Change in Prostate Cancer Stage over Time

Fei Zhang

Biostatistics and Data Science, Weill Cornell Medicine College, Cornell University, New York, U.S.A.

Keywords: PSA, Prostate Cancer, Chi-Squared Test, Proportionality Test, Early Diagnosis.

Abstract: Prostate cancer is a form of cancer that occurs in the prostate gland cells among males and it is the second

most common type of cancer among males in the US. In early 1990, the American Urological Association

(AUA) and the American Cancer Society (ACS) started recommending annual prostate cancer screening with

Prostate-specific antigen test (PSA) which is a blood test. In October 2011, the US Preventive Service Task

Force (USPSTF) published a final guideline recommending against the use of PSA based screening for

prostate cancer. The influence of the use of PSA on the diagnosis rate of prostate cancer, especially in the

early stage, has become a hot research topic. The goal of this paper is to determine whether there has been a

change in proportion of men diagnosed with localized/regional prostate cancer over time due to the changes

in PSA screening recommendations, and whether this change of proportion is associated with other risk

factors. This paper uses Chi-Squared test, proportionality test and other methods to analysis data. There was

significant difference between the proportion of localized/regional prostate cancer in year 2004 and 2015 as

USPSTF recommended against the use of PSA based screening. Age, racial, region and marital status

significantly affect the distribution of the proportion of initial stage prostate cancer.

1 INTRODUCTION

Prostate cancer is a form of cancer that occurs in the

prostate gland cells among males and it is the second

most common type of cancer among males in the US.

As per a 2016 CDC annual report, for every 100,000

men in the US, 101 new prostate cancer cases were

reported in the year 2014 and of those cases, 19

died(Centers for Disease Control and Prevention). In

early 1990, the American Urological Association

(AUA) and the American Cancer Society (ACS)

started recommending annual prostate cancer

screening with Prostate-specific antigen test (PSA)

which is a blood test. PSA is made by the prostate

gland and high levels of PSA may be indicative of

prostate cancer or other non-cancerous conditions.

PSA screening was a cheaper and non-invasive

alternative to a digital rectal exam which is one main

reasons for PSA based screening being recommended

even though there was no supported clinical trial

evidence for PSA accurate indicator of prostate

cancer. There was an alarming increase in the

incidence rates as PSA based screening became more

common and by 1992 the incidence rate of prostate

https://orcid.org/0000-0003-3199-0521

cancer in the US nearly doubled. Mei Aobing et

al(Aobing et al. 2017, Mistry, Cable 2003, Zhao,

Huang, Cheng et al. 2014, Kramer, Brown, Prorok, et

al. 2013). questioned the sensitivity and specificity of

PSA, especially when PSA is between 4.00 ng/mL

and 10.00 ng/mL. There is an overlap between

SERUM PSA levels in PATIENTS with benign

prostatic hyperplasia (BPH)and prostaticcancer

(PCa), making it difficult to distinguish benign

prostatic hyperplasia from prostate cancer. K. Mistry

et al (Mistry, Cable 2003). 's study found that chronic

prostatitis, indplacement of urinary ducts, prostate

massage, and other conditions can lead to abnormal

PSA test results, that is, PSA is a prostate-specific

marker rather than a marker of prostate cancer. In

October 2011, the US Preventive Service Task Force

(USPSTF) published a final guideline recommending

against the use of PSA based screening for prostate

cancer (USPSTF).

The significant change in incidence rates and

diagnosis levels of prostate cancer cases over the last

few decades points towards a possibility of

overdiagnosis and overtreatment due to these policy

changes. There is scope to further study and evaluate

the impact of this change in the policy and scientific

308

Zhang, F.

Change in Prostate Cancer Stage over Time.

DOI: 10.5220/0011368700003438

In Proceedings of the 1st International Conference on Health Big Data and Intelligent Healthcare (ICHIH 2022), pages 308-313

ISBN: 978-989-758-596-8

landscape over the years. Early diagnosis, timely

operation and effective endocrine therapy can greatly

reduce the mortality rate of prostate cancer.

Therefore, to study the causes and influencing factors

of prostate cancer and determine the susceptible

population will provide an important basis for

effective prevention, early diagnosis and improved

survival rate. The goal of this project is to determine

whether there has been a change in proportion of men

diagnosed with localized/regional prostate cancer

(out of the total number of diagnosed prostate cancer)

over time due to the changes in PSA screening

recommendations, and whether this change of

proportion is associated with age group, the race

groups, region groups and marital status. Chang et al

(

Chang 1996). 's study found that PSA increased with

age, and different age groups had different effects on

PSA. The older you are, the greater the impact. In

addition, the mean prostate volume of all ages also

increased with age, and the prostate volume increased

with age. There has been a change in proportion of

men diagnosed with localized/regional prostate

cancer (out of the total number of diagnosed prostate

cancer) over time due to the changes in PSA

screening recommendations. And this change of

proportion is associated with age group, the race

groups, region groups and marital status.

2 METHOD

2.1 Data

The Surveillance, Epidemiology, and End Results

(SEER: https://seer.cancer.gov/) database which is

maintained by the National Cancer Institute (NCI),

was used for this study. The database extract contains

28% of all cancer cases in the US, diagnosed between

2004 and 2015. The data was collected from 18

different population-based registries and contains

incidence as well as survival records of patients by

patient ID. The dataset is deidentified and is

compliant with HIPAA regulations regarding

protection of patient privacy and intended use of the

data for research purposes. There is a total of about

1.94 million patient records out of which 230,326

records are associated with prostate cancer. Each

record contains a patient ID, registry ID, year and

month of diagnosis, age at diagnosis, histology

(stage) and other demographic information such as

race, birth year, sex. A check for duplicates yielded

31 patients with 2 diagnoses at different points of

time, only initial records were as the evaluation is

primarily based on the initial prostate cancer

diagnosis.

2.2 Statistical Analysis

Since the raw data contained 133 columns, it was

essential to select the relevant variables, filter the

essential categories, and create categorical variables

for age groups as well as diagnosis dates (before or

after PSA final guidelines). In the cleaning process,

male patients diagnosed with prostate cancer in

interested stages were selected from the original

SEER dataset. Duplicate records, patients with age

under 50 years old, and unrelated variables and stages

were removed. Then The clean data was then

grouped cases by race, region, marital status, and age

group to yield number of cases as a function of time

(month-year). In order to test the difference in

proportion of localized relative to the overall cases in

different categories (race, age group, geographical

region, marital status), we used proportionality test

for two groups and Chi-squared test of independence

in case of multiple groups. These non-parametric tests

were used after making sure that the following

requirements were met. Variables are categorical

(binary) in nature: Prostate Cancer

Stage(Localized/Regional and Distant). All cases

belonged to a single population. Data management

and statistical analyses were performed using R,

version 4.1.1.

3 RESULTS

In general, the widespread adoption of PSA-based

prostate cancer screening caused a stage migration

toward earlier stage of prostate cancer at diagnosis

(95% CI 0.0347 - 0.0451) during the early 2000s.

Thus, there was significant difference between the

proportion of localized/regional prostate cancer in

year 2004 and 2015 as USPSTF recommended

against the use of PSA based screening. The dotted

line marks the time when USPSTF released their final

guidelines (October 2011) and after which, there is a

sharp linear decrease in the proportion of

localized/regional cases detected in the following

years (Figure 1).

Change in Prostate Cancer Stage over Time

309

Figure 1: Proportion of US Males Diagnosed with Initial Stage Prostate Cancer Over Time.

3.1 Age Groups

From 2004 to 2015, the proportion of

localized/regional prostate cancer for age group

greater than 70 years was less than that of 50-70 years

age group. Moreover, the proportions of both the age

groups were stagnant during the time period between

2004 and October 2011, however there was

significant decrease in proportions of both age groups

since October 2011(Table1). The two-proportion z-

test showed that there were differences in proportion

of men diagnosed with localized/regional disease by

age groups: 50-70 and over 70 (χ2 statistic: 327.07,

95% CI: -0.06 - -0.056). The influence of PSA

screening guideline change on the proportion was

different for both age groups (with PSA screening:

95% CI -0.0508 - - 0.0459, without PSA screening:

95% CI -0.0907 - -0.0807). The plot shows that the

age group of individuals over 70 years experienced a

steeper decrease in proportions as compared to the

50-70 years age group.

Table 1: Summarized Results of Statistical TestsConducted on All Groups.

3.2 Race Groups

During the period from 2004 to 2015, the proportion

of localized/regional cases decreased for both major

race groups (black and white) after October 2010. The

proportion among white males was greater than black

males and two-proportion z-test showed that the

difference in the overall proportion by race was

statistically significant (χ2 statistic: 117.92, 95% CI

0.012 - 0.018). The influence of PSA screening

guideline change in the proportion among black and

white patients was different (with PSA screening:

ICHIH 2022 - International Conference on Health Big Data and Intelligent Healthcare

310

95% CI -0.0508 - -0.0459, without PSA screening:

95% CI -0.0907 - -0.0807).

3.3 Region Groups

All the regions (Midwest, Northeast, South, and

West) showed a decrease from 2010 with slight

variations in trends. Chi-squared test showed that

there is an association between the US regions and the

proportions (χ2 statistic: 35.384, df = 3, p-value <

0.0001). So, there is sufficient evidence to state that

the influence of PSA screening on proportion of

localized/regional stage varies between different US

geographical regions.

3.4 Marital Status

Marital status was divided as Divorced, Married,

Separated, Single, Unmarried or domestic partner and

Widowed. In the period between 2004 and 2015,

there were slightly variance and experience decrease

since 2010 in marital status. The unmarried group has

some outliers on the lower end of the proportion range

in the time trend analysis, however smoothing shows

similar trend lines among all marital status. The

married group has the highest proportion of regional

stage prostate cancer cases from 2004 and 2015,

while widowed group had the least. Chi-squared test

of independence shows that there is an association in

the proportion of men diagnosed with

localized/regional disease with marital status:

Divorced, Married, Separated, Single, Unmarried or

domestic partner and Widowed (χ2 statistic: 1928.10,

df = 5, p-value < 0.0001). Additionally, the influence

of PSA screening on proportion of localized/regional

stage depends on marital status (with PSA screening:

χ2 = 9.088, df = 3, p-value = 0.02814, without PSA

screening: χ2 = 39.878, df = 3, p-value < 0.0001).

4 DISCUSSION

Many articles have confirmed that age, residence,

race, and marital status have a significant impact on

the diagnosis of prostate cancer. The incidence of

various tumors is very different in different countries

in the world. Even the incidence of different regions

in the same country is also very different. For

example, the country with the highest incidence of

gastric cancer is Japan, the incidence of colorectal

cancer is the highest in the United States, and Sweden

has the highest incidence of prostate cancer. For

different regions, the probability of occurrence of

each type of cancer is different in each region, which

may be affected by local eating habits, weather, air

quality, water quality and other external

environmental factors.

From the analysis of internal reasons, the

incidence of cancer may be related to mental state,

mental quality, happiness index, personal physical

fitness and so on. Many researchers have proven

through genetics that people of different regions and

races have different genes for prostate cancer

susceptibility, and the order of these genes is also

inconsistent, which will fundamentally affect the

prevalence and incidence of cancer. Nan Di et al (

nan,

Yun 2019, Li 2003) found that the differences in the

genotype and allele frequency distribution of

susceptibility genes between different races in

prostate cancer caused the abnormal incidence of

prostate cancer, which can directly participate in the

development of prostate cancer. Occurrence and

development. There are obvious differences in the

incidence of prostate cancer among people of

different races and regions, and the incidence varies

dozens of times. Studies by foreign scholars have

shown that there are obvious differences in the

incidence of prostate cancer among different ethnic

groups in the United States, such as Indians, African

Americans, Mexican Americans and Asian

Americans. Studies by domestic scholars have shown

that there are obvious differences in the distribution

of your genotypes under the front ranks of different

ethnic groups, which may affect the hormone levels

and biological effects of different individuals. VDR

genes and androgen-related gene polymorphisms

have obvious racial types, and they are different from

each other. The incidence of prostate cancer is the

same in different races.

Genetic factors are undoubtedly the main factors

affecting the incidence of prostate cancer, and the

differences in genetic gene sequences between

different races are the main factors contributing to the

huge differences in the incidence of prostate cancer

among different races. Those studies’ results are

consistent with this paper.

Besides, a study found a significant increase in the

incidence of prostate cancer among Asian

immigrants. It suggests that factors such as geography

and dietary habits may play a role in the development

of prostate cancer. Chuiguo Huang (

Huang 2018) used

multi-factor Cox regression analysis, survival

analysis and other methods to confirm that related

factors such as age, race, marital status, PSA

concentration, T stage in TNM staging, tumor tissue

grading, and the use of different interventions are

affecting the Gleason score of 8. Separate

Change in Prostate Cancer Stage over Time

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independent risk factors for the prognosis of prostate

cancer patients.

In addition, prostate-specific antigen (PSA), as

the most valuable tumor marker for prostate cancer,

only has the specificity of prostate tissue but not the

specificity of prostate cancer. Various prostate tissues

(including normal tissues, benign hyperplasia tissues

and cancer tissues) are PSA can be secreted, leading

to its lack of specificity and sensitivity in the

diagnosis of early prostate cancer. For a long time,

clinicians have used total PSA = 4.0 ng/ml as the

threshold for screening prostate cancer (PCa) and

non-prostate cancer and has been widely used.

However, a large number of studies have shown that

in patients with tPSA≤4.0 ng/ml, the incidence of

prostate cancer is not low; and among patients with

tPSA>4.0 ng/ml, 75% of patients do not have prostate

cancer. Therefore, the use of a single PSA indicator

with fixed threshold value to diagnose prostate cancer

has a higher false positive rate and false negative rate.

Many new studies have shown that the original

threshold of the PSA method should be adjusted

according to the patient's actual physical condition

and past medical history. For example, big data

analysis and machine learning methods can be used

to obtain a new PSA threshold for early warning PCa

in the T2DM population (the original threshold 4.0

ng/ml), and calculate its sensitivity and specificity.

Probability function fitting is used to estimate the

distribution of PSA levels in the overall population,

support vector machines are used to calculate new

thresholds, and receiver operating characteristic

(ROC) curves are used to test its diagnostic efficacy.

This article only analyzed several risk factors.

However, change in proportion of men diagnosed

with localized/regional prostate cancer over time due

to the changes in PSA screening recommendations

may associated with other factors other than age

group, the race groups, region groups and marital

status. Besides, this article can use survival analysis,

multivariate statistical analysis and other models to

study more risk factors and influencing factors of

prostate cancer in the future. MIC can be used to carry

out factor correlation analysis on the large and

complex medical data of major hospitals, and then

obtain more accurate relationships and visual images

from the complex data. New models or other methods

can be used to further analyze the impact of the policy

of discontinuing the PSA screening

recommendations.

5 CONCLUSIONS

A statistical analysis of the SEER dataset helped us

understand the effects of healthcare policies on

prostate cancer diagnosis levels over the years. The

overall proportion of cases with localized/regional

prostate cancer show a slight increase between 2004

and mid of 2008 which is due to the prominence of

PSA-based prostate cancer screening. In 2008, the

overall proportion started declining due to rising

awareness of overdiagnosis of initial stage

(localized/regional) of prostate cancer from PSA

screenings. Additionally, during this time (2008) the

USPSTF began recommending men over the age of

75, against PSA screening tests which led to a steeper

decline in the proportion of initial stage cases in the

above 70 years age category. In October 2011, the

USPSTF issued a draft recommending against PSA

screening for other age groups as well and due to this

a steep linear decline in the proportion of initial stage

prostate cancer can be seen across all categories: race,

region, marital status, and age group. Statistical tests

were conducted to determine if the proportions

between the groups (within each category) were

significantly different. Table 1 shows that the p-value

for the proportionality tests was consistently less than

the level of significance (0.05), due to which we could

reject the null hypothesis (proportions are equal).

Thus, we can conclude that the proportions of initial

stage (localized/regional) prostate cancer cases were

significantly different between age groups (50-70 and

above 70) as well as racial groups (black and white).

It was also found that the proportions of men

diagnosed with initial stage of prostate cancer were

statistically different between 2004 and 2015, based

on the sample size. In order to obtain a detailed

analysis, it was important to look at the proportion

trends by other factors like marital status and regions

in the US. Histogram of proportionvalues for

different regions showed that the distributions had

different variances, and Chi-Squared test indicated

the total proportions for the regions are statistically

different. Finally, marital status also significantly

affected the distribution of the proportion of initial

stage prostate cancer. Due to the differences in

domestic and foreign policies, the current domestic

research in China focuses on other research based on

PSA screening recommendations. The main research

directions are as follows. Factors affecting prostate

cancer. Whether the threshold value of the detection

index needs to be adjusted according to the patient's

actual situation such as past medical history and how

to adjust. In addition to the current detection methods

and indicators taken into account, do you need to add

ICHIH 2022 - International Conference on Health Big Data and Intelligent Healthcare

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other indicators to make the detection results more

reliable and effective, avoid biased results, and reduce

unnecessary testing for patients. At present, few

scholars or institutions have studied the influence of

the existence of PSA screening on the efficiency of

prostate cancer diagnosis. This article fills this

loophole very well, and hope that this article

encourages more scholars to study the detection

method itself. With the rapid development of

computers, statistical learning and artificial

intelligence deep learning algorithms are gradually

being integrated with medicine. Use artificial

intelligence, big data complex analysis and other

emerging computing methods to explore new

research methods based on medical observation data,

and then better diagnose. It is also possible to analyze

the influencing factors of prostate cancer from a new

perspective. In addition to the four factors mentioned

in the article, as well as many genes that are currently

being studied, there are actually many factors that can

be analyzed. Humans are social animals and are

affected by various factors, such as psychological

factors, diet, and water sources.

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