Survival of women with cervical cancer in East Africa: a systematic review and meta-analysis

Abstract Background The prognosis for cervical cancer varies greatly between nations. The disparity in cancer survival rates within nations is largely a result of disparities in public knowledge, the accessibility of cancer services, diagnosis and treatment. The purpose of this systematic review and meta-analysis is to assess the survival rate and associated factors among cervical cancer patients in East Africa. Methods Literature search was carried out using Google scholar, PubMed/Medline, Embase and CINHAL. Covidence, a web-based program, was used to import studies for review process. PRISMA guidelines were followed. A total of 110 abstracts were identified from electronic sources. There were five duplicate articles removed. We looked at 105 papers’ abstracts and titles, and we excluded 78 of them because they did not fit our inclusion criteria. We conducted a full-text analysis of the remaining 27 papers, leaving out 14 researches that did not fit our inclusion requirements. For final review, 13 studies were included. Using the Joanna Briggs Institute (JBI) assessment checklist, methodological quality was evaluated. Results The included articles were cohort studies. They were conducted in Ethiopia, Uganda, Zimbabwe, Kenya, Sudan, Tanzania and Rwanda. One-year, two-year, three-year, four-year and five-year overall survival rates ranged from 67% to 92%, 55% to 84%, 44% to 53%, 32% to 47%, and 26% to 43%, respectively. Conclusions The pooled one-year, two-year, three-year, four-year and five-year survival rates of cervical cancer patients in East Africa were 84%, 71%, 50%, 39% and 36%, respectively. HIV status, late presentation, treatment modalities, older age and presence of comorbidities were the most commonly mentioned prognostic factors for survival. PROSPERO Registration number CRD42023402551 PLAIN LANGUAGE SUMMARY Most women in developing countries present with advanced disease, often untreatable or suitable only for palliation. In East Africa, cervical cancer makes up 40% of all cases of cancer detected in women. This largely highlights the inadequacy of national cancer control initiatives in most African nations, including immunization, screening, and early detection. Cervical cancer survival rates vary throughout the world and are commonly associated with the country’s development status. The pooled five-year survival rate for cervical cancer patients in East Africa was 36%, according to this systematic review and meta-analysis, which is much lower than the rates in developed countries like the United States, Japan, and Australia but comparable to studies conducted in India.


Introduction
Despite only making up 9.4% of all women over the age of 20 worldwide, sub-Saharan Africa (SSA) accounts for 112,000 new diagnoses and 76,000 deaths out of the predicted 570,000 diagnoses and 311,000 deaths from cervical cancer in 2018 (Bach 2005, Shaw 2013, Bray et al. 2018, Kruk et al. 2018).In low-and middle-income countries, cervical cancer has the second-highest incidence and mortality rates after breast cancer, according to GLOBOCAN worldwide cancer data (Ferlay et al. 2019).In Africa, Southern Africa, Eastern Africa and Western Africa all have higher regional incidence and mortality rates (Bray et al. 2018).
Globally, among the 20 countries with the highest incidence of cervical cancer, 16 are African countries (Bray et al. 2018).Moreover, cervical cancer accounts for 40% of all cancer cases diagnosed among women in East Africa (Hull et al. 2020).This primarily indicates the absence or lack of national cancer control programs, including vaccination, screening and early detection, in most African countries (Kantelhardt et al. 2014).
WHO estimates that by 2030, the numbers of annual cervical cancer deaths will more than double the 200,000 anticipated deaths from pregnancy-related complications (Mathers and Loncar 2006).Most women in developing countries present with advanced disease, often untreatable or suitable only for palliation (Denny and Anorlu 2012).The remarkable inequality in cancer survival between and within countries is largely due to the differences in general awareness, availability of early detection practices, trained human resources and accessibility to cancer services, diagnosis and treatment (Sankaranarayanan 2011).
Cervical cancer shows large differences in global outcomes depending access to high-quality care and stage of presentation to the health care system.In Africa, facilities for treatment are limited, and where they are available are not affordable to most women in the region.The causes of high mortality and low survival rates in Africa are poor access to medical facilities, which is worst in the rural areas; poor nutrition and co-morbid conditions, high rate of loss to follow-up; and women not completing treatment because of barriers imposed by poverty.The availability of these options is typically limited to capital cities in several African countries or, in some cases, not available at all.Consequently, palliative care with symptom management and support may be the most likely option for severe latestage cervical cancer or for women with less advanced disease, but who cannot afford or access treatment (Khamis et al. 2021).
Even though attempt has been made to assess survival status of women with cervical cancer in Eastern Africa countries, these studies were not systematically presented.The objective of this systematic review and meta-analysis is, therefore, to review the survival status and associated factors of women with cervical cancer who are living in east African countries.

Selection process
Studies were imported to the web-based application Covidence for screening (Veritas Health Innovation 2020).The authors reviewed all abstracts for inclusion, applying the eligibility criteria outline.In cases of inclusion conflict, the abstracts were included for full-text article review.The decision for final inclusion of studies in this systematic review was considered after two investigators independently reviewed all full-text articles to confirm whether inclusion criteria were met or not.Potential discrepancies at any stage were resolved by the consensus of all authors.Two investigators then reviewed the full text of the article and extracted data using a uniform abstraction tool.

Quality assessment and data extraction
This systematic review followed PRISMA guidelines (PRISMA Guideline 2022).Six reviewers participated in the review process.Data extraction included: title, authors, publication year, study period, study design, survival rate and factors.Methodological quality was assessed by using Joanna Briggs Institute (JBI) (Moola et al. 2020).

Meta-analysis
The data were analysed using STATA version 17 Statistical (College Station, TX).A random effect model was used to compute the meta-analysis.It is appropriate whenever statistical generalisations beyond the included studies are considered.In the random-effects model, we assume a distribution of effects rather than a common identical effect size, and we assume that the meta-analysis summary effect size is an estimate of the mean of a distribution of genuine effects rather than a common shared effect size identical for all studies.
Using this model, pooled overall survival (OS) rates were  Heterogeneity across studies was checked using the inverse variance (I 2 ).The cut-offs of 25%, 50% and 75% were used to declare the heterogeneity as low, moderate and severe, respectively.

Publication bias
To assess publication bias, both the funnel plot and Egger's test were conducted in the meta-analysis.A publication bias was assessed using funnel plot and objectively by Egger's test at a 5% significant level.A funnel plot showed asymmetrical distribution evidencing publication bias, and Egger's tests were statistically significant with a p value ¼ .0006.

Characteristics of included studies
A total of 13 articles that examined cervical cancer survival status and associated factors of survival for women living in the eastern part of Africa were included for abstraction.The included articles were cohort studies and were conducted in Ethiopia, Uganda, Zimbabwe, Kenya, Sudan, Tanzania and Rwanda (Table 1).

Survival status
The pooled overall one-year survival of cervical cancer patients in East Africa with random-effect model was 84% (95% CI: 78%, 90%) (Figure 2).In Zimbabwe, the reported one-year OS rate was 67% (Chokunonga et al. 2004).The extent of cancer was reported to be 27.5%, 50% and 8.1% as localised, regional and distant, respectively.One-year OS after radical RT (n ¼ 5180) for International Federation of Gynaecology and Obstetrics (FIGO) stages IIA-IIIA was 89% in Ethiopia (Moelle et al. 2018).In Uganda, the one-year survival rate was 84% (Wabinga et al. 2003).The presenting stage was 27.9%, 41.9%, 20.6% and 9.6% as FIGO stages I, II, III and IV, respectively.Women who were treated with radiotherapy had a 73.3% one-year survival rate, compared to 58.2% of those who did not, according to Chokunonga et al. (2004) (Table 2).According to Wabinga et al. (2003), radiotherapy patients in Uganda had a higher first-year survival rate (82%) compared to untreated patients (78.5%) (Table 2).In a study by Moelle et al. (2018), 96% of cervical cancer patients who received radical radiation therapy and roughly 73% of patients who received palliative radiation therapy both survived for one year (Table 2).Furthermore, one-year survival among HIV-negative cervical cancer patients was 79%, while HIV-positive cervical cancer patients had a survival rate of 65% (Figure 3).
The pooled two-year survival of cervical cancer patients in East Africa with random-effect model was 71% (95% CI: 63%, 79%) (Figure 2).Patients who received radiotherapy survived at a rate of 59.5%, whereas those who did not survived at a rate of 51% (Chokunonga et al. 2004) (Table 2).The pooled three-year survival of cervical cancer patients in East Africa with random-effect model was 50% (95% CI: 45%, 55%) (Figure 2).In Rwanda, the majority of patients (67%) were in stage III or IV illness at the time of presentation and the three-year survival rate for radical hysterectomy was 94%, 66% for chemoradiotherapy, 11% for chemotherapy and 7% for no treatment (Table 2) (Umutoni et al. 2021).
Concomitant chemo radiotherapy was administered to 32% of patients with stage 2B, 3A, 3B and 4A.Furthermore, 60% of the patients received Brachytherapy.The overall five-year survival rate was discovered to be 43% (Mohamed and Ashmeig 2017).In Ethiopia, over two-thirds (65.1%) of cervical cancer patients presenting at advanced stages (III and IV), 90.5% received radiation treatment, and nearly half (50.3%) had only chemotherapy.Palliative radiation was given to 61.5% of patients.Five-year survival was recorded as 38% (Wassie et al. 2019).
Age, poverty, low literacy and lack of medical resources were mentioned factors that were related to survival status.Another frequent finding was an association between cervical cancer survival and late-stage disease manifestation.Anaemia and HIV status were co-morbidities linked to cervical cancer survival.HIV infection was substantially related to cervical cancer survival, according to studies by Wu et al. (2020), and Kigula- Mugambe and Kavuma (2006).Survival for cervical cancer was correlated with a single portion of radiotherapy, radiotherapy treatment termination, treatment methods and concurrent chemoradiotherapy.Cervical cancer patients who were more than 60 years old had lesser survival status than younger age groups (HR 1.44 0.96, 1.93) (Figure 4).It was found that stage presentation and survival status were significantly associated.Cervical cancer patients who were presented in FIGO stage IV had 3.22 times (HR 3.22 1.31, 5.2) risk of death than those who were presented in FIGO stage II (HR 1.65 0.14, 3.16) (Figure 5).

Discussion
Women living in Africa have the highest burden of cervical cancer.In spite of the heavy burden of disease and limited access to cervical cancer treatment, research is still limited for countries in Africa.Survival data for cervical cancer in African countries are limited.This systematic review and meta-analysis showed that the five-year overall pooled survival of cervical cancer in East Africa was 36%.This is much less than in the United States (62.8%),Japan (66.3%), Australia (67.1%),South Africa (54.9%),Chile (50.9%) and Brazil (61.1%) (Allemani et al. 2015).In Malaysia, the 5-year survival rate was 71.1% (Muhamad et al. 2015).In France, the 5-year survival rate was 62% (Lorin et al. 2015) but it was similar to the study conducted in India (32.5%) (Thulaseedharan et al. 2015).
Disease staging, which takes into account tumour size and the presence of distant metastases, has been shown to be an important prognostic factor in cervical cancer patient survival.In this review, Wassie et al. (2019) reported that in cervical cancer cases diagnosed in the early stages (I and II), the fiveyear survival rate was 81.04% and 67.94%, respectively, while those cases diagnosed in more advanced stages (III and IV) had survival rates of 23.33% and 20.03%, respectively.In a study done by Carneiro et al. (2017), the survival rates of stages IIA to IVB and IA to IB patients were 32.7% and 92.3%, respectively.A 2009 study in California, which included 353 cervical cancer survivors, also indicated that the cancer stage is a significant survival factor (Ashing-Giwa et al. 2010).In a study done in the region of Kerala, women with cervical cancer had 5-year survival rates of 69%, 61.5%, 52.8%, 43% and 28% for stages IB, IIA, IIB, IIIB and IVA, respectively (Sankaranarayanan et al. 1995).In Brazil, the survival rate of patients with metastasis was unfavourable, but the survival rate of metastasis-free patients was 81.5% (Carneiro et al. 2017).In India, the five-year observed survival was 32.5%, ranging from 9% for stage IV to 78% for stage I cancers.The five-year observed survival was 32.5%, ranging from 9% for stage IV to 78% for stage I cancers (Thulaseedharan et al. 2015).Stage at presentation was the strongest factor in the prediction of five-year survival; 86% in stage I survived compared with 58% in stage II, 31% in stage III and 0 in stage IV (Kaverappa et al. 2015).These data demonstrate that early diagnosis reduces the risk of death and that when the disease is treated in the initial phase.Furthermore, the effectiveness of treatment is restricted when the disease is in an advanced stage, even in countries with advanced diagnostic and treatment technologies as the survival rates have not been higher than 70-75% (Nakagawa et al. 2011).
Socioeconomic status, older age, stage presentation and HIV status were prognostic factors for survival found in this review.Women with poor socioeconomic status (SES) had up to a 70% higher risk of death (Thulaseedharan et al. 2015).In Malaysia, age and ethnic groups remain significant determining factors for cervical cancer survival rate (Muhamad et al. 2015).One possible cause for this might be that social support is a critical factor during a treatment series (Esophageal et al. 2020).Considering age as a factor, in this review, the highest risk of death was found among the older age group and this is similar to other studies (Nakagawa et al. 2011, Gonzaga et al. 2013, Lorin et al. 2015).This may be explained as the older age group has classically had a lower participation in screening and they're gynaecological follow-up is less frequent (Lorin et al. 2015).The treatment modality was the other prognostic factor for better survival.In this review, concurrent chemoradiotherapy was associated with cervical cancer survival.In other study also, chemoradiotherapy improves survival compared to radiotherapy alone, 81% vs. 71%, respectively (Peters et al. 2000).

Clinical implication
Survival studies provide critical information regarding factors that may be associated with illness prevention and treatment, which can lead to more effective health policies and health systems with higher patient survival rates.This review found that the diagnosis of an advanced illness state is a major contributor to poor survival.The result of this systematic review and meta-analysis also indicated the necessity of providing women with preventive and screening options in lowresource settings such as East Africa, as well as the need to improve the quality of healthcare facilities in rural areas.To ensure that all women diagnosed with cervical cancer have an equal chance of surviving, public health officials and policymakers must expand access to early detection programs in low-and medium-resource rural regions.Cervical cancer screening and treatment should be available and economically priced.Our findings also highlighted the importance of enhancing cancer treatment services and expanding prevention and screening options for women in East Africa.

Conclusions
Cervical cancer is a preventable disease yet remains the most common cause of cancer death among women in poor countries (ICO 2016).The pooled one-year, two-year, three-year, four-year and five-year survival rates of cervical cancer patients in East Africa were 84%, 71%, 50%, 39% and 36%, respectively.Late presentation, treatment modalities, age and HIV status are the most common prognostic factors for survival.

Limitations
We were unable to compute a pooled survival rate by disease stage and treatment type for 1, 2, 3, and 4 years.This is because survival rates by cancer stage for each year were not reported in most articles, and different staging systems were reported.Survival by treatment group was not reported in a similar manner to compute jointly.

Figure 2 .
Figure 2. Pooled survival status of cervical cancer patients in East Africa.

Figure 3 .
Figure3.One-year survival rate subgroup analysis by HIV status in East Africa.

Figure 4 .
Figure 4. Age and survival status of cervical cancer patients in East Africa.

Figure 5 .
Figure 5. Stage presentation and survival status of cervical cancer patients in East Africa.

Table 1 .
BasicJOURNAL OF OBSTETRICS AND GYNAECOLOGY computed for each year.Subgroup analysis was also done by HIV status, by age and stage of cancer.
characteristics of included articles in the systematic review and meta-analysis.Study Country Title Study design Study period Sample Moelle et al. (2018) Ethiopia Cervical cancer in Ethiopia: the effect of adherence to radiotherapy on survival Retrospective cohort study 2008-2012 Wu et al. (2020) Uganda The association between HIV infection and cervical cancer presentation and survival in Uganda Prospective cohort study 2013-2015 Chokunonga et al. (2004) Zimbabwe Survival of cervical cancer patients in Harare, Zimbabwe

Table 2 .
Survival of cervical cancer patients by HIV status, stage of cancer and treatment modalities in East Africa countries.