Prostate cancer is the most common malignancy among men in the Organization for Economic Co-operation and Development countries and the second most common malignancy worldwide.^1,2 According to GLOBOCAN data, there were 1,276,106 new prostate cancer cases and 358,989 prostate-cancer-related deaths in 2018, and the number of newly diagnosed cases is expected to double by 2040 (2,293,818); however, mortality is predicted to increase by 1.05%.³ In South Korea, the incidence of prostate cancer continues to increase, but the recent mortality rate has decreased rapidly.⁴ Since Billroth first performed radical perineal prostatectomy in 1867, the surgical technique has undergone several developments to robotic-assisted radical prostatectomy.⁵ In addition to radiation therapy, which has improved survival rates through the development of equipment and combination with hormonal therapy, the development of new drugs, such as androgen signaling target drugs and chemotherapeutic agents, continues to reduce mortality rates associated with single and combined therapy. To facilitate early diagnosis and to avoid unnecessary prostate biopsies, multiparametric magnetic resonance imaging (mpMRI) using a Prostate Imaging-Reporting and Data System (PI-RADS)⁶ and biomarkers such as free prostate-specific antigen (PSA), total/free PSA ratio and 4Kscore,⁷ prostate health index,⁸ and PCA3 (prostate cancer antigen 3)⁹ may be used to diagnose prostate cancer. The developed techniques of surgery, medicine, and diagnostic tools could help to reduce mortality of prostate cancer.

Recently, artificial intelligence technology and machine learning methods have been applied to analyze large amounts of data the medical field, and their adequacy and usefulness in diagnosis are increasing.¹⁰ Analysis using a combination of machine learning methods and mammograms has led to an accurate diagnosis of breast cancer,¹¹ and an automatic grading system has been applied to determine the Gleason grade of prostate cancer using histopathological images.¹² To our knowledge, there have been no studies to evaluate the prediction rate of prostate cancer using machine learning methods in Korea until now. Thus, in this study, we evaluated the applicability of machine learning methods that combine data on age and PSA levels in predicting prostate cancer.

This study was approved by the Ethics Committee of Chungnam National University Hospital (#2018-12-055). We analyzed 1,300 patients who underwent transrectal ultra-sonography (TRUS)-guided prostate biopsy at Chungnam National University Hospital between 2014 and 2018 because of elevated PSA levels and/or abnormal digital rectal examination and/or TRUS findings. Prostate biopsies were performed as outpatient procedures. All patients underwent a 12-core TRUS-guided conventional systematic biopsy with the 18-gauge biopsy needle using Flex Focus 400 ultrasound equipment with a 5-10 MHz bi-convex probe (BK medical, Peabody, MA, USA).

We retrospectively reviewed the patients' medical records for underlying diseases such as diabetes, hypertension, and cardiovascular disease as well as their laboratory findings such as white blood cell (WBC) count and hemoglobin, albumin, alkaline phosphatase, and serum PSA levels, and 943 patients were included in the study on the basis of feature importances and analytic factors. On the basis of pathologic confirmation, the patients were divided into 2 groups, namely, the prostate cancer group (n=394) and the nonprostate cancer group (n=549), which had benign prostate tissue, prostate hypertrophy, inflammation of the prostate, prostate atrophy, and atypical cells, etc.

Thereafter, we analyzed the prediction rate of prostate cancer and identified 20 feature importances that could be compared with biopsy results using 5 different algorithms: logistic regression (LR),¹³ support vector machine (SVM),¹⁴ random forest (RF),¹⁵ extreme gradient boosting (XGB),¹⁶ and light gradient boosting machine (LGBM).¹⁷ While classical LR is one of the most common utilized linear statistical models for discriminant analysis and for clinical classification and regression problems, we expect that these machine learning algorithms may perform better than LR, which is based on generalized linear regression. SVM is much more geometrically motivated by finding the optimal hyperplane between target classes. We expect SVM to perform marginally better than LR. Conversely, the tree-based machine learning algorithms are the state of the art for structured data. In this manner, we applied RF, XGB, and LGBM. Compared to other machine learning methods, tree-based methods provide interpretation of the results via feature importance scores, which is the advantage of these methods that is corroborated by our results. For all machine learning prediction models, 80% of the randomly chosen samples of data (same data set for each algorithms) were used for training, the remaining 20% were used as a test set. The predicting models were trained the data set combined with augmented samples generated by synthetic minority oversampling technique (SMOTE). Unlike random over sampling, SMOTE used inter-polation to create new observations near existing observations of the minority class. To prevent outliers from shrinking the decision boundary between 2 classes, we used outlier rejection of K=2 nearest neighbors. The performance of the predictive models was evaluated through an average of 20 samplings to prevent biased prediction and overfitting. When establishing the predictive model, typically, hyper-parameters for each algorithm were adopted for the classifications. The characteristics of the patients in the prostate cancer group and nonprostate cancer group were compared using Pearson chi-square test for categorical variables and Student t-test for continuous variables in IBM SPSS Statistics ver. 21.0 (IBM Co., Armonk, NY, USA).

Of the 943 patients, 394 (41.8%) were diagnosed with prostate cancer, and the mean age (69.7±6.8 years), WBC (6,899.3±1,834.1/ L), PSA (20.6±20.2 ng/mL), PSA density (0.64±0.66 ng/mL/cm³) and PZPSAD (0.93±0.97 ng/mL/cm³) of the prostate cancer group were significantly higher than those (mean age, 67.0±6.4 years; WBC, 6,650.7±1,785.8/ L; PSA, 8.8±8.1 ng/mL; PSA density, 0.38±0.32 ng/mL/cm³; and PZPSAD, 0.38±0.32 ng/mL/cm³) of the nonprostate cancer group (p＜0.05). Hemoglobin (14.2±1.5 g/dL), albumin (4.1±0.3 g/dL), prostate volume (36.0±15.7 cm³), prostate transitional volume (12.2±9.1 cm³), prostate peripheral volume (23.7±8.6 cm³), and biopsy counts (1.1±0.4) in the prostate cancer group were significantly lower than those (hemoglobin, 14.5±1.2 g/dL; albumin, 4.2±0.3 g/dL; prostate volume, 48.3±20.6 cm³; prostate transitional volume, 20.0±14.0 cm³), prostate peripheral volume (28.3±9.5 cm³), and biopsy counts (1.3±0.6) of the nonprostate cancer group (p＜0.05); however, there was no difference in the incidence of underlying diseases, such as diabetes, hypertension, and cardiovascular disease, between the 2 groups (Table 1).

The prediction rates for prostate cancer, according to age and PSA level, using various machine learning methods were as follows (median detection rate [minimum to maximum]): SVM, 69.2% (43.8%-78.3%); RF, 72.1% (65.0%-81.2%); XGB, 68.6% (55.0%-78.3%); LGBM, 68.3% (61.4%-81.2%); and LR, 67.1% (50.0%-75.4%). In 8 out of 9 groups, except in patients older than 75 years and with a PSA level of 2.5-10 ng/mL, the best prediction model for prostate cancer detection was the machine learning method. Among patients older than 75 years and with a PSA level less than 10 ng/mL, LR showed the best prediction rate (74.6%). In patients with a PSA level of 10-20 ng/mL or the 65- to 74-year age group, the best prediction model for prostate cancer detection was RF among the machine learning methods compared with LR analysis (Fig. 1).

The feature importances that affected the detection rate of prostate cancer were analyzed using the best machine learning method. SVM is a statistical-based machine learning method, and it cannot derive the feature importances influencing the detection rate analysis, so we used the 2nd ranked tree-based machine learning algorithms to identify feature importances. PSA density was highest scored feature importance in patients younger than 75 years and with a PSA level less than 20 ng/mL. Aspartate aminotransferase (AST) and alanine amino-transferase (ALT) levels were identified as feature importances in patients with aged less than 65 years and with a PSA level of 20-100 ng/mL. However, in patients older than 75 years, the feature importances were different. Among them, transitional zone volume was the highest scored feature importance in patients with a PSA level less than 10.0 ng/mL (Fig. 2).

The incidence and mortality rates of prostate cancer were higher in Western society than in Eastern society.¹⁸ Recently, it was reported that in South Korea, prostate cancer has a tendency to be expressed in patients in their 50s, similar to that in Western society.⁴ Prostate cancer is the most frequent cancer in men, and most cases are diagnosed at an age of approximately 66 years. Of the patients diagnosed with prostate cancer, 69% die at an age older than 75 years.¹⁹ Therefore, if prostate biopsy is performed considering the factors and feature importances that influence the detection rate of prostate cancer according to age, the detection rate of prostate cancer can be increased and the complications of prostate biopsy and un-necessary prostate biopsy, reduced, especially in elderly patients. Takeuchi et al.²⁰ reported that the prediction rate for prostate cancer improved by about 5%-10% when using a multilayer artificial neural network compared with LR analysis in 334 patients who underwent 3.0T mpMRI before TRUS-guided prostate biopsy. In this study, various machine learning methods were used to calculate the prediction rate for prostate cancer compared with conventional LR analysis. In patients aged over 75 years and with a PSA level of 2.5-10 ng/mL, LR analysis showed the best prediction rate (74.6%); however, machine learning methods were better than LR analysis in other patient groups. In particular, RF (prediction rate, 70.5%-72.4%) was the better than LR analysis (prediction rate, 65.6%-70.0%) in patients aged 65-74 years (Fig. 1). In South Korea, it is difficult to apply mpMRI owing to several cost issues and insurance coverage; however, we believe that it is best to apply mpMRI using the PI-RADS for the detection of prostate cancer. In this study, we also analyzed the feature importances influencing the prediction rate of prostate cancer in each patient group. PSA density was the highest scored feature importance in patients aged below 75 years and with a PSA level less than 20 ng/mL (Fig. 2). Several reports have shown that PSA density is one of the most important predictors of the detection of prostate cancer.^21,22 Sfoungaristos and Perimenis²³ reported that PSA density was a better predictor than the PSA level and Gleason score for poor pathologic prognostic factors such as a positive surgical margin, extracapsular disease, seminal vesicle involvement, and lymph node involvement. In our study, several feature importances that were less related to prostate cancer, such as AST and ALT levels and glomerular filter rate, were assessed in patients with aged below 65 years and with a PSA level of 20-100 ng/mL because of the small sample size of only 35 patients and the high detection rate of prostate cancer (26 patients, 74.3%) in patients in this group. However, in patients older than 75 years, the feature importances were different. Among them, transitional zone volume was the most feature importance in patients with a PSA level less than 10.0 ng/mL. It must be considered that benign prostatic hyperplasia influenced the elevation of PSA in this age group. In patients older than 75 years and a PSA level greater than 20.0 ng/mL, the most feature importance was a previous prostate biopsy history, and the detection rate for prostate cancer was 72.1%. It seems that the indication for biopsy was highly restricted, and biopsy was performed whenever necessary in this group. Hamilton et al.²⁴ studied the types of treatments chosen for patients with moderate-to-high-risk prostate cancer. Of the patients aged less than 75 years, 88.3% were treated with the aim of complete cure, but only 40.7% of the patients aged 75 years or older in the same risk group wanted to be treated with intent for cure. This implies that patients belonging to relatively older age groups choose curative treatment at a lower rate. In addition, the International Society of Geriatric Oncology recommended that patients aged 70 years or older with prostate cancer be managed with appropriate treatments after considering their health status, comorbidity, and cognitive function, and conservative or palliative managements be considered if the patients belonged to group 3 or 4 on geriatric screening using Geriatric 8 or mini-COG.¹⁹ Therefore, in most patients with a PSA level greater than 10-ng/mL prostate biopsy should be performed. However, as is known, it is associated with a smaller benefit to surgical treatment over active surveillance in patients over 75 years of age and in those with poor health status.²⁵ In terms of the minor benefits of cancer specific mortality and life expectancy, determining the feature importances that influence the prediction rate of prostate cancer may help to avoid unnecessary biopsy in patients of the older age groups, and it may be more persuasive for younger patient group.

We recognize that our present study has several limitations. This study is retrospective and evaluated outcomes for a relatively small number of patients. Additional randomized, prospective multicenter studies are needed to confirm our data. Furthermore, as medical records were sparse and the number of patients in each group were small, it was difficult to ensure sufficient training for machine learning. And the application of mpMRI using the PI-RADS may improve the prediction rate. Considering the low cancer-specific mortality in low-risk prostate cancer, further research is needed to predict clinically significant disease. Gleason score and TNM staging should be included in future studies for unfavorable prostate cancer.

In the future, using prostate MRI combined with artificial intelligence or a variety of newly developed biomarkers will markedly improve the diagnosis rate of prostate cancer and allow direct diagnosis of prostate cancer without a prostate biopsy. In the current scenario, this study will be useful in determining the requirement for prostate biopsy by considering the feature importances according to age and PSA levels for the prediction of prostate cancer.