Urologic Cancer Drug Costs in Low- and Middle-Income Countries

Abstract

All 189 World Bank member countries are classified by their capita gross national income into one of four income groups. In this review, we aim to explore the economic burden and management of urologic oncology conditions in low- and middle-income countries (LMICs), emphasizing disparities and challenges in treatment access. The current World Bank classification system highlights economic stratification, showing significant health outcome disparities, particularly in urologic oncology conditions including kidney, bladder, and prostate cancer. First, this review focuses on the management of advanced prostate cancer in Asian LMICs, revealing higher mortality-to-incidence ratios and a greater prevalence of metastatic disease compared to high-income countries (HICs). The prohibitive costs of novel hormonal therapies (NHTs) like abiraterone and enzalutamide limit their use and exacerbate outcome disparities. Second, we review Wilms tumor treatment with chemotherapy in African countries, noting significant price variations for adapted and non-adapted regimens across different economic settings. The cost of chemotherapy agents, particularly dactinomycin, acts as a primary driver of treatment expenses, underscoring the economic challenges in providing high-quality care. Lastly, bladder cancer treatment costs in Brazil and Middle Eastern countries are examined, highlighting how detrimental the economic burden of intravesical therapies, like mitomycin C and Bacillus Calmette–Guérin (BCG), is on treatment accessibility. Overall, this literature review emphasizes the financial strain on healthcare systems and patients, particularly in regions facing economic instability and drug shortages, and underscores the need for international cooperation and effective resource allocation to address the economic barriers to urologic care in LMICs, aiming to improve health outcomes and ensure equitable access to advanced treatments.

1. Introduction

The World Bank classifies all of its 189 member countries by their capita gross national income level into one of four income groups: low- (LICs), lower-middle- (LMICs), upper-middle- (UMICs), and high-income countries (HICs) [1]. Nearly all of the 27 LICs, with the exception of Afghanistan, North Korea, and the Syrian Arab Republic, are found in Southern Africa [2]. Lower-middle-income countries are more spread out globally, encompassing South America, East Asia, the Middle East, and Southern Africa [2]. By stratifying these groups, we can study the relationship between economics and health outcomes and identify countries where patients may be at higher risk for poor health outcomes [2]. Medical expenses are the second most common expenditure after food in LICs and MICs and financial constraints may lead to treatment refusal, which contributes to poor outcomes [3].

With regard to urologic conditions, the most common worldwide conditions include benign prostatic hyperplasia (BPH), urolithiasis, bladder and prostate cancer, and urethral stricture disease [2,4]. Additionally, patients in LIC and MICs are more likely to suffer from a vesicovaginal fistula than patients in HICs [4]. Several investigators have noted surgical disparities in LICs, such as delays in establishing a pre-operative diagnosis, a lack of intraoperative radiology, and a lack of disposables and implants [4].

The World Health Organization publishes a list of essential medications that are “those that satisfy the priority healthcare needs of a population” [5]. The urologic medications on this list include several chemotherapeutic agents, such as bleomycin, carboplatin, cisplatin, cyclophosphamide, dactinomycin, docetaxel, doxorubicin, etoposide, ifostamide, irinotecan, vinblastin, and vincristine. The antihormonal agents used in urologic oncology on this list include abiraterone, bicalutamide (or flutamide and nilutamide as alternatives), leuprorelin (or goserelin and triptorelin as alternatives), and prednisolone (or prednisone as an alternative). Notably, BCG is not on this list of medications. However, very little research has been conducted to address medical management and the cost of the management of urologic conditions in lower- and middle-income countries. This review aims to summarize and analyze the current research in this arena, particularly in oncology.

2. Methods

To systematically assess the costs associated with the management of urologic malignancies in low- and middle-income countries (LMICs), we conducted a literature search using PubMed. The search strategy was designed to identify relevant studies published in English that focused on drug costs related to the treatment of urologic cancers. “Prostate”, “bladder”, “kidney”, “testicular”, and “cancer” were employed along with MeSH terms related to the economic burden and treatment disparities in these regions. The retrieved articles were then screened by title and abstract for relevance, followed by a full-text review to ensure that they met the inclusion criteria. Of note, we chose to focus on urologic malignancies that require medications for their management, such as metastatic prostate cancer and chemotherapy used for Wilms tumor, as well as intravesical therapies for NMIBC. The final selection of studies was used to synthesize data on the economic impact of drug costs in the management of urologic malignancies across different income settings, highlighting financial barriers to accessing advanced therapies in LMICs.

3. Management of Advanced Prostate Cancer in Asia

The treatment of advanced prostate cancer has changed rapidly over the last decade and now includes oral medications such as relugolix and novel hormonal therapies (NHTs), including abiraterone and enzalutamide. However, the use of these medications internationally has been minimally studied in the literature, particularly in LICs and MICs. One study published by Lim et al. in 2021 compared prostate cancer epidemiology and androgen deprivation therapy and NHT between Japan, an HIC, and Malaysia, an MIC [6]. Prior to comparing the drug costs, it is important to highlight the differences in prostate cancer incidence and mortality between these two countries. In particular, the authors examined the cancer mortality-to-incidence ratio, which is a marker of the long-term success of cancer surveillance and the efficacy of screening. In MICs such as China, Malaysia, Thailand, Indonesia, the Philippines, and Vietnam, the mortality-to-incidence ratio of prostate cancer ranges from 0.39 to 0.46, which is much higher than in Asian HICs such as Singapore, South Korea, and Japan, where the ratio ranges between 0.087 and 0.21 [6]. Japan reported a mortality-to-incidence ratio of 0.087, whereas, in Malaysia, this ratio was 0.41, nearly five times greater [6].

Additionally, patients in MICs are more likely to be diagnosed with metastatic disease than those in HICs. MICs, such as Indonesia and Malaysia, report that metastatic disease represents 46.6 and 53.9% of all new prostate cancer diagnoses, respectively [6]. However, in Japan, metastatic disease comprises 10.2% of new diagnoses, and this number is even lower in South Korea, where this percentage is only 4.5% [6]. Patients in Asian MICs are more likely to be diagnosed with metastatic disease at presentation and have significantly higher mortality-to-incidence ratios when compared with patients in HICs.

With rapid advancements in prostate cancer treatment, it is crucial to consider the costs of these new treatments and how they may impact their use. In Malaysia and Japan, these medications can be incredibly expensive, and, in the cohort studied here, they are not used very frequently due their cost and the lack of national health insurance coverage [6]. In both Malaysia and Japan, at the time of this publication in 2021, less than 1% of patients with metastatic castrate-sensitive prostate cancer were treated with the combination of generic abiraterone and prednisone [6]. In Japan, abiraterone/prednisone, enzalutamide, and apalutamide were approved around the time of this publication; thus, their usage has not yet been studied. Notably, docetaxel for widely metastatic disease remained uncovered by insurance in Japan at the time of this publication [6]. In Malaysia, the cost of abiraterone monthly is roughly 2800 US dollars (USD), twice the country’s median monthly household income [6]. Additionally, data from the ASEAN Costs in Oncology (ACTION) study showed that 48% of cancer patients in Malaysia were at risk of financial catastrophe and 45% faced economic hardship within one year of their diagnosis due to medical costs, including inpatient and outpatient care and purchasing supplies, drugs, and equipment [6]. Not only do patients in MICs in Asia face a greater burden of metastatic disease, but they are unlikely to be able to access all treatment options; however, treatment with NHT remains limited in HICs as well.

4. Management of Wilms Tumor with Chemotherapy in African Countries

The mainstay of treatment for Wilms tumor is a combination of surgery and neoadjuvant or adjuvant chemotherapy depending on the local practice patterns. In one study published by Habashy et al. in 2023, the authors described the variation in the global prices of chemotherapy agents for childhood cancers in low- and lower-middle-income countries (LLMICs), UMICs, and HICs [3]. The study focused on chemotherapy agents included in the World Health Organization’s (WHO) Essential Medicines List for Children, specifically those that were used in first-line regimens for specific cancers prioritized by the WHO’s Global Initiative for Childhood Cancer. The study covered data on chemotherapy prices and purchase volumes from 2012 to 2019 and aggregated them according to the WHO region and World Bank income classification. For Wilms tumor, the authors investigated the variation in prices for both regimens adapted to low-resource settings and non-adapted regimens. The estimated median prices for both adapted regimens and non-adapted regimens in LLMICs, UMICs, and HICs are recorded in

Table 1. Chemotherapy dosing in treatment regimens for Wilms tumor.

Regimen	Chemotherapy Doses	Price in LLMICs	Price in UMICs	Price in HICs	Source
Adapted Regimens
SIOP Localized 1 (4 Weeks Pre-Op, 4 Weeks Post-Op)	Dactinomycin 135 μg/kg Vincristine 12 mg/m2	USD 116	USD 146	USD 942	[3,7]
SIOP AFR Coop Met 6 Pre/AV14 Post	Dactinomycin 360 μg/kg Doxorubicin 190 mg/m2 Vincristine 21 mg/m2	USD 343	USD 408	USD 2523	[3,8]
SIOP AFR Coop Met 9 Pre/AV26 Post	Dactinomycin 630 μg/kg Doxorubicin 330 mg/m2 Vincristine 33.5 mg/m2	USD 594	USD 708	USD 4397	[3,9]
Non-Adapted Regimens
EE 4A	Dactinomycin 315 μg/kg Vincristine 21 mg/m2	USD 260	USD 327	USD 2159	[3,9]
DD 4A	Dactinomycin 225 μg/kg Doxorubicin 150 mg/m2 Vincristine 25 mg/m2	USD 242	USD 284	USD 1653	[3,10]
DD 4A Regimen M	Cyclophosphamide 6600 mg/m2 Dactinomycin 145 μg/kg Doxorubicin 195 mg/m2 Etoposide 1500 mg/m2 Vincristine 25 mg/m2	USD 277	USD 281	USD 1937	[3,11]
Regimen UH-1	Carboplatin 2800 mg/m2 Cyclophosphamide 14,800 mg/m2 Doxorubicin 225 mg/m2 Etoposide 2000 mg/m2 Vincristine 22.5 mg/m2	USD 397	USD 356	USD 2197	[3,12]

. The estimated median prices for adapted regimens include SIOP Localized 1 (USD 116; USD 146; USD 942), SIOP AFR Coop Met 6 Pre/AV14 Post (USD 343, USD 408, USD 2523), and SIOP AFR Coop Met 9 Pre/AV26 Post (USD 594, USD 708, USD 4397) [3,7,8]. The estimated median prices for non-adapted regimens in LLMICs, UMICs, and HICs were as follows: EE 4A (USD 260, USD 327, USD 2159), DD 4A (USD 242, USD 284, USD 1653), DD 4A regimen M (USD 277, USD 281, USD 1937), and Regimen UH-1 (USD 397, USD 356, USD 2197) [3,9,10,11,12]. Generally, the median prices for these regimens in HICs were significantly higher than those in UMICs and LLMICs [3]. The cost for non-adapted regimens in HICs could be up to 6.2 times higher than in UMICs and 6.5 times higher than in LLMICs [3]. Further, the authors reported that dactinomycin was the primary driver of the price for adapted regimens, being 1.4 to 1.6 times higher in price compared to the non-adapted regimens [3].

Additionally, in one systematic review by Fung et al. 2019, looking at the cost of childhood cancer treatment in LMICs, the authors found four peer-reviewed articles describing the cost of Wilms tumor treatment [13]. First, Paintsil et al. 2015 conducted a cost analysis for the treatment of Wilms tumor in Ethiopia, Cameroon, Malawi, and Ghana and found that the cost per treated patient ranged widely from USD 122 in Malawi to USD 1110 in Ghana [14]. Second, Israels et al. 2018 conducted a cost analysis for Wilms tumor in Malawi, Cameroon, and Ghana, which found that the cost per treated patient ranged from USD 105 to USD 1151 [15]. Third, Neal et al. 2018 conducted a cost analysis from the perspective of a hospital in Rwanda, which found that the cost per treated patient per year ranged from USD 1362 to USD 1913, with about USD 350 coming from the chemotherapy regimen alone [16]. Lastly, Kanyamuhunga et al. 2015 conducted a cost analysis for Wilms tumor from the perspective of both the patient and the hospital in Rwanda and found that the cost per treated patient ranged from USD 1831 for early-stage disease and USD 2419 for advanced disease, with the difference in price mainly attributable to the more intensive chemotherapy required [17]. For context, the median household income of Rwanda as of 2022 was approximately USD 930 USD, demonstrating how the current chemotherapy costs are likely contributing to access disparities. The gross national income data for several African countries can be seen in

Table 2. Gross national income (GNI) per capita in Africa in 2022 by country (USD) [13].

Country	Gross National Income (GNI) per Capita (2022)
Ethiopia	USD 1020
Cameroon	USD 1660
Malawi	USD 640
Ghana	USD 2350
Rwanda	USD 930

[18].

Certainly, the considerable disparities in the cost of Wilms tumor management varies across different economic and geographic settings. The variation in chemotherapy pricing, particularly when looking at the influence of dactinomycin on regimen costs, highlights the complex nature of providing high-quality Wilms tumor care globally.

5. Bladder Cancer Treatment in Brazil and Middle Eastern Countries

Bladder cancer is one of the most prevalent and most expensive urologic cancers in the world; thus, a proper understanding of the economic burden is crucial in allocating a limited number of healthcare resources efficiently.

In one study by Raadabadi et al. looking at the direct and indirect costs of medical care for bladder cancer in Iran, the authors estimated the total annual economic burden of intravesical mitomycin C for low-grade Ta and recurrent NMIBC to be USD 274,254 and that of intravesical Bacillus Calmette–Guérin (BCG) therapy for high-grade Ta, T1, CIS, and recurrent NMIBC to be USD 4,409,786 [19]. They reported that the average cost of the intravesical instillation of mitomycin C (40 mg) in Iran in 2018 was USD 45.40 [19]. With a 2022 GDP per capita in Iran of USD 4669.60, the cost of intravesical mitomycin C can be quite financially burdensome for patients [20].

Further, one study by Raad et al. studied the cost of medications and procedures for the treatment of bladder cancer in Lebanon before and after the Lebanese economic crisis in 2019, which manifested as currency devaluation, skyrocketing inflation, and growing numbers of Lebanese individuals experiencing poverty [21]. They found the following pre- and post-economic collapse costs calculated at an exchange rate of USD 1 = LBP 1500 and USD 1 = LBP 23,000, respectively: MMC instillation (USD 370; 268), BCG instillation (USD 262; 156), ddMVAC four cycles (USD 5061; 3380), gemcitabine–cisplatin four cycles (USD 4189; 2590), gemcitabine–carboplatin four cycles (USD 3757; 2177), immunotherapy first line (USD 20,365; 4565), and immunotherapy second line (USD 67,256; 58,497) [21]. With a 2022 GDP per capita in Lebanon of USD 4136.10, the cost of intravesical instillation or cycles of chemotherapy would likely easily match or exceed the median household income of Lebanese citizens [22].

Additionally, one study by Wroclawski et al. analyzed the costs of alternative therapies to BCG for the treatment of NMIBC in light of the BCG shortage in Brazil and other LMICs. When examining the cost of importing several strains of BCG to compensate for the shortage, the authors found that each vial in Brazil cost approximately USD 70, whereas the RIVM strain (BCG-Medac, Wedel, Germany) and the Tice strain (Onco-Tice, Merck, Rahway, NJ, USA) were much more expensive at approximately USD 780 per vial after accounting for shipping costs and import taxes [23]. The authors did not comment on the specific price details for mitomycin C or gemcitabine but suggested that the cost and logistics of importing mitomycin C, in a similar manner to importing BCG, would be high.

These studies looking at cost variations in medications for bladder cancer highlight the substantial financial implications of bladder cancer treatment across different regions. The variations in costs for standard treatments and the economic impact of BCG shortages underscore several challenges faced by global healthcare systems in managing this high-burden disease effectively. Therefore, effective resource allocation and international cooperation directed towards ensuring the affordability and availability of these treatments are crucial.

6. Limitations

While this review provides valuable insights into the economic burden of urologic malignancies in low- and middle-income countries, several limitations must be acknowledged. First, the study relies heavily on the available published literature, which additionally was subject to selection bias due to using English language-containing articles and the use of PubMed as the sole platform for the systematic literature review. The use of peer-reviewed data meant that we could not identify the practical, real-world, real-time pricing that many global communities face for their oncologic medications. Furthermore, there is a significant shortage of data in this arena, and, given that there is significant variability in the healthcare systems, drug pricing, and economic conditions across different LMICs, the findings may not be generalizable. There is significant potential for currency fluctuations and inflation to affect drug pricing, which could lead to discrepancies in cost estimates over time. Further, there is absence of patient-level data in many studies, limiting the ability to assess the real-world impact of drug costs on treatment accessibility and outcomes, emphasizing the need for further research with more robust data collection methodologies. Additional limitations of the articles identified include the narrow focus of the drug costs related to specific countries or geographic regions, rather than a fully global perspective on the drug costs associated with urologic malignancies.

7. Conclusions

Differences between healthcare in HICs and LMICs may lead to disparities in health outcomes, and stratifying countries by their income groups allows us to compare differences in their healthcare models. In countries around the globe, treatment differences are notable between HICs and LMICs in urologic oncology in prostate, bladder, and pediatric urologic cancers, as demonstrated throughout this review. In Asian LMICs, patients face a higher disease burden, including a higher mortality-to-incidence ratio and greater prevalence of metastatic disease than those in Asian HICs. With NHT being an incredibly expensive treatment option, it is crucial to consider the fact that these medications may be cost-prohibitive, even in HICs. When investigating pediatric Wilms tumor, there are significant price variations among the various adapted and non-adapted regimens in African countries. Interestingly, the prices for chemotherapy regimens were higher in HICs and increased costs were driven primarily by the high cost of dactinomycin. Finally, we investigated the bladder cancer treatment costs for intravesical therapies such as BCG and mitomycin C in Brazil and Middle Eastern countries. Studies show that intravesical therapies are costly in these countries, particularly when compared to the median household incomes in these countries. Unfortunately, there is no international standard or guidelines for the treatment of these diseases. The creation of resource-limited guidelines by an over-arching body such as the World Health Organization would be beneficial to help standardize treatment regimens across countries. Additionally, cost-saving measures such as dose adjustments can be considered. For example, the NCCN guidelines for prostate cancer include the possibility of abiraterone 250 mg/day with a low-fat meal as an alternative to 1000 mg/day after an overnight fast as a possible cost-saving measure [24]. However, there is no standard resource for cost-saving measures in urologic oncology. More research should be conducted in this arena, which would benefit patients worldwide and especially those in LMICs. This article aims to expand the knowledge of the current research in drug costs in LMICs and demonstrate the need for further study in this arena.