. Obinna Ikechukwu Ekwunife

Academic Editor

PLOS ONE