Trends of Prostate Cancer Morbidity in Low-Incidence Countries from 1990–2019

This article is featured in Selected Articles from This Issue, p. 177

Prostate cancer stands as the second most prevalent malignancy among males and was the fifth leading cause of cancer-related deaths in 2020, with an estimated 1.4 million new cases and 375,000 fatalities globally (1). In countries characterized by high-incidence rates, for instance, in the United States, prostate cancer incidence rose sharply with the introduction of PSA screening in the early 1990s. This increase in diagnoses of advanced cases eventually led to a decline in incidence rates and a stabilization of prostate cancer morbidity (2). Despite the United States, Norway, and Sweden exhibit high-incidence rates, their mortality rates are comparable with those in low-incidence countries. This suggests significant progress in treatment and early detection in these countries (1).

Another study analyzing prostate cancer–related mortality across 36 representative countries globally revealed significant reductions in mortality rates in most regions, whereas Asian countries with low incidence saw an increase in mortality (3). Globally, countries with relative low prostate cancer incidence rates are primarily situated in Asia and North Africa, with many experiencing an upsurge in incidence rates, such as Vietnam, China, and Sudan (1, 4). The underlying trends and influencing factors in these low-incidence countries remain obscure. Zhu and colleagues (5) indicated that the adoption of a Western-style diet in East Asian nations contributed to a rapid increase in prostate cancer incidence. Meanwhile, enhanced healthcare systems and improved case reporting mechanisms in Africa potentially account for the rising incidence rates (6). These dynamics among low-incidence countries are multifaceted, involving treatment disparities, socioeconomic status, lifestyle factors, various patterns of prostate cancer screening, and genetic predisposition (7, 8). Therefore, comprehending the incidence patterns of prostate cancer in low-incidence countries is pivotal for effectively addressing shifts in prostate cancer cases within these regions.

The present study leveraged data from the Global Burden of Disease Study 2019 (GBD 2019) to comprehensively address the objectives, methods, and framework of investigation (9). Information pertinent to prostate cancer disease burden was sourced from the GBD 2019 dataset, encompassing cases and age-standardized incidence rates (ASIR) for prostate cancer across 195 countries and territories, spanning the years 1990 to 2019.

The socio-demographic index (SDI) serves as a composite measure reflecting the developmental status of nations. Derived from per capita income, years of schooling beyond age 15, and general fertility rate, SDI values were adopted in our study to stratify countries into five quintiles of development: low SDI (0–0.45), low-middle SDI (0.45–0.60), middle SDI (0.6–0.69), high-middle SDI (0.69–0.80), and high SDI (0.80–1).

Our investigation used ASIR and estimated annual percent change (EAPC) as metrics to delineate the overarching trends of prostate cancer incidence. ASIRs, expressed as cases per 100,000 person-years, were calculated using a previously established formula (9).

The EAPC metric was introduced to portray changes in ASIRs over specified intervals (9). This approach assumed the linearity of the natural logarithm of ASIRs over time and used a linear regression model: y = α + βx + ε, where y signifies in ASIR, x denotes the calendar year, and ε accounts for the error term. The calculation of EAPC involved deriving 100 × [exp(β) − 1] was deduced from the linear regression model.

Low-incidence countries were classified as those with incidence rates falling below 10% of the maximum value of ASIR among all countries after eliminating outlier. Specifically, we defined countries with incidence rates in 2019 under 20 cases per 100,000 person-years as having relatively low prostate cancer incidence.

The relationship between EAPC and SDI was assessed through correlation testing and a smoothed curve was fitted to the observed pattern. Threshold of a P value of <0.05 is of statistical significance. All data visualization and statistical analyses were conducted using R Studio (Version 4.1.3).

The data that support the findings of this study are available from the corresponding author upon reasonable request.

The incidence of prostate cancer displayed notable disparity across low-incidence countries, as illustrated in Supplementary Fig. S1A. The range spanned from 8.8 cases per 100,000 person-years in Bangladesh (Southern Asia) to 235 per 100,000 in Saint Kitts and Nevis (eastern Caribbean sea). Accordingly, we identified 35 low-incidence countries, such as China, Vietnam, India, Kyrgyzstan, Egypt, and Sudan (Table 1). Despite the relatively low incidence, these 35 countries contributed to one seventh of global new prostate cancer cases in 2019. Among them, China exhibited the highest case count and the most substantial increase over time, with new cases escalating from 26,440 in 1990 to 153,448 in 2019. Conversely, Samoa and Kiribati exhibited minimal growth. Notably, Malawi registered the highest ASIR at 20 cases per 100,000 person-years, whereas Bangladesh demonstrated the lowest ASIR at 8.87 cases per 100,000 person-years.

In terms of geographical distribution (Fig. 1), low-incidence countries predominantly clustered in East Asia (Mongolia, Democratic People's Republic of Korea), the Southeast Asian peninsula (Vietnam, Thailand), Central Asia (Kyrgyzstan, Tajikistan), South Asia (India, Sri Lanka), and North Africa (Sudan, Morocco). Conversely, sub-Saharan Africa encompassed Malawi and Mozambique. No low-incidence countries were identified in Europe or the Americas.

Table 1 presented the morbidity of prostate cancer for 1990 and 2019 within the 35 low-incidence countries. Comparatively, the incidence in 1990 was notably lower across these countries than in 2019. In 2019, Bangladesh, India, and Nepal displayed the lowest incidence rates, each below 10 cases per 100,000 person-years. Trends of ASIRs and EAPC from 1990 to 2019 were depicted in Figs. 2 and 3. Thirty two countries were observed signifying upward trends with positive EAPC, whereas Kiribati, Kyrgyzstan, and Samoa exhibited declining morbidity with EAPC values of −0.26%, −0.4%, and −0.14%, respectively. The global ASIR's average EAPC was 0.26% (depicted by a vertical dotted line in Fig. 3), with 32 countries surpassing this value. Rapid-growth countries, including Uzbekistan, Sri Lanka, China, Maldives, Timor-Leste, and Vietnam, exhibited a sharp increase in ASIR in 2019.

Supplementary Figs. S2–S7 demonstrated that, irrespective of the year (1990 or 2019), individuals ages over 90 years, particularly the 90–94 age group, exhibited the highest ASIR of prostate cancer across most low-incidence countries. Tajikistan and Kyrgyzstan experienced a shift from the 75–79 age group in 1990 to those ages over 90 in 2019.

Figure 4 highlights a substantial rise in morbidity within the 20 to 44 age group, signifying pronounced growth among the younger population in low-incidence countries between 1990 and 2019. Mongolia observed the most substantial change in the 35 to 39 age group, with a 238% increase over three decades. Notably, men ages 30 to 34 witnessed a 215% increase in prostate cancer incidence. Countries with rapid growth exceeding 150% in this age group included China, Vietnam, Maldives, Thailand, Sudan, Serbia, and Yemen. Conversely, Kyrgyzstan reported a declining trend in ASIR for this age group. For men ages 45 to 69, the majority of countries exhibited upward trends. Apart from the rapid-growth countries mentioned, Iran and Morocco also displayed a 150% increase in morbidity in the 50 to 59 age group. Conversely, Kiribati, Tajikistan, and Kyrgyzstan demonstrated a mild decrease in the 45 to 69 age group. For those ages over 70, considerable variation was observed between low-incidence countries. Although Bangladesh, Thailand, India, Egypt, and Algeria experienced a slight decrease in prostate cancer morbidity, Tajikistan and Uzbekistan noted an increase, particularly among those ages 85 and older.

Within low-incidence prostate cancer countries, we introduced SDI as a composite indicator to assess social, demographic, and economic status. In 2019, the majority of low-incidence countries fell within low, low-middle, and middle SDI categories, with SDI values below 0.7. Figure 5 illustrated a generally positive correlation between ASIR and national-level SDI, consistent with prior research. However, no significant correlation (ρ = 0.143, P = 0.413) existed between EAPC and SDI among low-incidence countries, as depicted in Fig. 6.

Across the world, 35 countries were screened as a low incidence of prostate cancer, with a substantial concentration in Asia and North Africa, whereas other nations were dispersed throughout sub-Saharan Africa and Oceania. Within this group of 35 countries, China stood out with the highest number of cases, whereas Malawi reported the highest ASIR of prostate cancer, approximately half of the global ASIR. It is worth highlighting that the emergence of new prostate cancer cases in 35 low-incidence countries contributed to roughly one seventh of the total global prostate cancer count in 2019. This fact greatly underscores the imperative to acknowledge that the burden of prostate cancer is anything but negligible.

Regarding the age-related distribution of morbidity within low-incidence countries, the ASIR of prostate cancer experiences a gradual increase as individuals grow older, as reported by Malik and colleagues (10). Interestingly, the highest ASIR among low-incidence nations is observed in men ages over 90, in contrast with high-risk countries like the United States where it is the population ages 80 to 85, as depicted in Supplementary Fig. S8. This discrepancy could be attributed to the likelihood that low-incidence countries are characterized by shorter life expectancies. For instance, consider countries in Central Asia and Sub-Saharan Africa; Uzbekistan, Kazakhstan, Malawi, and Mozambique have life expectancies of 65.9, 67.4, 61.4, and 54.8 years, respectively, in contrast with the global average of 71 years in 2019 (11). Given that age is a major non-modifiable risk factor for prostate cancer, and the elderly population is not heavily represented in low-incidence countries, it follows that the ASIR tends to be lower.

An additional factor contributing to the delayed diagnosis of prostate cancer might stem from the relatively constrained medical resources (12) and a lack of disease awareness compared with countries where diagnoses are made at earlier ages. For example, in a 2012 report, Msyamboza and colleagues (13) emphasized that only a solitary private hospital in Malawi provided access to PSA blood testing and digital rectal diagnosis. In Mali, a substantial 55% of prostate cancer cases had undefined staging, in stark contrast with a mere 4% in the United States (14). Similarly, the scarcity of prostate cancer cases in Iraq was demonstrated linked to limited public awareness and ineffective implementation of PSA screening (15).

In the context of most Asian countries, where morbidity has historically been perceived as relatively low, large-scale PSA screening tests are not common. Kazakhstan (16) and Viet Nam (17) are examples of countries that previously experimented with mass PSA screening, observing a gradual rise in the proportion of stage I/II diagnoses, which increased from 37% to 75% by 2016 in Kazakhstan (18). However, these initiatives were eventually discontinued due to concerns about their cost-efficiency, particularly for developing nations. Currently, Japan stands alone in having established guidelines for clinical prostate cancer screening (19), and a slight increase in morbidity was observed following the implementation of PSA screening, with the incidence peaked 35.85 cases per 100,000 person-years in 2010, and subsequently dropping to 32.76 cases per 100,000 person-years in 2019, a rate significantly lower than that of Western countries. In 2019, the age group with the highest ASIR in Japan was men ages 85–89, a notable difference from the predominant age range of individuals in low incidence countries, as depicted in Supplementary Fig. S8.

These findings suggest that despite the introduction of PSA screening, prostate cancer rates remain lower compared with Western countries. This implies that prostate cancer incidence is influenced by various factors beyond healthcare policies and public perception, such as genetics, environment, diet, and more.

Numerous studies (20) have underscored the association between ethnicity and prostate cancer risk on a global scale. Ranasinghe and colleagues (21) made an observation in England, revealing that despite equitable access to medical care, the incidence of prostate cancer among South Asian descendants remains substantially lower, at 49.5 cases per 100,000 person-years, compared with native whites. In addition, the TMPRSS2:ERG fusion occurs early in the disease's development and is prevalent in many aggressive cases. It is common in 49% of European patients with prostate cancer but only in 16.4% of Chinese patients based on a large-sample study (22). Collectively, these insights hint at racial disparities possibly explaining lower prostate cancer rates in Asia, adding a new perspective to its understanding. Vincent (23) analyzed prostate cancer in French communities and found North African descendants had better outcomes with fewer cancer-invaded tissue cores compared with Caucasians and Black French individuals. This points to the possibility that migrants in these regions uphold the low-incidence characteristics of their ancestral backgrounds. Furthermore, in low-incidence countries like Gambia, Mozambique, Malawi, Mali, and Ethiopia, predominantly inhabited by Black populations, their ASIR differs significantly from American Black men's (172.6 cases per 100,000 person-years), who had a 73% higher ASIR compared with White men between 2014 and 2018 (24). This suggests that individuals of African lineage encounter an increased susceptibility to disease development when healthcare access remains uniform. It is likely that the Black population in our study area may not precisely represent the ancestral origins of African Americans. Micheletti and colleagues's (25) genetic ancestry analysis suggests that many African Americans brought to the Americas via the transatlantic slave trade have West African origins, including regions like Angola and the Democratic Republic of the Congo.

Specific dietary patterns are likely intertwined with the characteristics of prostate cancer. In North Africa, the Mediterranean diet, featuring olive oil, tomatoes, and allium vegetables, is considered a protective factor against cancer, part of the traditional Moroccan diet (26). Ranasinghe and colleagues (21) found that South Asian diets rich in carbohydrates and daily phytoestrogen intake from lentils and beans are linked to reduced prostate cancer risk. Meanwhile, India's vegetarian cuisine and use of specific spices have demonstrated positive effects on prostate cancer prevention (27). Yang and colleagues (28) illuminated the anticancer potential of curcumin, revealing its capacity to induce apoptosis and protective autophagy in castration-resistant prostate cancer cells by means of iron chelation. Similarly, in East Asia, polyphenols from green tea and lycopene found in tomatoes have been linked to the lower incidence of prostate cancer (29). Hoang and colleagues (30) unveiled a dose–response relationship between tea consumption frequency and prostate cancer risk reduction in Vietnamese men. A comprehensive review of 133 Chinese prostate cancer patients' diets by Lee and colleagues (31) unveiled that soy foods and isoflavones (such as tofu and soybeans) are correlated with a diminished prostate cancer risk. Amidst these dietary intricacies, the carbohydrate-rich and phytoestrogen-heavy diets in East and South Asia, as well as the Mediterranean diet in North Africa, stand out as potential contributors to the low incidence of prostate cancer. In the Middle East (32), high-calorie and animal-fat-rich diets resembling the Western lifestyle are prevalent. Although the Middle East's incidence of prostate cancer is not as elevated as in Western countries, it is the highest across Asia, with a substantial 5-fold increase compared with the lowest incidence in South Asia (33). Central Asia's diet shares some parallels with Eastern Asia and European nations, featuring red meat, fermented dairy products, and butter-fried baked goods, coupled with a tradition of frequent tea consumption. In summary, whereas dietary patterns can offer intriguing insights into the context of low-incidence countries, their effects remain intricate and multifaceted. Despite the potential protective impact of diets rich in carbohydrates, daily phytoestrogens, and plant-based foods, the intricate interplay of dietary factors, environmental influences, genetic backgrounds, and other potential pathways necessitates further investigation.

As anticipated, low-incidence countries exhibit a distinct pathological profile characterized by a relatively heightened prevalence of advanced prostate cancer. This trend is vividly evident in India, where approximately 85% of cases are identified at stages III and IV, diverging from the United States where only 15% are diagnosed in the later clinical stages (34). Mukherji and colleagues (15) findings mirror this pattern, noting a significant prevalence of locally advanced and metastatic prostate cancer at diagnosis in Iraq. The substantial occurrence of extensively advanced prostate cancer during diagnosis poses a substantial burden on healthcare systems, particularly in low-incidence regions that often grapple with limited economic and medical resources.

Beyond the low initial incidence, morbidity has increased over the past 29 years in 32 of these countries. The China Prostate Cancer Consortium data show a trend of diagnosing more localized-stage prostate cancer cases between 2008 and 2013 (35). This suggests that the increase in prostate cancer may be attributed to an increase in localized cases.

As mentioned earlier, heightened public health awareness, advancements in healthcare, increased PSA screening, an aging population, and changes in dietary patterns, all of which may contribute to the increased occurrence of prostate cancer in these regions. For example, although mass screening in Vietnam (17) has not been definitively proven to yield clinical benefits, this observation underscores the value of the PSA screening program in detecting more cases during the early stages (I and II) of prostate cancer. Furthermore, in Morocco (36), a substantial 62% increase in incidence was observed in Casablanca, attributed to the implementation of PSA blood testing practices and the nationwide cancer awareness campaign initiated by the Foundation Lalla Salma since 2005. In regions where both medical resources and public awareness of prostate cancer are lacking, the augmentation of awareness promotion activities and the enhancement of prostate cancer medical services can play a significant role in bringing about positive changes.

Furthermore, a significant contributing factor is the correlation between age and prostate cancer risk. As countries with low incidence experience economic growth and improvements in healthcare, life expectancy has risen across most nations. For instance, in China, the population aged 65 and over has surged from 5.6% in 1990 to 12.0% in 2020 (37). Consequently, it is worth noting that the aging society may partially elucidate the upsurge in morbidity among the majority of low-incidence countries. Mathew (38) noted that in comparison with 1991, the average life expectancy of Indian men increased by a decade in 2012, which in turn led to a 93% increase in the tumor burden. This suggests that the persistent upward trajectory in prostate cancer morbidity could be linked to the aging populations in these nations.

Interestingly, the adoption of a westernized lifestyle has been highlighted as a potential explanation for the rising trend in low-incidence countries. As reported (39), many Asian nations have undergone a dietary transition from the traditional pattern, primarily composed of plant-based foods rich in carbohydrates and fiber, to a westernized diet centered around animal-based foods, higher in total fat and processed meat. Supporting this notion, an epidemiological study (40) documented the daily dietary habits of 43,435 Japanese men, revealing a dose-dependent relationship between dairy product consumption and prostate cancer risk over a seven-year period. Furthermore, the consumption of saturated and trans fatty acids, along with processed meat products, has long been implicated in elevating the risk of prostate cancer. These dietary factors disrupt prostate hormonal regulation, trigger oxidative stress and inflammation, and alter lipid metabolism (41). In a study by Lee and colleagues (42), involving 133 cases and 265 controls across 12 Chinese cities, daily fat intake and the percentage of energy from fat were found to be 3.6 times higher in prostate cancer cases compared with controls. In aggregate, shifts in national dietary patterns may play a pivotal role in the escalating incidence of prostate cancer in numerous countries.

The majority of the changes mentioned above have occurred in conjunction with a country's development and progress. Among the 35 low-incidence countries, most fall within the range of low SDI to middle SDI, with only Libya and Sri Lanka positioned at high-medium levels in 2019. Variations in the economic status of regions impact the incidence of prostate cancer. In China, economically advanced regions like Beijing and Shanghai have higher prostate cancer incidence rates compared with other cities (43). Economic disparities lead to unequal healthcare access and education, which in turn results in differing prostate cancer detection rates. In China, data from 255 national cancer registries in 2013 found a positive association between ASIR and Gross Domestic Product per Capita (GDPPC) level, whereas negative associations were observed between ASIRs for lung, stomach, esophageal, and liver cancer and GDPPC levels (44). This means that prostate cancer tends to affect high SDI men with longer life expectancy and increased access to screening and diagnosis.

This trend suggests a plausible correlation between the increasing burden of prostate cancer and a combination of factors, including heightened awareness, improved screening practices, shifting societal dynamics, an aging population, and evolving dietary habits—all coinciding with economic growth. However, It is important to note that several studies posit that economically disadvantaged countries lacking comprehensive registration systems might yield inaccurate data, leading to varying degrees of underestimation in these regions. This underscores the imperative to remain attentive to the challenges posed by prostate cancer and to continue investing in research efforts to comprehensively address these multifaceted dynamics.

Notably, a pronounced surge in the number of young patients has been observed in these countries. The age group exhibiting the highest growth rate consists of individuals ages 20 to 44 in low-incidence countries, followed by those ages 45 to 69 and 70 years and older. This trend aligns with the findings of Bleyer and colleagues (45), who documented a consistent global increase with an EAPC of 2.0 from 1990 to 2017 for men ages 15 to 39 years. These observations underscore a more substantial increase among younger patients in low-incidence countries, warranting further investigation into the underlying causes. It is worth noting that the growth rate in the population ages 70 and above develops gradually due to its substantial size, rendering it less prone to dramatic fluctuations as compared with the 20 to 44 age group.

In terms of limitations, our study's definition of low-incidence countries is a relative concept, and it is essential to acknowledge the potential for selection bias within these limitations. Regrettably, GBD2019 lacks comprehensive data on PSA screening levels and the clinical baseline characteristics of newly diagnosed prostate cancer cases in low-prevalence countries. This absence hinders our ability to gain a more nuanced understanding of the composition of the clinical features contributing to the rise in incidence. Conducting more extensive research is imperative to elucidate whether this upsurge can be attributed to early-onset or advanced cases of prostate cancer.

To our knowledge, this study represents the inaugural exploration into the trends of prostate cancer in low-incidence countries. Countries are predominantly located in North Africa and Asia, where most pertain to the heightened incidence of advanced-stage prostate cancer cases upon diagnosis, encompassing a SDI spectrum from low to high-middle. Across the last few decades, the prevalence of prostate cancer has exhibited a notable upward trend and individuals ages over 85 years typically manifest the highest ASIR, whereas the age bracket experiencing the most rapid growth rate is 20 to 44 years. The intricate landscape of prostate cancer may be multifactorial in origin, stemming from various elements such as limited healthcare access, reduced longevity, genetic predispositions, economic inequalities, and adherence to conventional dietary protective behaviors. Gaining a clear understanding of prostate cancer morbidity could significantly aid in making informed management decisions.

J. Jiang reports grants from National Natural Science Foundation of China and Sichuan Science and Technology Program during the conduct of the study. J. Li reports grants from National Natural Science Foundation of China and Sichuan Science and Technology Program during the conduct of the study. Q. Wei reports grants from National Natural Science Foundation of China and Sichuan Science and Technology Program during the conduct of the study. No disclosures were reported by the other authors.

J. Jiang: Conceptualization, resources, data curation, software, formal analysis, investigation. B. Chen: Resources, data curation, methodology. B. Tang: Data curation, software, funding acquisition, investigation, visualization. J. Yang: Formal analysis, writing–original draft. T. Zhang: Visualization. J. Li: Methodology, writing–original draft, project administration. D. Tan: Resources, methodology, writing–original draft, project administration. Q. Wei: Conceptualization, resources, data curation, methodology, writing–original draft.

This research received funding from the National Natural Science Foundation of China, with grants awarded to Q. Wei (grant numbers: 81974098, 82000721, and 82170784) and to B. Tang (grant number: 82102778). It also received support from the Sichuan Science and Technology Program (grant number: 2020YFS0068).

The publication costs of this article were defrayed in part by the payment of publication fees. Therefore, and solely to indicate this fact, this article is hereby marked “advertisement” in accordance with 18 USC section 1734.