The Rebound Effect of the COVID-19 Pandemic on Clinically Significant Prostate Cancer Diagnosis

Abstract

Background and aim: The effect of the COVID-19 pandemic on delayed screening and consequent diagnosis of prostate cancer (PCa) is yet to be defined. This study aimed to evaluate the impact of the COVID-19 pandemic on PCa diagnosis by comparing the number of prostate biopsies performed and observing the PCa detection rate during pre-COVID, COVID and post-COVID periods. Materials and Methods: A prospectively maintained database was queried to identify patients who received prostate biopsy between January 2018 and December 2022. The cohort was stratified into pre-COVID, COVID and post-COVID periods based on Italian government regulations. The primary study outcomes were the number of biopsies performed and the detection rate of clinically significant PCa (csPCa) in each period. Changes in the median number of biopsies were evaluated using the Kruskal–Wallis test, whereas changes in csPCa were evaluated using the chi-square test. The loess function depicted changes in the number of prostate biopsies and the csPCa detection rate across the study period. Results: Overall, 2502 patients were included; their median age was 68 (62–74) years. The median number of biopsies performed in the pre-COVID, COVID and post-COVID period was 46 (43–56), 39 (27–43) and 46 (40–58), respectively (p = 0.02). The most significant decrease in the number of biopsies performed was observed during the peak of the pandemic, from March to May 2020. The detection rate of csPCa in the three periods was 37%, 34% and 39%, respectively (p = 0.01). The loess function demonstrated a rebound effect on the number of biopsies performed and consequent csPCa diagnosed starting from November 2020, while the same effect was not observed for non-cs PCa. Conclusion: The COVID-19 pandemic caused a significant decrease in the number of prostate biopsies performed and csPCa diagnosed. We demonstrated a rebound effect on csPCa diagnosis after the pandemic. Future studies with longer follow-ups are needed to address the effects of the observed grade migration on the burden of PCa treatment and oncological outcomes.

1. Introduction

During the COVID-19 pandemic, a radical change in medical priorities was enforced across all health systems, particularly in Italy where the pandemic hit the hardest. Healthcare professionals have indeed faced the challenging task of prioritizing the treatment of non-deferrable conditions over the deferrable ones [1,2,3]. Policy has focused all human and economic resources on the management of the pandemic rather than on the diagnosis and management of cancer patients. People also neglected chronic diseases for fear of possible COVID-19 infections in hospitals.

While the effects of postponing the treatment of deferrable conditions are yet to be defined, previous studies have shown a decrease in the cancer diagnoses at different sites during the COVID-19 pandemic [4,5]. Specifically, during the period 1 March–31 December 2020, all non-screenable cancers experienced statistically significant disruptions in both early and late stages across the US [6]. The pandemic also had a relevant impact on the timely diagnosis of screenable cancers, such as prostate cancer (PCa) [7]. Indeed, the diagnosis of early-stage PCa was 20.8% lower than expected (95% prediction interval [PI], 19.1–22.5%) [8,9], with a negative impact on the quality of life of prostate cancer patients and increasing rates of advanced or metastatic cases [10].

Accordingly, a notable shortfall was observed in the number of cancer treatments delivered during the first year of the COVID-19 pandemic due to the reduction in the number of cancer diagnoses [11].

Although the World Health Organization (WHO) has declared the end of the pandemic [12], hospitals are still experiencing the consequences of that period, resulting in longer waiting lists and disrupted follow-ups. This establishes the relevance and timeliness of our research. It emphasizes that even though the pandemic is officially over, its effects on healthcare, particularly for sensitive diagnoses such as PCa, are ongoing.

Even though PCa has a relatively slow progression, its early detection is crucial to guarantee optimal cancer control and functional outcomes [13].

In this perspective, we aimed to evaluate the impact of the COVID-19 pandemic on PCa diagnosis by comparing it with the pre-pandemic and post-pandemic period in terms of the number of prostate biopsies performed and the number and type of PCa diagnosed.

2. Materials and Methods

2.1. Study Population

Following Internal Review Board (IRB) approval, we conducted a retrospective review of patients having undergone prostate biopsy at a single institution between January 2018 and December 2022. The cohort was categorized according to the period in which patients received prostate biopsy, namely by convention pre-COVID (from 1 January 2018 to 9 March 2020), COVID (10 March 2020 to 3 May 2020) and post-COVID (3 May 2020 to 31 December 2022), based on the restrictions imposed by the Italian government to face the pandemic diffusion. Specifically, the first and most stringent social restriction lasted from March 9th to May 3rd [14]. During that period, surgical activities were reduced to 15–30% of total operating capacity across the entire country, and daily activities were limited to emergency surgeries, oncological priorities, or life-threatening cases [2,15]. After 3 May 2020, a progressive recovery of routine activities was observed, although slowly and widely varied across the country compared to the volume operated before the pandemic.

2.2. Biopsy Procedure and Pathology Examination

Preoperatively, all patients received serum-PSA testing and digital rectal examination (DRE). Prostate biopsy was performed under the supervision of two senior urologists with more than 10 years’ experience in this procedure. Following local anesthesia [16], PBx was performed according to our 18-core standard biopsy template [17] under TRUS guidance (Flex Focus 500, BK Medical, Copenhagen, Denmark) and using an 18-gauge/25 cm biopsy needle (Bard Max-Core, BD, Franklin Lakes, NJ, USA). In patients who had a pre-biopsy prostate MRI showing PIRADS ≥ 3 lesions, MRI–US fusion biopsy was performed, and three to five additional cores were taken from each such lesions. All patients received antibiotic prophylaxis during the procedure and were checked for post void residual urine (PVR) before being discharged. All specimens were analyzed by two experienced uropathologists, and the results were referred according to the International Society of UroPathology (ISUP) recommendations [18].

2.3. Statistical Analysis

The primary outcomes of the present study were the number of prostate biopsies performed and the detection rate of csPCa, defined as ISUP Gleason grade ≥ 2. The secondary study outcome was the detection rate of clinically insignificant PCa (ISUP Gleason grade = 1).

Continuous variables were reported as median and interquartile range (IQR), while categorical variables were reported as number and percentage. First, we calculated the number of prostate biopsies performed and the percentage of csPCas detected per month. Then, data were stratified into pre-COVID, COVID and post-COVID period, in accordance with the aforementioned timing criteria, and differences in the median number of prostate biopsies and the detection rate of csPCa over the three periods were calculated using the Kruskal–Wallis test and chi-square test, respectively. The loess function depicted the relationship between changes in biopsies and diagnosis across all study periods. Specifically, in addition to measuring the expected reduction in prostate biopsies performed, we aimed to compare the pre-pandemic and post-COVID periods to assess whether the gradual resumption of full activities resulted in a delayed return to pre-pandemic biopsy numbers. All tests were two-sided; statistical significance was set at p < 0.05. All analyses were performed using Stata 14 (StataCorp LP, College Station, TX, USA).

3. Results

A total of 2502 patients underwent prostate biopsy between January 2018 and December 2022. The median (IQR) age of patients was 68 (62–74) years. Population characteristics are described in

Table 1. Histological characteristics of prostate biopsies performed in a cohort of 2502 patients between January 2018 and December 2022.

	N = 2502
Age, years	68 (62, 74)
Any PCa, n (%)
Absent	1055 (42.2%)
Present	1447 (57.8%)
csPCa, n (%)
Absent	1567 (62.6%)
Present	935 (37.4%)
ASAP, n (%)
Absent	2422 (96.8%)
Present	80 (3.2%)
PIN, n (%)
Absent	2412 (96.4%)
Present	90 (3.6%)
Glandular atrophy, n (%)
Absent	1499 (59.9%)
Present	1003 (40.1%)

Any PCa: any grade prostate cancer; csPCa: clinically significant prostate cancer; ASAP: Atypical Small Acinar Proliferation; PIN: Prostatic Intraepithelial Neoplasia.

.

PCa was detected in 1447 (57.8%) patients, including 935 (37.4%) with csPCa. Atypical Small Acinar Proliferation (ASAP) was found in 80 patients (3.2%), while at least one biopsy core with Prostatic Intraepithelial Neoplasia (PIN) was found in another 90 (3.6%) patients. Glandular atrophy was present in as many as 1003 patients (40.1%).

We observed a significant decrease in the number of biopsies performed during the COVID period when compared with the pre-COVID and post-COVID periods. Specifically, the median (IQR) number of biopsies performed per month was 46 (43–56), 39 (27–43) and 46 (40–58) before, during and after the pandemic, respectively (p = 0.02,

Table 2. Histological diagnoses from prostate biopsies performed in a cohort of 2502 patients between January 2018 and December 2022.

	Pre-COVID	COVID	Post-COVID	p Value
N of biopsy performed, per month, (IQR)	46 (43, 56)	39 (27, 43)	46 (40, 58)	0.022
N of Any PCa, (IQR)	26 (20, 32)	23 (16, 28)	30 (25, 33)	0.048
N of non-csPCa, (IQR)	8 (6, 10)	9 (7, 11)	10 (7, 11)	0.8
N of csPCa, (IQR)	18 (13, 21)	12 (8, 17)	20 (15, 23)	0.015
Cancer Detection Rates (%)	37 (32, 41)	34 (30, 38)	39 (36, 42)	0.091

Any PCa: any grade prostate cancer; csPCa: clinically significant prostate cancer.

).

The most significant decrease in the number of procedures performed was recorded from March to May 2020 (Figure 1).

The decrease in the number of biopsies performed resulted in a similar decrease in csPCa diagnosed per month (median n = 12), when compared with before (n = 18) and after (n = 20) the pandemic (p = 0.02). A similar trend was not observed for non-csPCa, since its detection rate was similar across the three periods (p-value = 0.8, Table 2). Notably, the highest csPCa detection rate was observed in the post-COVID period (39%) as compared to the COVID (34%) and pre-COVID period (37%), but this difference did not reach statistical significance (p = 0.1, Table 2). The loess function (Figure 1) depicted the relationship between changes in the number of biopsies performed and the PCa detection rate across the three periods. We observed a significant rebound effect on the number of biopsies performed and csPCa diagnosed in the post-COVID period, which was particularly evident from November 2020 onwards. A similar rebound was not observed for ncsPCa. The distribution of csPCa and ncsPCa diagnosis for each single month within the study period is reported in Figure 2.

4. Discussion

While it is well established that the COVID-19 pandemic led to delays in screening and treatment for various malignancies, including major urological cancers, our study aimed to precisely quantify the impact of delayed prostate biopsy on prostate cancer diagnosis. As expected, the COVID period was associated with a significant decrease in the number of biopsies performed when compared with the pre-COVID and post-COVID period. This reduction was particularly evident between March and May 2020, when the pandemic reached its peak in Italy. Interestingly, the decrease in the number of biopsies performed resulted in a decrease in the detection rate of csPCa but not in the detection rate of non-cs PCa, which remained stable across the three periods. This is of particular clinical relevance, as the delay in diagnosing csPCa may lead to disease progression, potentially affecting treatment outcomes and patient prognosis. By providing a more precise quantification of this impact, our study contributes valuable data to the ongoing discourse on how healthcare disruptions during the pandemic influenced prostate cancer detection.

A systematic review assessing the impact of COVID-19 on the screening and diagnosis of PCa [19] analyzed 40 studies and found that the majority of them reported a significant decrease in prostate-specific antigen (PSA) tests during the COVID-19 pandemic, when compared with the pre-pandemic period. This decline in screening led to a delay in cancer diagnosis. The decrease in PCa screening and diagnosis indeed varied widely across examined studies, ranging from nearly 0% to 78% for screening and from 4.1% to 71.7% for diagnosis. Similarly, a Dutch report [20] showed a significant decrease in PCa diagnosis during the first wave of the COVID-19 pandemic, with a subsequent recovery by the end of 2020, although there was still a shortfall of at least 5% in the expected diagnosis rate. Our study pointed out that the reduction in PCa diagnosis occurred for csPCa only, while the detection rate of non-csPCa surprisingly remained stable throughout all tested periods. Differently from the Dutch study, there was a rebound effect in the detection rate of csPCa in the post-COVID period; this finding was somehow expected as the consequence of the reduced number of prostate biopsies and csPCa diagnosis over the COVID period, suggesting a possible stage migration due to delayed diagnosis.

However, questions remain whether such findings have an impact on oncological outcomes [21]. While it is logical that delaying diagnosis and treatment may hamper the oncological outcome, a recent study [22] showed that the increased surgical wait time due to the COVID pandemic did not increase the risk of node-positive prostate cancer. It is, however, worth mentioning that this may be true for low-intermediate-risk PCa but may not apply to high-risk PCa. In the above-mentioned systematic review [19], the reduction in the cancer detection rate of low/intermediate-stage cancers during the COVID period was somewhat greater than that observed for cancers of advanced stages. We acknowledge that the lack of long-term oncological outcomes is a notable limitation of our study. However, we believe that a minimum follow-up of ten years is required to accurately evaluate even intermediate endpoints such as biochemical recurrence and metastasis. Given the relatively short timeframe of our study, drawing meaningful conclusions on oncological outcomes remains challenging, even if the follow-up was extended to the present.

Another relevant issue is the time between medical consultation and surgery for PCa. A recent study [23] comparing the COVID and pre-COVID periods pointed out that the COVID period was associated with a shorter time between biopsy and medical consultation (69.5 days vs. 114 days, p < 0.001), a longer time between medical consultation and surgery (124 vs. 107 days, p < 0.001), and a shorter overall time between biopsy and surgery (198.5 days vs. 228 days, p = 0.013). Most importantly, no difference in PCa features and oncological outcome was noticed.

Taken together, the above-mentioned studies depict a complex scenario marked by fluctuations in prostate cancer (PCa) diagnoses and changes in cancer grades and stages throughout the COVID-19 pandemic. While short-term data suggest that these disruptions have primarily affected PCa characteristics rather than oncological outcomes, questions remain regarding potential long-term effects. Further research is needed to address this issue, particularly to develop strategies that ensure the continuity of organized cancer screening, diagnosis and treatment during periods of crisis, minimizing disruptions to cancer detection and optimizing patient outcomes. To this end, we have launched a new pilot project on organizing prostate cancer screening. Under this initiative, patients undergo an initial PSA test and are referred for further investigations (MRI, urologic consultation) only when clinically necessary [24]. The primary objective of this project is to reduce the overtreatment and overdiagnosis of prostate cancer in our region while establishing a structured screening program that ensures no patient is left behind, even during future emergency situations. A strong point of our study is having the largest reported cohort of patients undergoing prostate biopsy around the onset of the COVID-19 pandemic. One potential limitation is not having addressed the oncological outcomes of our patients, but this was not the aim of the study and was not feasible with such a short follow-up.

5. Conclusions

The COVID-19 pandemic caused a significant decrease in the number of prostate biopsies performed and csPCa diagnosed in our center. While there was a rebound effect on csPCa diagnosis in the post-COVID period, the detection rate of non-csPCa remained stable throughout the pre-COVID, COVID and post-COVID periods. The potential effect of the observed grade migration on the burden of PCa treatment and oncological outcomes deserves further study. Meanwhile, reported data may be useful in case of periods of crisis.