Prostate cancer (PCa) is the most common solid malignancy, ranking third in cancer in 2017 with approximately 161,360 new diagnoses and 26,730 deaths in the United States.¹ The incidence of PCa has increased gradually in several Asian countries, and PCa has consistently become one of the main cancers of Asian people.² Likewise, in Korea, patients of PCa has steadily increased over the last 10 years.³

Prostate-specific antigen (PSA) is the most valuable serum marker used for the early detection and management of PCa.⁴ It is a noted fact that elevation of serum PSA levels and/or abnormal digital rectal examination findings are indications for prostate biopsy.⁵ Prostate biopsy is the reliable standard method to diagnose PCa.⁶ However, in many cases, an initial prostate biopsy is negative.⁷ Approximately more than 20% of patients are diagnosed with PCa upon a first biopsy; however, the remaining patients are followed clinically via regular of sampling serum PSA or performing a second prostate biopsy.⁸ Because the volume of prostate obtained during a biopsy is considerably little, these patients may have PCa, in spite of presenting negative results at the initial biopsy.⁹

There are no clear guidelines concerning to repeat prostate biopsy in men with negative results upon an initial biopsy. Indications for a second prostate biopsy includes consistently rising and/or stationary high PSA serum levels, abnormal digital rectal examination findings,⁶ atypical small acinar proliferation or prostatic intraepithelial neoplasia revealed upon initial prostate biopsy,⁵ or treatment strategies such as active surveillance of PCa.¹⁰ However, there are no fixed guidelines on when or whether to repeat prostate biopsies in patients with negative findings in the initial biopsy.¹¹

The preceding studies demonstrated when repeating a prostate biopsy, the diagnosed PCa is less seem to be of high grade.^12,13 Furthermore, other studies have suggested that a patient who undergoes radical prostatectomy after repeat biopsy harbors PCa which is associated with better pathological outcomes.^14,15 However, to date, there have been few studies concerning the relationship between the number of prostate biopsies and perioperative complications or biochemical recurrence (BCR) after radical prostatectomy.

Therefore, we analyzed whether repeated prostate biopsies before radical prostatectomy were related to different perioperative complications or oncologic and pathological outcomes. In particular, we presumed that 2nd or more repeated prostate biopsies would be related to better oncologic and pathological outcomes, but perioperative outcomes were worse.

Among 1,112 patients, 1,046 patients (94.1%) did 1st biopsy and only 66 (5.9%) did 2nd or more repeated biopsies. Perioperative characteristics and pathologic outcomes according to the number of prior biopsies are shown in Table 1. The mean age was 66.6±6.3 years, and the mean BMI was 24.2±2.8 kg/m²; there were no significant differences between the 2 groups (p=0.144 and p=0.897, respectively). Preoperative PSA levels in the "1st biopsy" group were 11.8±10.7 ng/mL, and in the "2nd or more repeated biopsies" group was 12.0±7.5 ng/mL, but there was no significant difference (p=0.883). There were no significant differences in the D'Amico classification (low versus inter-mediate versus high), surgical technique (open versus laparoscopic versus robot-assisted), or presence of lymphovascular invasion (LVI) between the 2 groups (p=0.058, p=0.451, and p=0.614, respectively). However, the "2nd or more repeated biopsies" group exhibited more localized pathologic T stage cancers and this was statistically significant (p=0.003). Furthermore, the "2nd or more repeated biopsies" group exhibited lower Gleason scores and lower rates of positive surgical margins, both being statistically significant (p=0.002 and p=0.001, respectively).

There were no significant differences in estimated blood loss volumes, operation times, hospital stays, and time to removal of urethral catheter between the 2 groups (all p＞0.05). There were no significant differences in the rates of Clavien-Dindo complications between the 2 groups (p＞0.05). The mean follow-up period (at least more than 12 months) was 43.2±18.6 months and overall BCR rate was 19.0%. There were no significant differences in BCR rates between the 2 groups (19.2% vs. 15.2%, p=0.414) according to univariate analysis.

According to multivariable Cox regression analyses, the significant risk factors for predicting BCR after radical prostatectomy were pathologic T stage, Gleason score, presence of LVI, and positive surgical margins (all p<0.05) (Table 2). However, the Cox proportional hazards model indicated that there was no association between the number of prior prostate biopsies and BCR (p=0.210).

To minimize confounding, positive surgical margin (PSM) analysis was performed to compare the 1st biopsy and 2nd or more repeated biopsies groups in 66 matched pairs. Likewise, there were no significant differences in estimated blood loss volumes, operation times, hospital stays, and time to removal of urethral catheter between the 2 groups after PSM analysis (all p＞0.05) (Table 3).

Kaplan-Meier curve analysis indicated that BCR-free survival rates between the 2 groups were similar (p=0.711) (Fig. 1).

In the United States, more than 160,000 transrectal ultrasound (TRUS) guided prostate biopsies are performed each year.¹⁶ Prostate biopsy is uncomfortable, invasive for patients, and there are many related complications, including very low percent ratio of sepsis.¹⁷ Standard procedure, TRUS guided biopsy is not lesion-targeted and cause frequent false-negative results with samples less than 1% of the prostate gland.¹⁸ Although the application of a randomized prostate biopsy as a standard method of the biopsy for PCa significantly improves the accuracy of diagnosis, but just 20-30% of PCa lesions are detected during an initial biopsy; the rest is clinically followed and may require repeated biopsies.^8,19 It is not easily understood why an initial prostate biopsy results may be negative for prostate with cancer, but several factors such as unskillful urologist to target the prostate and the spatial distribution, multifocal and size of carcinoma foci may provide some explanation.²⁰

To date, there are no definite guidelines about when or whether performing a second prostate biopsy in suspected patients to harbor PCa clinically, but who present negative findings upon an initial biopsy. Therefore, it is important to understand the clinical significance of PCa detected upon repeat biopsy when counseling patients who were not diagnosed with cancer upon the initial prostate biopsy.

In 2016, Elshafei et al.²¹ demonstrated a lower risk of pathological outcome after radical prostatectomy in men diagnosed with a favorable risk PCa when repeating a prostate biopsy than men who were diagnosed with initial prostate biopsy. They divided 422 patients who met the National Comprehensive Cancer Network's "very low-risk" (n=199) and "low-risk" (n=223) PCa definitions and who underwent radical prostatectomy. They found that compared with repeating prostate biopsies, patient diagnosed with an initial prostate biopsy displayed higher Gleason scores (≥7) (57.7% vs. 42.1%, p=0.005) and extraprostatic extension (14.1% vs. 5.4%, p=0.01). However, they did not analyze whether there were any associations between biopsy session and perioperative complications.

More recently, in 2017, Rosenbaum et al.⁶ retrospectively analyzed the medical records about 12,624 patients who had radical prostatectomy from 2007 to 2013. According to this study, 10.8% underwent 2nd or more repeated sessions of prostate biopsy. With a median follow-up of 36.6 months, multiple prostate biopsy groups more often presented with organ-confined tumors and more favorable perioperative complication rates (p<0.05). Gleason scores and status of surgical margin were not different. They concluded that the overall BCR rate was 18.9% and it could be comparable among the groups. There is no association between the number of prostate biopsies and BCR.

In our study, 2nd or more repeated prostate biopsies were not related to adverse pathologic results in Korean patients and the number of biopsy sessions did not reveal any negative effects on BCR or perioperative complications. In 2001, Djavan et al.¹² demonstrated that patients undergoing repeated biopsies more tend to have organ-confined disease during radical prostatectomy. At least 10% of patients with negative prostate biopsy were diagnosed with PCa during repeated biopsies. Although there were differences in location and multifocality, they concluded that the pathological and biochemical characteristics of cancers detected upon initial and repeated biopsies were similar, suggesting similar biological behaviors; thus, advocating repeated prostate biopsies in cases of negative findings upon an initial biopsy. A comparable study was also reported in 2006. Lopez-Corona et al.¹⁴ retrospectively reviewed 1,357 patients performed with retropubic radical prostatectomy between 1983 and 2001. PCa was diagnosed in 1,042 patients (77%) during the first biopsy, in 227 (17%) upon second biopsy, in 59 (4%) upon third biopsy, and in 29 (2%) upon fourth or later biopsy. Patients who underwent 2nd or more repeated biopsies revealed a higher proportion of clinical T1c-stage cancer (p<0.0001). They found that despite these more favorable pathological results, there were no differences in BCR rates. Other 2 similar studies exist that support these results.^15,22 In 2012, Kopp et al.¹⁵ retrospectively analyzed 2,739 men with PCa who underwent radical prostatectomy enrolled in the SEARCH database. Multiple prostate biopsies are not associated with BCR. Another study performed by Park et al.²² in 2012, patients diagnosed as PCa after repeat biopsy showed more favorable pathologic outcomes after radical prostatectomy (initial biopsy group [n=637] vs. repeat biopsy group [n=63]).

The present study has some limitations. First, it is a retrospective design. Second, the number of patients who underwent 2nd or more repeated biopsies is too small a number (n=66). Heterogeneous groups of patients, no single surgeon and variable surgical techniques are also limitation. Third, this study did not evaluate whether the gap between the biopsy and the radical prostatectomy affected the perioperative results. In 2014, Park et al.²³ showed that biop-sy-to-surgery interval did not affect positive surgical margin status, operative time, or estimated blood loss in radical prostatectomy. Fourth, we could not gather the exact number of prostate biopsy cores from the other centers. In 2017, Carneiro et al.²⁴ demonstrated that a greater number of transrectal ultrasound-guided prostate biopsy cores were shown to be related to higher blood loss volumes and perioperative complications during radical prostatectomy. They included a total of 1,042 patients in group 1 (≤12 cores) and 1,012 patients in group 2 (＞12 cores). The incidence of perioperative complications increased with the number of biopsies (group 1, 6.4% vs. group 2, 8.5%; p=0.03). Multivariable logistic regression analysis indicated that group 2 presented with a 39% higher rate of experiencing perioperative complications during robot-assisted radical prostatectomy. In our study, it was impossible to analyze whether the number of biopsy cores influenced perioperative complications. It is the same for mean prostate volume and tumor volume, for which we could not collect the pathologic reports from other centers. Therefore, large-scale, prospective studies are needed in the future.

Repeated prostate biopsies are not related to a rising risk of perioperative complications, adverse outcomes of pathology, or higher rates of BCR in men who have undergone radical prostatectomy.

The authors claim no conflicts of interest.