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\begin{document}

\title{4K\selectlanguage{ngerman}® score test in the time of COVID-19 quarantine - implications for
timely diagnosis of high-risk prostate cancer\selectlanguage{english}}



\author[1]{Boris Friedman}%
\author[2]{Ami Neuberger}%
\author[1]{Omer Ephrat}%
\author[3]{Yoav  Manaster }%
\author[1]{Yuval Freifeld}%
\author[1]{Yoram Dekel}%
\affil[1]{Lady Davis Carmel Medical Center}%
\affil[2]{Rambam Health Care Campus}%
\affil[3]{progenetics}%


\vspace{-1em}



  
  \date{June 14, 2024}


\begingroup
\let\center\flushleft
\let\endcenter\endflushleft
\maketitle
\endgroup





\selectlanguage{english}
\begin{abstract}
The diagnosis of clinically significant prostate cancer is often
challenging. The 4K\selectlanguage{ngerman}® score test may assist in evaluating the risk of
significant malignancy and avoid biopsies in non-significant disease.
The COVID-19 pandemic caused a remarkable disruption in managing
patients with suspected prostate cancer. The aim of this study is to
evaluate the effect of the COVID-19 pandemic on 4K ®score test results
by comparing tests performed in Israel between April to July 2020 to a
control group of the same period in 2019. During the COVID-19 era there
were few quarantine periods in which citizens were allowed to leave
their homes for specific reasons only (eg, medical consultations).
Meanwhile, medical clinics were operating in limited schedule with
intention to treat emergent cases only. We assumed that focusing on
coping with the pandemic and its implications will decrease prostate MRI
tests and prostate biopsies and as a result, there will an increase in
the 4K score blood tests as well as a change in the pre-biopsies
prostate risk stratification.%
\end{abstract}\selectlanguage{ngerman}%



\sloppy


4K\selectlanguage{ngerman}\textsuperscript{®} score test in the time of COVID-19 quarantine -
implications for timely diagnosis of high-risk prostate cancer

Friedman Boris\textsuperscript{1},Neuberger Ami\textsuperscript{2},
Ephrat Omer\textsuperscript{1}, Manaster Yoav\textsuperscript{3},
Freifeld Yuval\textsuperscript{1}, Dekel Yoram\textsuperscript{1}

1- Urology Department, Carmel Lady Davis medical center, Haifa, Israel

2 - Infectious Disease Department, Rambam Health care Campus, Haifa,
Israel

3 - Progenetics company LTD

Friedman Boris -- friedmanboris173@gmail.com

Neuberger Ami -- a\_neuberger@rambam.health.gov.il

Ephrat Omer -- omerephratmed@gmail.com

Manaster Yoav -- yoav@progenetics.co.il

Freifeld Yuval -- yuvalfr@clalit.org.il

Dekel Yoram - yoramd@clalit.org.il

\textbf{Conflict of interests}

The authors declare that there is no conflict of interests.

\textbf{Funding statement}

The authors received no financial support for the research, authorship,
and/or publication of this article.

\emph{Abstract}

\emph{Background}

The diagnosis of clinically significant prostate cancer is often
challenging. The 4K® score test may assist in evaluating the risk of
significant malignancy and avoid biopsies in non-significant disease.
The COVID-19 pandemic caused a remarkable disruption in managing
patients with suspected prostate cancer.

The aim of this study is to evaluate the effect of the COVID-19 pandemic
on 4K ®score test results by comparing tests performed in Israel between
April and July 2020 to a control group of the same period in 2019.

We assumed that focusing on coping with the pandemic and its
implications will decrease prostate MRI tests and prostate biopsies and
as a result, there will an increase in the 4K score blood tests as well
as a change in the pre-biopsies prostate risk stratification.

\emph{Methods} - A retrospective cohort study comparing the
characteristics of the study group to the control group was done using
diagnostic multi-variables statistical analysis.

\emph{Results} - A 37\% reduction in the number of 4K ® score tests
performed (450 versus 721) was noted. The reduction was seen mainly
among men older than 65 years. A significantly higher percentage of
patients with 4K ® scores indicating a high risk of clinically
significant prostate cancers (\textgreater{}20\%) was noted among men
younger than 65 years compared to the control group.

\emph{Conclusions} - The COVID-19 pandemic had an influence on the
number of tests performed, especially in the elderly. Delay or lack of
supportive imaging during the pandemic may be the reason for the higher
4K ® scores among younger patients.

The reduction in the number of 4K tests on the one hand and the fact
that non-urgent diagnostic procedures and exams (eg prostate MRI exams,
prostate biopsies etc.) were less available during the COVID-19 era
could have caused a delay in prostate cancer diagnosis and treatment.

\emph{Key words} - 4K\textsuperscript{®} score test, COVID-19, prostate
cancer, PSA.

\emph{Introduction}

Prostate cancer is the most common malignancy among men {[}1{]}. For
many years the evaluation and diagnosis of this disease was based on PSA
blood test {[}2{]} and digital rectal examination (DRE). In the last
decade, new tests are available and may assist physicians distinguish
between patients who harbor a high-risk significant prostate cancer and
those with low-risk prostate cancer and thus rationally select patients
who need prostate biopsies. One of the diagnostic options today is the
4K\textsuperscript{®} score test which is a blood test sampling the
level of three serological markers besides the PSA: free PSA, intact PSA
and human kallikrein-related peptidase 2 (hK2) {[}3{]}. Different
studies reported a greater efficiency in diagnosing aggressive prostate
cancer by using the 4K\textsuperscript{®} score test comparing the
standard PSA level, allowing avoiding biopsies among patients assuming
to have less aggressive disease {[}4,5{]}.

Patients with 4K ® score of 7.5\% or less are considered to have a
low-risk for diagnosis of a prostate cancer of Gleason score of 7 or
higher if a biopsy was performed. Also, these patients have less than a
1\% risk of having metastasis within 20 years {[}6{]}. In contrast,
patients with a 4K® score above 33\% are 33\% more likely to have a
Gleason score \selectlanguage{english}[?]7 prostate cancer if a biopsy was performed {[}4, 7{]}.

COVID-19 has a global effect with substantial mortality as well as
indirect effect on evaluating other diseases {[}8{]}, reducing human
resources, reducing budgets, directing clinics to treat only COVID-19
patients, and reducing primary evaluating facilities with local or
regional instructions to reduce visits in hospitals and outpatient
clinics with other diseases. This reality may cause delayed diagnosis of
other diseases, including malignancies. The diagnosis rates of different
malignancies reduced significantly in USA comparing the pre-COVID 19
era, a finding which its implications may be noticeable for years to
come {[}9{]}. A study using a mathematical model to evaluate the
expected influence of a delayed diagnosis on the mortality rate,
predicted an incline in preventable mortality rate the next years among
patients with different malignancies {[}10{]}.

In Israel, during the COVID era, few quarantine periods were declared in
which people were instructed not to leave their homes unless for
prespecified reasons such as essential medical treatment. In addition to
that, the Israeli ministry of health instructed hospitals and clinics to
reduce elective procedures.

\emph{Goal}

The goal of this study is to evaluate the effect of the COVID-19
pandemic on the 4K (r) score test array among men in Israel.

\emph{Methods}

This is a retrospective cohort study evaluating the results of 4K (r)
score tests performed in Israel before and during the COVID-19 pandemic.

Institutional ethical approval was obtained. The Data was obtained and
collected anonymously from the Bioreference Laboratories which performs
the 4K scores in Israel; As this is the only one lab in Israel
responsible for 4K tests, the numbers and results represent the entire
tests performed in Israel in a given period. As the data is
retrospective and anonymous some details are missing such as family
history of prostate cancer, findings on digital rectal examination,
previous TURS-guided biopsies and the results and PSA kinetics

The study group was defined as males who completed the 4K (r) score tests
between April 1\textsuperscript{st} 2020 and July 31th 2020 during the
first quarantine period in Israel. The control group was defined as
males who completed the tests during April-July 2019, before the
COVID-19 pandemic. Clinical and demographic data were compared between
the groups. Multivariate analyses were used to define factors
independently associated with 4K(r) scores indicating increased risk for
malignancy.

The primary outcome was defined as the percentage of patients with a 4K
(r) score above 20\% indicating an increased risk for a clinically
significant prostate cancer {[}4{]}. Secondary outcomes were the
percentages of patients with 4K (r) scores indicating a low-risk and a
very high-risk for clinically significant prostate cancers
(\textless{}7.5\% and \textgreater{}33\%, respectively).

The database was obtained from Bioreference Laboratories, which performs
the tests in Israel. The bilateral value of 0.05 was defined as
statistically significant. All statistical analyses were performed using
IPSS software version 25.

The study was approved by local Helsinki committee. As the study is
retrospective and does not identify patients, a waiver of informed
consent was granted by the ethical committee.

\emph{Results:}

The study included 1171 subjects. The study group included 450 patients
for whom 4K (r) tests were performed during April-July 2020 whereas the
control group included 721 patients for whom tests were performed during
April-July 2019. The age range was between 41 and 86 years and the mean
age was similar between the two groups (66 versus 67 years in the study
and control groups, respectively, p=0.535). The mean PSA level was
similar between the two groups (7, p=0.865) -- Table 1.

Table 2 shows 4K (r) scores divided using 7.5\%, 20\% and 33\% cut-offs ,
dividing patients to low-risk (\selectlanguage{english}[?]7.5\%) ,moderate-risk
(7.5\%\textless{}4K (r) score \selectlanguage{english}[?]20\%), high-risk (\textgreater{}20\%) and
very high-risk (\textgreater{}33\%). As could be seen, a higher
percentage of patients in the study group had a 4K (r) score
\textgreater{}20\% indicating a high risk for clinically significant
prostate cancer {[}146/450 (32.4\%) versus 195/721 (27\%), respectively,
p=0.048{]}. Similarly, a very high risk of malignancy with 4K (r) of 33\%
or more, was found to be significantly more common in the study group
{[}80/450 (18\%) versus 93/721 (13\%), p=0.022). On the other hand,
there was no significant difference between the study group and the
control group regarding low-risk range {[}164/450 (36.4\%) versus
279/721 (39\%) respectively, P\textgreater{}0.1).

When examining the results distributed by age groups -- 65 years or
younger and older than 65 (table 3), we can see that there was a
significant difference between the study group and the control group in
patients 65 years old and younger using 4K (r) scores of 20\% {[}68
(32.2\%) versus 43 (16.6\%), respectively, p\textless{}0.05{]} and 33\%
{[}35 (16.6\%) versus 13 (5\%), respectively, p\textless{}0.05{]}. on
the other hand, there was no significant difference between the groups
in patients older than 65 using 4K (r) scores of 20\% and 33\% {[}45
(18.8\%) versus 80 (17.3\%), respectively, p=0.62{]}.

\emph{Discussion:}

Prostate cancer is the most common cancer in men {[}11{]}. Since the
beginning of screening for prostate cancer with serum PSA, we have seen
a significant decline in prostate cancer mortality {[}12{]}.

A systematic analysis suggested that up to 60\% of prostate cancers
diagnosed in contemporary studies can be safely observed without a need
for immediate intervention {[}13{]}. However, 20\% to 30\% of men who
are diagnosed with prostate cancer are found to have high-grade disease
at presentation {[}14{]}. Diagnosis should focus on detection of
aggressive tumors, that are more likely to progress to metastatic
disease and death, and not the indolent ones.

The 4K (r) scores test is a relatively new blood test that identifies the
risk of aggressive cancer and has a role as an initial test before
performing prostate biopsies in men with an elevated PSA level or an
abnormal digital rectal examination result, or after a previous negative
prostate biopsy with persistently elevated PSA level. The test result is
a personalized positive predictive value of finding Gleason score \selectlanguage{english}[?] 7
cancer on biopsy of the prostate. This provides the patient and
physician with quantitative information to aid in clinical decision
making regarding performing prostate biopsies.

The COVID-19 era in general had a major effect on health-care related
issues such as allocating medical resources to cope with COVID and its
implications, delaying or postponing non-emergent diagnostic procedures
and even limited availability of primary care providers, not to mention
expert consultation

This study is intended to examine the extent of the effect during the
first quarantine period of COVID-19 pandemic on performing 4K(r) blood
tests in Israel. We found that the number of tests performed during the
study period decreased significantly by about 37\% compared to the
corresponding period the year before. This fact is consistent with that
described in the literature on reduction in malignancy-related tests
during the COVID-19 period. One of the subjects being investigated
recently is the risk of late diagnosis and mortality from
life-threatening diseases in general {[}15{]} and cancer in particular
{[}16{]}. These studies found an increased risk of morbidity and
mortality from serious diseases due to neglect and reduction in
follow-up and late diagnosis of malignant diseases during this period.

Another component is the psychological consequences of living during a
pandemic that causes anxiety and seclusion that have a negative effect
on the diagnosis and treatment of patients with serious illnesses
{[}17{]}.

Our study found a significant difference between the study and control
groups in the percentage of tests indicating a high-risk (4K(r) score
above 20\%) and a very high-risk (4K (r) score above 33\%) for clinically
significant prostate cancer.

A reasonable explanation for these differences would have been an
increased PSA levels during screening, which incited both the referring
physician and the patient to perform the 4K(r) test. However, no
significant difference in PSA level was found between the study group
and the control group. The mean age was not significantly different
between the groups but the ratio of patients 65 years or younger out of
the total subjects in the study period (211/450=0.47) was higher
relative to their ratio in the control group (259/721=0.36). This may be
because older patients tended to be more isolated and secluded during
the first quarantine period included in the study period.

The patients' age was found to be an influencing factor on higher 4K (r)
scores during the study period, even in multivariable analysis. During
the study period, more patients aged 65 or younger with high 4K(r) scores
\selectlanguage{english}\selectlanguage{english}were found compared to the corresponding period the year before. One
possible explanation is that 4K (r) tests were performed instead of MRI
imaging that were canceled or postponed due to the pandemic working
schedule {[}18{]}.

This is the first study to address the implications of this challenging
era on the diagnosis of prostate cancer using biological markers.

The strengths of the study are a uniform database with a large number of
tests performed in one central laboratory.

The limitations of the study are a relatively short period of time
during the pandemic period taken as the study period as well as the lack
of the actual biopsy results.

Extensive research with a larger database is required to validate the
research findings.

\emph{Conclusions and summary:}

The number of tests performed among patients older than 65 years has
decreased during the study period, possibly because of the quarantine
and the concerns related to performing blood tests during this period.
On the other hand, there was an increase in the percentage of the tests
indicating a high-risk disease among men aged 65 years or younger,
possibly because of less accessibility to other imaging tests during the
pandemic period following the outbreak of COVID-19.

\textbf{Table 1 -- baseline characteristics of men in the study}\selectlanguage{english}
\begin{longtable}[]{@{}llll@{}}
\toprule
\textbf{Characteristics} & \textbf{Study group} & \textbf{Control group}
& \textbf{P-value}\tabularnewline
\midrule
\endhead
Number of patients & 450 & 721 & -\tabularnewline
Mean age (yr) & 66 & 67 & P=0.535\tabularnewline
Mean PSA {[}ng/ml{]} & 7.08 & 7.03 & P=0.865\tabularnewline
\bottomrule
\end{longtable}

\selectlanguage{ngerman}\textbf{Table 2 -- 4K ® scores divided using 7.5\%, 20\% and 33\%
cut-offs , dividing patients to low-risk ([?]7.5\%) ,moderate-risk
(7.5\%\textless{}4K (r) score [?]20\%), high-risk (\textgreater{}20\%) and
very high-risk (\textgreater{}33\%)}\selectlanguage{english}\selectlanguage{english}
\begin{longtable}[]{@{}lllll@{}}
\toprule
\selectlanguage{ngerman}\textbf{4K ® score} & \textbf{Time frame} & \textbf{Time frame} &
\textbf{Total} & \textbf{P-value}\tabularnewline
\midrule
\endhead
& \textbf{April-July 2019 -- Control group} & \textbf{April-July 2020 --
study group} & &\tabularnewline
[?]7.5\% - low-risk & 279 (39\%) & 164 (36.4\%) & 443 (37.8\%) &
P\textgreater{}0.1\tabularnewline
\textgreater{}7.5\% -moderate-risk & 442 (61\%) & 286 (63.6\%) & 728
(62.2\%) &\tabularnewline
[?] 20\% - moderate-risk & 526 (73\%) & 304 (67.6\%) & 830 (70.9\%) &
P\textless{}0.05\tabularnewline
\textgreater{}20\% - high-risk & 195 (27\%) & 146 (32.4\%) & 341
(29.1\%) &\tabularnewline
[?]33\% & 628 (87.1\%) & 370 (82.2\%) & 998 (85.2\%) &
P\textless{}0.05\tabularnewline
\textgreater{}33\% & 93 (12.9\%) & 80 (17.8\%) & 173 (14.8\%)
&\tabularnewline
\bottomrule
\end{longtable}

\selectlanguage{ngerman}\textbf{Table 3 -- 4K ® scores distribution by age groups}\selectlanguage{english}
\begin{longtable}[]{@{}llllll@{}}
\toprule
\textbf{Age group} & \selectlanguage{ngerman}\textbf{4K ® score} & \textbf{Time frame} &
\textbf{Time frame} & \textbf{Total} & \textbf{P-value}\tabularnewline
\midrule
\endhead
& & \textbf{April-July 2019 -- Control group} & \textbf{April-July 2020
-- study group} & &\tabularnewline
[?]65 & [?] 20\% & 216 (83.4\%) & 143 (67.8\%) & 359 (76.4\%) &
\textless{}0.05\tabularnewline
& \textgreater{}20\% & 43 (16.6\%) & 68 (32.2\%) & 111 (23.6\%)
&\tabularnewline
& [?]33\% & 246 (95\%) & 176 (83.4\%) & 422 (89.8\%) &
\textbf{\textless{}0.05}\tabularnewline
& \textbf{\textgreater{}33\%} & \textbf{13 (5\%)} & \textbf{35 (16.6\%)}
& \textbf{48 (10.2\%)} &\tabularnewline
\textgreater{}65 & [?] 20\% & 310 (67.1\%) & 161 (67.4\%) & 471 (67.2\%) &
P=0.944\tabularnewline
& \textgreater{}20\% & 152 (32.9\%) & 78 (32.6\%) & 230 (32.8\%)
&\tabularnewline
& [?]33\% & 382 (82.7\%) & 194 (81.2\%) & 576 (82.2\%) &
\textbf{P=0.62}\tabularnewline
& \textbf{\textgreater{}33\%} & \textbf{80 (17.3\%)} & \textbf{45
(18.8\%)} & \textbf{125 (17.8\%)} &\tabularnewline
\bottomrule
\end{longtable}

\emph{Data availability} :

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

\emph{References:}

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