Comparing presentations and outcomes of children with cancer: a study between a lower-middle-income country and a high-income country

Substantial progress has been achieved in managing childhood cancers, with overall cure rates reaching 90% in many high-income countries (HICs) [1]. In contrast, the 5-year overall survival (OS) rates in the lower-middle-income countries (LMICs) range from 5 to 60% [1, 2]. More than 80% of children with cancer reside in LMICs [3].

Several factors may contribute to the significant differences in survival rates between children with cancer in HICs and LMICs [4]. A previous descriptive study indicated that survival rates were directly associated with various socioeconomic and health-related factors, including per capita Gross Domestic Product (GDP), Gross National Income, and the ratio of physicians and nurses to the population. The availability of annual governmental funding for health care per capita emerged as a particularly crucial factor [2]. Although all the facts mentioned above, only 1% of child deaths in LMICs are due to cancer, compared to 5% in HICs.

It seems logical for LMICs governments to prioritize their resources towards managing their more prevalent health issues. For instance, children's deaths in LMICs are predominantly caused by diseases such as parasitic and other types of infections and maternal and child health issues related to complications during pregnancy and delivery. Therefore, most of the resources in these countries are directed to solving these problems compared to less frequent diseases such as cancer [5].

A problem that affects childhood cancer epidemiological studies in LMICs is underdiagnosis and under-reporting [6]. Previous studies have shown a higher incidence of childhood cancers in capital cities of LMICs compared to smaller cities, such as Jordan and Honduras. This suggests that children with malignant tumors living in rural areas or distant small cities may have less access to accurate diagnosis and treatment [7, 8]. There is a scarcity of specialized tertiary healthcare centers, particularly in rural areas, resulting in parents traveling long distances with their sick children [9], incurring transportation costs. This prolonged absence from home affects the rest of the family, including loss of income when parents cannot work [10]. The number of pediatric oncologists is limited [6], with a patient-to-specialist ratio ranging from 1:50 to 1:750 in many LMICs, which is inadequate for properly managing such a complex disease [2]. Both quantitative and qualitative shortages of nurses exist, with reports from Uganda indicating a nurse-to-patient ratio of 1:15 during the day and 1:45 at night [6]. A deficiency of well-trained pathologists [6, 10] often results in significant diagnosis delays. In Tanzania, for instance, final pathology reports could take up to one month [2]. LMICs also face a scarcity of both laboratory and radiological diagnostic equipment. Modern diagnostic methods are typically only available in major cities in many LMICs, such as Egypt, Honduras, Morocco, and the Philippines, depriving many patients in rural areas of easy access [2].

In many low-income countries, health insurance does not cover cancer therapy. There is also a shortage of effective drugs, including chemotherapy, antimicrobials, and supportive care drugs. A large study involving 10 LMICs (Bangladesh, Egypt, Honduras, Morocco, the Philippines, Senegal, Tanzania, Ukraine, Venezuela, and Vietnam) found that only three of them (Egypt, Ukraine, and Venezuela) provided childhood cancer patients with access to chemotherapy, antimicrobials, blood products, and radiotherapy [2]. Shortages in other therapy disciplines, such as surgical and radiation oncology, are also observed [6, 11, 12]. The insufficient availability of blood products and lack of screening for infectious diseases further contribute to the challenges [11].

Illiteracy, lack of health-related knowledge, and delays in seeking medical advice are common among parents in LMICs [13]. Treatment abandonment is highly prevalent in these countries, ranging from 25 to 50%, and poses a significant barrier to successful therapy [4, 14, 15].

Research in the pediatric oncology field in different areas of the world can identify the problems in the respective settings, which may lead to finding solutions to overcome the difficulties, thus increasing survival. Adapted protocols to decrease toxicity may be important in resource-limited settings [16].

Approximately 1.800 children are diagnosed with cancer each year in Germany. It has been estimated that the likelihood of a newborn child developing a malignant disease within the first 15 years of life is 0.2% [17]. Unfortunately, there is a lack of epidemiological data on childhood cancer that covers the entirety of Egypt.

Currently, only two cancer Institutes in Egypt are affiliated with universities. The first is the National Cancer Institute, affiliated with Cairo University in Cairo. And the second is the South Egypt Cancer Institute (SECI), affiliated with Assiut University in the southern region of Egypt. As a result, SECI serves as the primary referral center for the entire south part of Egypt. In contrast, as of August 2012, Germany had established 56 pediatric oncology departments [18].

Many previous studies have focused on the characteristics and survival outcomes of children with cancer in HICs, while others have highlighted the challenges faced in managing childhood cancer in LMICs. However, to our knowledge, no study has directly compared these two settings. Therefore, the objective of this study was to conduct a direct comparison between a center in an LMIC (SECI, Assiut University, Egypt) and another in a HIC (Cologne University Hospital, Uniklinik Köln (UKK), Germany) by examining the characteristics and outcomes of children with cancer. This study was carried out by the same researcher who worked in both centers. We aimed to identify the primary factors contributing to the disparity in survival rates for childhood cancers between these two centers. By identifying these differences, we hope to identify transferable structures and conditions that can be implemented in LMICs settings, ultimately improving both the quantity and quality of survival outcomes for children with cancer.

The available data from electronic or paper-based reports of all included patients were retrospectively reviewed to gather information on various aspects. This included the duration between the patient's initial symptoms and their first presentation at the cancer center (in weeks), the date of the first presentation at the pediatric oncology department, age, gender, diagnosis, and disease stage at presentation. Additionally, data on travel time from home to the cancer center (in hours, estimated using Google Maps), the duration from first presentation to the start of therapy, treatment-related severe adverse events (graded as 3 or 4 according to the common terminology criteria for adverse events, CTCAE version 4.03) [19], compliance with therapy, site, and date of disease progression or relapse if occurred, date of the last visit, prior clinical status, and causes and date of death if applicable. In cases with combined causes of death (therapy-related and tumor progression), the predominant cause of death was determined by two expert physicians or attributed to the unknown category.

Compliance in this study referred to the acceptance of the proposed therapy and adherence to the prescribed protocols. Treatment refusal was defined as the act of rejecting any treatment for a potentially curable malignant disease after a final diagnosis had been made. Non-compliance with therapeutic rules encompassed situations such as unexplainable delays in scheduled treatment appointments for one or more consecutive weeks during ongoing therapy, refusal of further therapy or recommended investigations, or abandonment of treatment. Abandonment of therapy was determined when patients missed four or more consecutive weeks of treatment without returning to continue their therapy.

A Comparison of the basic structure of the pediatric oncology department in SECI and UKK is presented in Supplemental Table S1. For detailed information regarding the included and excluded patients in both institutions, please refer to Supplemental Figs. 1 and 2.

In this retrospective study, the management of childhood cancers was compared between two centers: one located in an LMIC (Egypt) and the other in a HIC (Germany). The SECI included a significantly larger number of patients than the UKK group. The common diagnoses in SECI were leukemia, lymphomas, and solid tumors, however brain tumors were rarely observed. On the other hand, brain tumors were common in UKK.

Compared to the patients in UKK, those in the SECI group were younger, had longer travel times to reach the treatment center, received therapy earlier because of substantial outside initial diagnosis, exhibited less treatment compliance, and experienced earlier relapses. The SECI group had a higher frequency of deaths, primarily attributed to delayed presentation and complications, predominantly caused by infections. In contrast, the deaths in the UKK group were mainly related to the disease itself.

It is well acknowledged that this study is not a formal epidemiological study that encompasses the entire population of children in a specific area. Nonetheless, the study was over five years, providing a real-world perspective without any exceptions. The research reflects the daily work carried out by the same researcher in both a HIC and an LMIC. It compared the real everyday problems obstructing proper management of childhood cancers in a center in an LMIC through a comparison with another center in a HIC.

The significant disparity in survival rates between UKK and SECI appeared to be linked to several unique problems encountered in tumor management in SECI. These challenges include a limited number of specialized treatment centers in Egypt, which results in overcrowded patient rooms where multiple patients often stay together, a higher patient-to-healthcare team ratio, and long distances between patients' homes and the cancer center. Furthermore, there are deficiencies in certain diagnostic facilities and intermittent shortages of blood products and drugs. These factors contribute to misdiagnoses, late presentation of patients at advanced stages, and non-compliance with therapy.

This study has limitations due to the small sample sizes and the random selection of centers for analyses. However, the comparison made in this study offers valuable insights and identifies areas where immediate actions can be taken. Conducting larger-scale research nationally or including more hospitals would be beneficial, particularly when a comprehensive cancer registry representing a whole country in an LMIC is available.

The findings of this study shed light on the challenges faced by SECI, which are likely applicable to many similar centers in LMICs. One major issue is the deficiency of well-established pediatric oncology centers that cover all regions of Egypt, as better healthcare facilities are predominantly available in the capital and major cities [20]. As a result, SECI receives a higher number of patients compared to UKK. It should be noted that many children come to SECI for RTH or surgery without being referred to the Pediatric Oncology Department, highlighting the shortage of these specialties in most parts of southern Egypt. The main points related to this problem are as follows:

Compounding this problem, a number of non-malignant cases were misdiagnosed as malignant tumors by inexperienced healthcare providers in rural areas and were subsequently referred to SECI. These misdiagnosed patients accounted for 14% of all patients seen at the pediatric oncology department in SECI, further straining the financial resources of the center as they also required supportive care until an accurate diagnosis was established. This issue could be alleviated by improving transportation infrastructure, establishing a dedicated parents' house at SECI, and establishing well-equipped primary or secondary cancer care centers that operate under the supervision of the tertiary cancer care center and employ well-trained personnel.

Unfortunately, Egypt lacks a childhood cancer registry that could be used for comparison with SECI's rates of cancer types and survival rates. In most LMICs, registries are often inaccurate and limited to local hospitals [21, 22]. Accurate hospital-based registries are crucial in countries without a national cancer reistry to provide insights into patients' demographic and clinical characteristics, treatment outcomes, and challenges, ultimately leading to national solutions. It is essential to review these data periodically [23].

Among the patients in SECI, the most common tumors were leukemia, followed by NHL, Hodgkin lymphoma, neuroblastoma, and Wilms tumor. The high proportion of leukemia cases (approximately 50% of all SECI patients) is likely due to the relatively better supportive care available at SECI compared to the other centers in the south of Egypt, which used to refer leukemia patients to SECI. In contrast, brain tumors were infrequent as other cancer centers in south Egypt would directly refer brain tumor patients to Cairo, where superior neurosurgical care facilities were accessible. It is worth noting that UKK is renowned for its expertise in managing brain tumors, thus attracting patients from more distant areas than other patients in Cologne. Brain tumors were the most prevalent tumor type among this group.

In the SECI group, the time from diagnosis to the initiation of treatment was significantly shorter overall, especially in patients with bone tumors and Wilms tumors. This was because many of these patients had previously been admitted to the university hospital and were referred to SECI with all investigations completed and ready to start chemotherapy. However, in patients with ALL, the time until treatment initiation was significantly longer in SECI. This was because bone marrow aspirates and biopsies were only performed once or twice a week at SECI, and these procedures were carried out exclusively by clinical pathologists within the center. In contrast, at UKK, pediatric oncologists performed these procedures daily and personally reviewed the bone marrow slides.

Although both centers used the same therapy protocols, UKK had a slightly higher incidence of complications. The variation in complication rates may be misleading because UKK had a more comprehensive system for documenting complications, including printed documentation of severity grades and a well-defined follow-up program for cancer survivors. In contrast, due to financial constraints at SECI, investigations were primarily conducted based on clinical suspicion of organ function deterioration.

Analysis of therapy-related complications revealed several problems that SECI encountered:

A large-scale study involving 101 countries worldwide, using survey and population data, revealed that out of 155,088 children under 15, 23,854 (15%) were newly diagnosed with cancer but abandoned therapy. Alarmingly, 83% of these new childhood cancer cases and 99% of treatment abandonment were reported in LMICs [25]. Limited data are available from Arab countries, especially regarding therapy abandonment [20]. The findings regarding non-compliance with therapy in SECI in this study were consistent with results from other LMICs studies [26]. UKK demonstrated significantly higher compliance with treatment than the SECI group, with rates of 97.1% vs. 85.1%, respectively. No patient in UKK abandoned treatment or was discharged in demand. It is important to note that SECI provides free-of-cost cancer treatment, including hospital care, medical supplies, and investigations to most patients.

This study aimed to identify factors affecting survival in both groups to contribute to global improvements in survival rates. The relapse occurrence at the first presentation was excluded from further analysis, as its worse prognosis is well-known in each disease category. Analyzing the effect of non-compliance with therapy on survival was challenging due to the low numbers of non-compliant cases in UKK and the unknown fate of approximately 50% of non-compliant patients in SECI who either abandoned or refused therapy. A comparison of survival and related factors between both groups within the same diagnosis and stage would be more useful, but this was not one of the aims of this study.

The significant difference in OS and EFS between the two groups is unsurprising. The study highlighted the importance of better management of complications and early presentation of patients at the time of their initial diagnosis to the cancer center, which are crucial factors for improving the OS in SECI. Effective management of complications and increased awareness among the general population and healthcare providers, particularly in rural areas, regarding the signs and symptoms of childhood cancers, can help decrease the time lag until referral to the cancer center and improve survival rates in these children.

Analysis of the causes of death between the groups revealed another crucial finding: Deaths in UKK were primarily attributed to relapse and disease progression (79.1%). In comparison, deaths in SECI were predominantly related to therapy (66%). Therapy-related factors can be considered avoidable causes. These results align with studies conducted in Indonesia by Saskia Mostert [13], which demonstrated that infection and bleeding were the most common causes of treatment-related death. Adapting therapy protocols in LMICs based on the availability and efficacy of supportive care may lead to better chances of survival, as opposed to using the original aggressive protocols used in HICs.

Enhancing the model of care for LMICs requires several crucial elements, including raising public awareness through education, improving the training of healthcare professionals, strengthening cancer services, conducting research that is relevant to local needs, establishing regional hospital networks, fostering international collaboration, and ensuring access to health insurance [10].

In conclusion, there is a significant disparity in managing childhood cancers and subsequent survival rates between HICs and LMICs. The direct institutional comparison of pediatric cancer patients between a HIC and an LMIC can help identify factors associated with poorer outcomes in LMICs. Many specific problems related to tumor management in LMICs were highlighted, such as late presentation, non-compliance with therapy, deficiencies in specialized treatment centers, and shortages of well-trained specialists and nurses in pediatric oncology. Outcome differences were associated with different causes of death and other less prominent factors.

Our recommendations for improving cancer care in SECI, as well as other LMICs, are: Proper management of therapy-related complications, improvement of cancer awareness as a disease can affect children in general and its principal curability, efforts are needed to reduce the abandonment of therapy and establishment of country-based cancer registry.