The burden of breast cancer (BC) is rising in Nigeria. The International Agency Research on Cancer (IARC) recorded 28,380 new BC cases in Nigeria in 2020, representing 22.7% of new cancers and accounting for the highest proportion of all cancer types [1]. According to a 2013 study [2], BC accounts for 45.5% and 38.2% of cancers among women younger than 45 years and women aged 45 years or older, respectively, in the Ibadan population-based registry, and 55.6% and 45.7% among women younger than 45 years and women aged 45 years and older in the Abuja population-based cancer registry. The same study reported a four-fold increase in the age-standardized rate from 13.7 per 100 000 in 1998-1999 to 54.3 per 100 000 in 2009-2010.

Nigeria has one of the world’s highest age-standardized mortality rates of BC and the highest in Africa [3]. GLOBOCAN 2020 reported BC as the most common cause of cancer-related death in Nigeria, accounting for 14,274 (18.1%) of all cancer deaths [4]. A recent sub-Saharan African (SSA) multinational study by McCormack et al. found that BC patients in Nigeria had the lowest three-year survival rate of six countries evaluated: 36% in Nigeria, compared to 44% in Uganda, 47% in Zambia, 56% for Black women in Namibia and 59% for Black women in South Africa [5].

Prior research has identified delayed presentation, late-stage diagnosis, and inadequate treatment as challenges linked to poor BC outcomes in Nigeria and most SSA settings. Many reports have focused on patient-related and health system challenges from symptom development through diagnosis. In contrast, treatment, which is also a critical determinant of BC outcomes, has been under-reported. McCormack et al. [5] predicted a remarkable absolute survival gain of up to 12% by improving BC treatment alone, similar to the expected survival gain by early diagnosis.

This review aimed to aggregate data on treatment (surgery, chemotherapy, radiotherapy, hormonal and targeted therapy) and outcomes of BC in Nigeria to identify gaps in research, challenges, and potential targets for future intervention.

Fifteen articles met the eligibility criteria (Figure 1).

Articles reported surgery, chemotherapy, radiation therapy, hormonal therapy, and HER2-targeted therapy. All patients received at least one treatment modality in five reports [11, 15, 18, 22, 24]. In two reports, the uniform treatment was hormonal therapy alone [15, 18]. In one report, all patients received hormonal and chemotherapy [11]. Two reports purposively sampled patients receiving neoadjuvant systemic therapy: one included premenopausal patients only [23], and the second included all patients who received neoadjuvant systemic therapy [24]. Another study purposively sampled patients who combined surgery, chemotherapy, and radiotherapy [22]. To assess the overall prevalence of each treatment modality, we pooled all treatments ‘N’ and found the proportion accounted for by each treatment modality ‘n. Nine studies [10-12, 14, 15, 17, 18, 19, 22], including 5744 instances of treatment, contributed to the treatment modality’s prevalence analysis. The most prevalent modality was chemotherapy (41%, 95% CI 19-54, n-2044), followed by surgery (31%, 95% CI 13-45, n 1671), hormonal therapy 18 (4-31, n-777), radiotherapy 10% (95% CI 1-23, n-1246) and HER2 targetted therapy (0% (95% CI 0-3, n-6) (See Supplementary file).

Using only articles with nonpurposive sampling, it was possible to estimated the probability of receiving each of the three main modalities of treatment [Chemotherapy, Surgery and Radiotherapy] by finding the summary estimate of the proportion in each article. Where N is the number eligible for the treatment modality in the article, and ‘n’ is the number that received the treatment modality. The overall probability of receiving chemotherapy was 85% (95% CI66-97 ) contributed by seven articles [10, 12, 14, 15, 17, 18, 19] with 2308 subjects. The overall probability of receiving surgery was 62% (95% CI 51-73), contributed by eight articles [10-12, 14, 15, 17, 18, 19] with 1293 subjects. The overall probability of receiving radiation therapy was 31% (95% CI 8-59) contributed by seven articles [10-12, 14, 15, 17, 19] with 1884 subjects. (See supplementary file).

The indication for chemotherapy was explicitly documented as neoadjuvant or adjuvant, and there was no report on salvage therapy. The utilization rate of neoadjuvant and adjuvant chemotherapy was extractable in Olaogun et al. [18]. In this study, 36 of 82 (44%) patients who qualified for neoadjuvant chemotherapy received it, while 9 of 45 (20%) patients who qualified for adjuvant received it. The number eligible specifically for neoadjuvant or adjuvant chemotherapy was not extractable in other articles.

In four articles [10], 766 subjects contributed to data on the type of chemotherapy. Anthracycline-based therapy was the most frequent regimen, accounting for 78%, followed by taxane-based 12%. All available reports on chemotherapeutic regimens described intravenous cycles of six doses every three weeks, with no dose-dense or metronomic therapies and no oral therapies. The prevalence of non-completion or haphazard use of chemotherapy was extracted from four articles [10, 15, 18, 23], including 319 subjects. In this cohort, 156 (48%, 95% CI 35-60) subjects did not complete the recommended number of chemotherapy doses or received it at irregular intervals. Four studies [14, 23-25], including 433 subjects, contributed data on response to neoadjuvant chemotherapy. Overall, 85% of patients who received neoadjuvant chemotherapy experienced a clinical benefit: 26% had a complete response, 41% had a partial response, and and 18 had stable disease. Fifteen percent had tumor progression.

Overall, 6 articles [10, 17, 18, 19, 22, 25] with 1010 subjects contributed to data on the type of surgery. Modified radical mastectomy (MRM) accounted for 90% of surgeries. Only two percent had breast-conserving surgery; the others received simple or toilet mastectomy.

Four articles reported on hormonal therapy. The use of hormonal therapy based on immunohistochemistry (IHC) testing was extractable in Olasehinde et al. [19] only, where 39 of 53 (74%, 95% CI 60-85) patients with hormone-receptor-positive tumors received hormonal therapy. Three other articles reported routine use of hormonal therapy without IHC testing [11, 17, 18]. HER2- targeted treatment data were extractable in Olasehinde et al. only, where 6 of 43 (14%, 95% CI 5.3-30) HER2- positive patients received HER2-targeted therapy [19].

One in ten patients utilized radiation therapy in the overall analysis. Sensitivity analysis showed a heterogeneous distribution of radiation therapy used across the country. One in five patients received radiation therapy in centers/states with radiation oncology services compared with one in 20 patients in centers/states without radiation oncology services.

Among studies with nonpurposive sampling, three articles [10, 12, 14], and 983 subjects contributed data on multimodal therapy. The prevalence of receiving multimodality treatment with surgery and chemotherapy was 56% (95% CI 46-68), and the prevalence of receiving surgery, chemotherapy, and radiation therapy was 24% (10 -43). In this cohort, the stage distribution was 3%, 14%, 46%, and 37% for stages I, II, III, and IV, respectively.

Overall, the one-year survival estimate was 80%, declining sharply to 43% at the end of the second year and 32% at five years. The overall survival estimates based on tumor biology were similar for triple-negative and hormone receptor-positive diseases. After surgery, the overall prevalence of recurrence was 28% (95% CI 11-48) from data in 4 articles [10, 13, 16, 19] with 484 subjects. Two of the studies [Titiloloye et al [16] 7% (0-20%), Olaogun [10], 61% (95% CI 48-73) recorded recurrence in 3 years. Titiloye et al. l included all cases whereas Olaogun included LABC cases only and less than 10% received radiotherapy], one [Adeniji e t al [13], 33% (95% CI 24-42)] recorded in recurrence in 5 years and one, [Olasehinde [19], 19% (95% CI 15-24)] recorded in 9 years. Olasehinde et al [19] reported the recurrence pattern as 70% locoregional, 11% contralateral breast, and 19% distant. The summary estimate of the loss to follow- up was 45% in 3-5 years.

The survival gains in early [AJCC stages I & II] versus advanced disease increased with time elapsed. At two and 3-5 years, there was a 30% (95% CI 5-54) and 32% (95% CI 23-40) survival difference, respectively, in favor of early disease. A single study of 196 subjects, Adejumo et al [25]., recorded data with estimated six-month and 1-year survival differences of 23% (95% CI 16-30) and 53% (95% CI 41-65), respectively, in favor of early disease.

The summary for survival estimates appeared higher among patients receiving multimodal therapy. In Ali-Gombe et al. [22]., completing the multimodal treatment of surgery-chemotherapy-radiotherapy achieved 2-year disease-free survival of 67% (95% CI 61-71). The three-year survival estimate was 68% among the surgery-chemotherapy subgroup whereas the overall 3-year survival was 43%. In Makanjuola et al. [12]., the five-year survival difference between those receiving surgery-chemotherapy-radiotherapy compared to surgery-chemotherapy alone was 30% (95% CI 18-41).

This first meta-analytical review on the treatment and outcomes of BC in Nigeria found a low prevalence of multimodality treatment with the combination of surgery, chemotherapy, and radiation therapy. Most patients received single modality treatment or a combination of surgery and chemotherapy. Most mortality occurred between the first and second year of therapy, and receiving the multimodal combination of chemotherapy, surgery, and radiotherapy or presenting at an earlier stage was associated with longer survival.

Research on BC in Nigeria focuses largely on breast health awareness, early detection, and diagnosis; hence, it is not surprising to find only 15 eligible articles, with fewer than 4000 total subjects, reporting on BC treatment and outcomes. Evidence-based BC treatment is necessary to reduce morbidity, improve quality of life and prolong survival, particularly in a setting such as Nigeria, where most patients present with late-stage disease.

BC treatment varies across centers throughout Nigeria. The disparity is worst in radiation therapy, with patients treated in centers with radiation services having a 64% probability of receiving radiotherapy compared to just 12% in centers without radiation services. Most countries in Africa lack access to radiotherapy or have a deficit of radiation services [26], and the number of cancer patients is predicted to increase from 844 279 in 2012 to over 1.5 million in 2030 [27]. Samie [26] documented Africa was short of radiotherapy megavoltage by over 5000 units in a 2013 report, noting that Europe had 17 times as many radiotherapy units as were available in Africa per million inhabitants. According to the International Atomic Energy Agency (IAEA), 60% of African cancer patients need radiotherapy at least once in their treatment [26]. Ordinarily, each radiotherapy machine has the capacity to treat approximately 500 persons per year, yet there were over 124,000 new cancers diagnosed in Nigeria in 2020 [4], and only ten radiotherapy centers [28]. The gap for megavoltage units in Africa is estimated as 1018 megavoltage units deficit from the number needed to serve more than 1.1 million patients with cancer in 2020 [27]. In Nigeria, our findings that 21% of breast cancer is diagnosed at an early stage, and 26% of those receiving neoadjuvant chemotherapy had a complete response., show that availability of radiation services could allow for more breast-conserving therapy (BCT), hence improving patient adherence to surgical treatment recommendations. BCT could be offered by synchronizing treatment with centers that have radiation facilities. Patients planned for BCT might have separate bookings to ensure scheduled treatment.

Included studies reported using recommended chemotherapeutic agents. However, utilizing appropriate drugs is not the only prerequisite for improving cancer treatment outcomes. Optimal dosing and scheduling as well as compliance with treatment recommendations are necessary to achieve the maximum benefit from chemotherapy. One study [18] reported haphazard scheduling and a high non-completion rate of close to 50%. With the 26% complete clinical response in patients receiving neoadjuvant chemotherapy found in this review, ensuring appropriate planning of treatment regimens, having medication available to mitigate side effects, and encouraging patient compliance can help improve treatment completion and outcome.

Considering dose-dense or metronomic therapy where available and ensuring regular scheduling might prolong survival or time to recurrence and progression- free survival [29-31] in advanced BC. Also, studies show potential clinical benefits of metronomic therapy in the primary palliative setting and salvage therapy [32-34]. While the dose-dense treatment is resource-intensive and demands more supportive care, metronomic chemotherapy is more tolerable [30].

We found high mortality rates during BC treatment and shortly thereafter. This is likely due to under-staging, as the most common staging work-up in the studies reviewed was a chest x-ray and abdominal ultrasound. Chest x-ray and abdominal ultrasound is the recommended metastatic work-up in resource-limited settings where advanced imaging is largely unavailable [35]. However, plain chest radiograph has low sensitivity for pulmonary metastasis, missing lesions smaller than 1.6cm, and abdominal ultrasound is less than 70% sensitive for hepatic metastasis [36]. Accurate staging of disease at presentation is crucial for effective BC management, sparing patients unnecessary side effects from treatment unlikely to change outcomes, and appropriate resource allocation. Notwithstanding, recommending high-resolution imaging routinely to stage BC is not practical in resource-poor settings. Innovative, resource-appropriate solutions are desperately needed.

The complementary role of biochemical prognostic markers for the initial diagnostic workup is relatively inexpensive and virtually unexplored in resource-limited settings. Tumor markers could potentially be used as a pre-staging tool to select patients to undergo more costly investigations. A study evaluating serum markers in BC showed that CEA and CA 15-3 rose by 41.3% and 80.3%, respectively, in metastatic disease. CEA and CA15-3 rose in 30 and 70% of patients with recurrence [37]. Other studies similarly found increased levels of CA15-3 as tumor burden increased [37, 38], with CA15-3 elevation above 30 units/ml in 12% of stage I, 22% of stage II, 36% of stage III, and 80% of stage IV disease [37]. At the time of this review, in early 2022, CA15-3 and CEA cost 10USD- 25USD in Nigeria, compared to$100-$120 USD for a CT scan.

The survival gaps between early- and late-stage diseases are widely known. For example, a Ghanaian study recorded over 90% 5-year survival for stage 0 and I BC, compared to approximately 15% 5-year survival in stage IV disease [39]. However, the time-related widening of survival gaps between early- and late-stage disease are not as commonly reported and might be another representation of under-staging. The elevated short-term mortality rate seen in stage I and II disease likely existed until most erroneously under-staged patients died.

There are several limitations associated with this review. Several of the studies included used purposive sampling, which has the potential to skew the analysis. To minimize bias, these studies were excluded in sensitivity analysis as appropriate. Importantly, while the disease stage and treatment modalities received both influenced disease survival, the available data made it impossible to describe the interaction between these two variables. Reasons for not receiving treatment or for not completing it are beyond the scope of this study. Additionally, there was significant heterogeneity in the results because of the reporting pattern in the available report. Deliberately designing studies with uniform or standard reporting patterns in Nigeria will improve data quality and reduce heterogeneity in subsequent reviews.

In conclusion, the utilization of multimodality treatment with the combination of chemotherapy, surgery, and radiation therapy is low in Nigeria. Receipt of complete chemotherapy and access to radiation are inadequate. Survival is poor, with the highest mortality occurring in the first year with short-term mortality in early-stage BC is paradoxically elevated, likely due to under-staging. Receiving the multimodal combination of chemotherapy, surgery, and radiotherapy or presenting at an earlier stage is associated with longer survival. Improving BC staging and access to complete chemotherapy, surgery, and radiation should be targets of future interventions.

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