Transrectal Ultrasound

Number: 0001

(Replaces CPB 286)

Policy

Aetna considers transrectal ultrasound (TRUS) medically necessary for any of the specific conditions involving the prostate, rectum and surrounding tissues listed below:
1. For prostate biopsy in men, see CPB 0698 - Prostate Saturation Biopsy; or
2. Assessment of anal sphincter dysfunction; or
3. Clinical staging of a member with prostate cancer; or
4. Clinical staging of a member with rectal carcinoma; or
5. Determining volume of the prostate prior to brachytherapy; or
6. Evaluation of anal and/or rectal fistula; or
7. Evaluation of anal and/or rectal peri-rectal abscesses; or
8. Evaluation of hematospermia (hemospermia), to distinguish idiopathic from secondary causes; or
9. Evaluation of malignant or benign peri-rectal tumors; or
10. Evaluation of members who have had definitive treatment for carcinoma of the rectum where recurrent disease is noted; or
11. Infertility and azoospermia where an ejaculatory duct cyst is suspected. (Note: Some benefit plans exclude coverage of infertility services. Please check benefit plan descriptions for details); or
12. Metastatic lesions of unknown source, with a high PSA level (PSA greater than 10 ng/ml), which could have their origin in the prostate.
Aetna considers TRUS experimental and investigational as a screening test for prostate disease and for all other indications because peer-reviewed medical literature does not support its use for these indications.
Aetna considers TRUS elastography (sono-elastography or shear-wave elastography) experimental and investigational for the evaluation of prostate cancer because its effectiveness has not been established.
Aetna considers intraoperative magnetic resonance imaging/ultrasound fusion optimization for low-dose-rate prostate brachytherapy experimental and investigational because the effectiveness of this approach has not been established.
Aetna considers photoacoustic imaging for prostate cancer angiogenesis experimental and investigational because the effectiveness of this approach has not been established.
Aetna considers positron emission tomography (PET) image-directed, three-dimensional ultrasound-guided prostate biopsy experimental and investigational because the effectiveness of this approach has not been established.
Aetna considers biplane TRUS combined with ultrasonic elastosonography plus contrast-enhanced ultrasound experimental and investigational for staging of rectal cancer because the effectiveness of this approach has not been established.

Background

Prostate cancer is the most common cause of cancer and the second most common cause of cancer deaths in men in the United States. Prostatic carcinoma generally is slowly progressive and may cause no symptoms. Approximately 50 % of patients with carcinoma of the prostate have either advanced local disease or metastases at the time of diagnosis. This emphasizes the need to detect those patients with potentially curable carcinoma of the prostate at a localized pathologic state. With the development of prostatic ultrasonographic technology, urologists have gained a tool that allows better visualization, more accurate biopsy and earlier detection of carcinoma of the prostate.

Carcinoma of the prostate should be suspected on the basis of abnormal digital rectal findings, hypoechoic lesions on transrectal ultrasound (TRUS), or elevated levels of prostate-specific antigen (PSA). However, diagnosis requires histologic confirmation, most commonly by TRUS-guided transrectal needle biopsy, which can be done without anesthesia. The advent of TRUS-guided biopsies of the prostate, as opposed to blind finger-guided biopsies, has increased the detection rate of prostate cancer when performed in the presence of an abnormal digital rectal examination (DRE) or with an elevation of PSA above 10 ng/ml.

Among several treatment options available, transperineal prostate brachytherapy has evolved as a medically successful, cost-effective outpatient procedure for treating localized prostate cancer. Transperineal prostate brachytherapy utilizes TRUS as the primary imaging procedure to accurately plan and execute the placement of radioactive seeds into the prostate.

There is insufficient information in the published medical literature to support the use of TRUS alone as a screening tool for prostate cancer; however, TRUS can reduce the number of missed cancers in patients with signs or symptoms that may be related to prostate cancer.

In the pre-operative staging of rectal cancer, TRUS is the most accurate imaging modality. It is possible to evaluate the layers of the rectal wall, the depth of tumor penetration and the peri-rectal lymph nodes. TRUS is 85 to 95 % accurate in determining bowel wall penetration and 70 to 80 % accurate in identifying lymph node involvement. The accuracy of the findings, as with all ultrasound examinations, depends on the operator.

Obstructive azoospermia represents approximately 10 % of male hypofertility cases. Cystic lesions of the prostate involving the ejaculatory duct are uncommon in healthy, fertile men; their prevalence increases in infertile men whose examination and semen analyses make them “at risk” for having ductal obstruction. TRUS accurately visualizes abnormalities of the caudal junction of the vas deferens and seminal vesicles, providing a definitive diagnosis without scrototomy.

Transrectal ultrasound is a useful clinical tool for specific conditions involving the prostate, rectum and surrounding tissues. It is less expensive than computed tomography (CT) or magnetic resonance imaging (MRI); the equipment is more mobile, and the procedure can be performed more quickly. Finally, TRUS is well-tolerated by patients, and involves no radiation exposure.

Transrectal ultrasound is the imaging procedure of choice for patients with hematospermia. Polito et al (2006) stated that the presence of blood in ejaculate represents 1 % of all andrological and urological symptoms. In most cases it has a benign character and tends to regress spontaneously after the first episode. But in the same case it can be caused by bladder-prostate or systemic malignant pathology, so it is necessary to subject the patient to laboratory and instrumental tests in order to find the best treatment that, as for hematospermia, is an etiological one. Most important for correct diagnosis are patient history, physical examination, laboratory tests, TRUS examination of the prostate, MRI, CT, cystoscopy. Hematospermia is rarely associated with significant pathology, especially in younger men. The three factors that dictate the extent of the evaluation and treatment are age of patient, the duration and recurrence of the hematospermia, and the presence of any associated hematuria. Thus, it is possible to distinguish idiopathic from secondary hematospermia, because secondary hematospermia, namely, the one in which the bleeding cause is known or suspected, requires an etiologic treatment. Understanding the pathophysiology and prevalence in populations of different ages helps minimize the likelihood of problems. When in doubt, performing a TRUS, cystoscopy, and basic laboratory analyses limits exposure. Also, Zhang et al (2003) reported that TRUS-guided transperineal aspiration of seminal vesicle fluid was helpful to the etiologic diagnosis of persistent hematospermia. Furthermore, Yagci et al (2004) noted that TRUS is a safe, non-invasive method for examining causes of hematospermia. These researchers believed that it should be the first radiological investigation to be performed in patients presenting with hematospermia.

Tissue elasticity has been employed as a qualitative biomarker for prostate cancer and sono-elastography is an emerging imaging tool for providing qualitative as well as quantitative measurements of prostate tissue stiffness. Hoyt and associates (2008) reported that elasticity images obtained with quantitative sono-elastography agree with mechanical testing and histological results. They stated that sono-elastography is a promising biomarker for prostate cancer.

Although elastography is a pormising method, prospective studies are needed to define its applications. Janssen (2008) stated that (endo)sonographic real-time elastography is a new method to describe the mechanical properties of tissue. Similar to color-flow Doppler ultrasonography, a region of interest is defined. The relative stiffness of the tissues within this area is described by colors superimposing on the B-mode image. Real-time elastography can be performed with linear scanners for transcutaneous use, rigid endocavitary probes and with flexible echoendoscopes. The probes can be used to compress the tissue. The elasticity modulus is calculated from the resulting deformation of the tissue. In endoscopic ultrasound, arterial and cardiac pulsations or respiratory movements cause the deformation of the tissue that is used for the calculation. The author concluded that (endo)sonographic real-time elastography is a promising new method. Nevertheless, prospective studies are needed to define useful applications and the clinical significance of the method.

There is emerging evidence to suggest that elastography has the potential to increase ultrasound-based prostate cancer detection. Salomon et al (2008) noted that conventional gray scale ultrasound has a low sensitivity and specificity for prostate cancer detection. These researchers determined sensitivity and specificity for prostate cancer detection with ultrasound-based real-time elastography in patients scheduled for radical prostatectomy (RP). A total of 109 patients with biopsy-proven localized prostate cancer (PCa) underwent elastography before RP. The investigator was blinded to clinical data. A EUB-6500HV ultrasound system with a V53W 7.5 MHz end-fire transrectal probe was used pre-operatively. Areas found to be suspicious for PCa were recorded for left and right side of the apex, mid-gland, and base. These findings were correlated with the obtained whole-mount sections after RP. Sensitivity and specificity for detecting PCa were 75.4 % and 76.6 %, respectively. A total of 439 suspicious areas in elastography were recorded, and 451 cancerous areas were found in the RP specimens. Positive predictive value, negative predictive value, and accuracy for elastography were 87.8 %, 59 %, and 76 %, respectively. Nevertheless, there are limitations to these findings because these researchers investigated specific patients scheduled for RP with apparent PCa. Whether elastography is practical as a diagnostic tool or can be used to target a biopsy and be at least as sensitive in tumor detection as extended biopsy schemes has yet to be determined. The authors concluded that elastography can detect prostate cancer foci within the prostate with good accuracy and has potential to increase ultrasound-based PCa detection. They stated that further studies are needed to validate these data and to assess if tumor detection can be increased by elastography-guided biopsies.

However, there is other evidence to suggest that elastography does not improve cancer detection rates. Eggert and colleagues (2008) found that elastography-guided prostate biopsies did not improve cancer detection in men with suspected prostate cancer. A total of 351 prospectively randomized patients underwent prostate biopsies for the first time. The indication for biopsy was abnormal DRE in 25 % or suspicious PSA elevation in 75 %. In the elastography group (n = 189) and the control group (n = 162), these researchers assessed PSA, DRE, and B-mode TRUS. Both groups underwent classic TRUS-guided 10-core biopsy. Patients in the elastography group underwent additional elastographic examination prior to biopsy using a Voluson 730 ultrasound system. According to the ultrasound or elastographic findings for each biopsy location, the researcher tried to predict whether cancer was present. This prediction was correlated with histopathological findings. The statistical power of this study was sufficient to detect a 15 % difference in detection rate. The study groups did not differ in PSA, clinical stages, or prostate volume (p < 0.05). The overall cancer detection rate was 39 % (137/351): 40.2 % (76/189) in the elastography group and 37.7 % (61/189) in the control group, respectively. The difference in detection rate in clinical stages T2 and T3 between the elastography and the control groups was not statistically significant (p < 0.05). Within the T1c subgroup, elastography showed a slightly higher detection rate of 55.6 % versus 50 % without reaching statistical significance (p > 0.05). Histopathological findings were adequately predicted by elastography in only 44.5 %. The authors concluded that elastography did not improve the cancer detection rate in this cohort of patients.

In a review on the value of real-time elastography in the diagnosis of prostate cancer, Salomon et al (2009) stated that randomized biopsy sampling under TRUS guidance is the gold standard for the diagnosis of prostate cancer. In addition, improvements in the quality of conventional ultrasound, new methods that complement conventional TRUS are opening the door to earlier and better targeted diagnosis of prostate cancer. One of these new methods is sono-elastography. However, its impact on prostate cancer diagnostics has not yet been fully investigated.

Elastography is among a number of new technologies under development for improvement in prostate cancer detection. Trabulsi et al (2010) stated that standard grayscale TRUS has a poor sensitivity for detection of prostate cancer. Saturation biopsy schemes have improved prostate cancer detection rates over standard template biopsy schemes, but carry additional morbidity and cost. Enhanced ultrasound modalities (EUM), including color and power Doppler, contrast-enhancement, harmonic and flash replenishment imaging, as well as elastography have the potential to improve prostate cancer detection. Enhanced ultrasound modalities targeting areas with increased or abnormal vascularity or firmness for biopsy offer improved prostate cancer detection. These new approaches detect prostate cancer more efficiently than standard ultrasound guided biopsies. The authors concluded that these emerging technologies may potentially augment standard prostate biopsy in clinical practice.

Eggert et al (2010) noted that previous studies investigated the clinical impact of elastography for pre-operative staging and as an additional imaging modality to improve prostate cancer detection during prostate biopsy. This rapidly improving technique has facilitated progress toward feasibility and reproducibility of transrectal elastography. Recent studies show significant improvements using the latest generation of elastographic devices. Moreover, the authors stated that further studies are needed to evaluate on the one hand elastography-guided prostate biopsy schemes and results of saturation biopsies; and on the other hand to compare sensitivity and specificity of elastographic detection of prostate cancer with different imaging techniques, especially MRI and spectroscopy.

Aboumarzouk et al (2012) synthesized published data of transrectal elastosonography (TRES) using diagnostic review methodology. Transrectal elastosonography increases prostate cancer detection as compared with grey-scale US. Also, the study highlighted limitations and strengths of data in this area and included recommendations for future research. Two reviewers independently extracted the data from each study. Quality was assessed with a validated quality assessment tool for diagnostic accuracy studies. Diagnostic accuracy of TRES in relation to current standard references (TRUS biopsies and histopathology of RP specimens) was estimated. A bi-variate random effects model was used to obtain sensitivity and specificity values. Hierarchical summary receiver operating characteristic (HSROC) were calculated. In all, 16 studies (2,278 patients) were included in the review. Using histopathology of the RP specimen as reference standard, the pooled data of 4 studies showed that the sensitivity of TRES ranged between 0.71 to 0.82 and the specificity ranged between 0.60 to 0.95 (pooled diagnostic odds ratio [DOR] 19.6; 95 % confidence interval [CI]: 7.7 to 50.03). The sensitivity varied from 0.26 to 0.87 and specificity varied from 0.17 to 0.76 (pooled DOR 2.141; 95 % CI: 0.525 to -8.737) using TRUS biopsies (minimum of 10) as a reference standard. The quality of most studies was modest. SROC estimated 0.8653 area under the curve predicting high chances of detecting prostate cancer. There were no health economics or health-related quality of life of the participants reported in the studies and all the studies used compressional technique with no reported standardisation. The TRES technique appears to improve the detection of prostate cancer compared with systematic biopsy and shows a good accuracy in comparison with histopathology of the RP specimen. However, the authors noted that studies lacked standardization of the technique, had poor quality of reporting and a large variation in the outcomes based on the reference standards and techniques used.

Pummer et al (2014) performed a Medline literature search of the time frame between 01/2007 and 06/2013 on imaging of localized PCa. Conventional TRUS is mainly used to guide prostate biopsy. Contrast-enhanced ultrasound is based on the assumption that PCa tissue is hyper-vascularized and might be better identified after intravenous injection of a microbubble contrast agent. However, results on its additional value for cancer detection are controversial. Computer-based analysis of the TRUS signal (C-TRUS) appears to detect cancer in a high rate of patients with previous biopsies. Real-time elastography seems to have higher sensitivity, specificity, and positive-predictive value than conventional TRUS. However, the method still awaits prospective validation. The same is true for prostate histo-scanning, an ultrasound-based method for tissue characterization. Currently, multi-parametric MRI provides improved tissue visualization of the prostate, which may be helpful in the diagnosis and targeting of prostate lesions. However, most published series are small and suffer from variations in indication, methodology, quality, interpretation, and reporting. The authors concluded that among ultrasound-based techniques, real-time elastography and C-TRUS seem the most promising techniques. Multi-parametric MRI appears to have advantages over conventional T2-weighted MRI in the detection of PCa. Moreover, they stated that despite these promising results, currently, no recommendation for the routine use of these novel imaging techniques can be made; prospective studies defining the value of various imaging modalities are urgently needed.

Penzkofer and Tempany-Afdhal (2014) stated that the primary role of imaging for the detection and diagnosis of PCa has been TRUS guidance during biopsy. Traditionally, MRI has been used primarily for the staging of disease in men with biopsy-proven cancer. It has a well-established role in the detection of T3 disease, planning of radiation therapy, especially 3-D conformal or intensity-modulated external beam radiation therapy, and planning and guiding of interstitial seed implant or brachytherapy. New advances have now established that prostate MRI can accurately characterize focal lesions within the gland, an ability that has led to new opportunities for improved cancer detection and guidance for biopsy. Two new approaches to prostate biopsy are under investigation. Both use pre-biopsy MRI to define potential targets for sampling, and the biopsy is performed either with direct real-time MR guidance (in-bore) or MR fusion/registration with TRUS images (out-of-bore). In-bore and out-of-bore MRI-guided prostate biopsies have the advantage of using the MR target definition for the accurate localization and sampling of targets or suspicious lesions. The out-of-bore method uses combined MRI/TRUS with fusion soft-ware that provides target localization and increases the sampling accuracy of TRUS-guided biopsies by integrating prostate MRI information with TRUS. The authors concluded that newer parameters for each imaging modality, such as sono-elastography or shear-wave elastography, contrast-enhanced ultrasound and MRI elastography, show promise to further enrich datasets.

Magnetic resonance imaging-targeted, TRUS- guided transperineal fusion biopsy has shown encouraging results for detecting clinically significant prostate cancer. However, the clinical value of this approach in routine clinical practice has not been established.

Marks et al (2013) stated that prostate cancer may be detected on MRI. Fusion of MRI with ultrasound allows urologists to progress from blind, systematic biopsies to biopsies, which are mapped, targeted and tracked. These investigators reviewed the current status of prostate biopsy via MRI/ultrasound fusion. Three methods of fusing MRI for targeted biopsy have been recently described:

MRI-ultrasound fusion,
MRI-MRI fusion ('in-bore' biopsy) and
cognitive fusion.

Supportive data were emerging for the fusion devices, 2 of which received Food and Drug Administration (FDA) approval in the past 5 years:

Artemis (Eigen, USA) and
Urostation (Koelis, France).

Working with the Artemis device in more than 600 individuals, these researchers found that targeted biopsies are 2 to 3 times more sensitive for detection of prostate cancer than non-targeted systematic biopsies; nearly 40 % of men with Gleason score of at least 7 prostate cancer are diagnosed only by targeted biopsy; nearly 100 % of men with highly suspicious MRI lesions are diagnosed with prostate cancer; ability to return to a prior biopsy site was highly accurate (within 1.2 ± 1.1 mm); and targeted and systematic biopsies were twice as accurate as systematic biopsies alone in predicting whole-organ disease. The authors concluded that in the future, MRI-ultrasound fusion for lesion targeting is likely to result in fewer and more accurate prostate biopsies than the present use of systematic biopsies with ultrasound guidance alone.

Schilling et al (2013) noted that multi-parametric MRI represents the most accurate imaging modality for prostate cancer imaging to-date. Transrectal ultrasound is easily applied and therefore remains the gold standard for systematic prostate biopsies. However, the advantages of both modalities can be combined by image fusion. Currently, several image fusion devices are being implemented into clinical routine. First data showed an increased detection rate of prostate cancer compared to systematic TRUS biopsies. The authors concluded that a present prostatic deformation and intracorporeal movement represent technical challenges yet to be overcome.

Dumus et al (2013) examined if prostate cancer detection rates of TRUS-guided biopsy may be improved by an image fusion of state-of-the-art ultrasound (CEUS, elastography) and MR (T2w, diffusion-weighted imaging [DWI]) imaging. A total of 32 consecutive patients with a history of elevated PSA levels and at least 1 negative TRUS-guided biopsy with clinical indication for a systematic re-biopsy underwent multi-parametric 3 T MRI without endorectal coil. MR data (T2w) were uploaded to a modern sonography system and image fusion was performed in real-time mode during biopsy. B-mode, Doppler, elastography and CEUS imaging were applied to characterize suspicious lesions detected by MRI. Targeted biopsies were performed in MR/US fusion mode followed by a systematic standard TRUS-guided biopsy. Detection rates for both methods were calculated and compared using the Chi²-test. Patient age was not significantly different in patients with and without histologically confirmed prostate cancer (65.2 ± 8.0 and 64.1 ± 7.3 years [p = 0.93]). The PSA value was significantly higher in patients with prostate cancer (15.5 ± 9.3 ng/ml) compared to patients without cancer (PSA 10.4 ± 9.6 ng/ml; p = 0.02). The proportion of histologically confirmed cancers in the study group (n = 32) of the MR/US fusion biopsy (11/12; 34.4 %) was significantly higher (p = 0.01) in comparison to the TRUS systematic biopsy (6/12; 18.8 %). The authors concluded that real-time MR/US image fusion may enhance cancer detection rates of TRUS-guided biopsies and should therefore be studied in further larger studies.

National Comprehensive Cancer Network (NCCN) prostate cancer guidelines (2015) state that the use of multiparametric MRI (mpMRI) in the staging and characterization of prostate cancer has developed in the last few years. To be defined as ‘multi-parametric,’ MRI images need to be acquired with at least one more sequence apart from the anatomical T2 weighted one, such as diffusion weighted images (DW() or dynamic contrast enhanced images (DCE). Furthermore, a high quality mpMRI requires a 3.0T magnet; the need for an endorectal coil remains controversial.

NCCN guidelines (2015) state that evidence supports the implementation of mpMRI in several aspects of prostate cancer management. First, mpMRI helps detect large and poorly differentiated tumors (i.e., Gleason score >7). MpMRI has been incorporated into MRI-TRUS fusion targeted biopsy protocols, which has led to an increase in the diagnosis of high grade tumors with fewer biopsy cores, while reducing detection of low-grade and insignificant tumors. Second, mpMRI aids in the detection of extracapsular extension (T staging), with high negative predictive values in low-risk men. MpMRI results may inform decision-making regarding nerve-sparing surgery. Third, mpMRI has been shown equivalent to CT scan for N staing. Finally, mpMRI out-performs bone scan and targeted X-rays for M-staging, with sensitivity 98% to 100% and specificity 98% to 100% (vs. sensitivity 86% and specificity 98-100% for bone scan plus targeted X-rays).

Kuru et al (2013) evaluated MRI-targeted, TRUS- guided transperineal fusion biopsy in routine clinical practice. Included in this prospective study were 347 consecutive patients with findings suspicious for prostate cancer. Median age was 65 years (range of 42 to 84) and mean PSA was 9.85 ng/ml (range of 0.5 to 104). Of the men 49 % previously underwent TRUS- guided biopsies, which were negative, and 51 % underwent primary biopsy. In all patients 3 T multi-parametric MRI was done. Systematic stereotactic prostate biopsies plus MRI-targeted, TRUS- guided biopsies were performed in those with abnormalities on MRI. Imaging data and biopsy results were analyzed. A self-designed questionnaire was sent to all men on further clinical history and biopsy adverse effects. Of 347 patients, biopsy samples of 200 (58 %) showed prostate cancer and 73.5 % of biopsy proven prostate cancer were clinically relevant according to National Comprehensive Cancer Network (NCCN) criteria. On multi-parametric MRI, 104 men had findings highly suspicious for prostate cancer. The tumor detection rate was 82.6 % (86 of 104 men) with a Gleason score of 7 or greater in 72 %. Overall targeted cores detected significantly more cancer than systematic biopsies (30 % versus 8.2 %). Of 94 patients without cancer suspicious lesions on MRI, 11 (11.7 %) were diagnosed with intermediate risk disease. Regarding adverse effects, 152 of 300 patients (50.6 %) reported mild hematuria, 26 % had temporary erectile dysfunction and 2.6 % needed short-term catheterization after biopsy. Non-septic febrile urinary tract infections developed in 3 patients (1 %). The authors concluded that MRI- targeted, TRUS-guided transperineal fusion biopsy provided high detection of clinically significant tumors. Moreover, they stated that since multi-parametric MRI still has some limitations, systematic biopsies should currently not be omitted.

Shoji et al (2015) reported their early experience with manually controlled targeted biopsy with real-time multi-parametric MRI and TRUS fusion images for the diagnosis of prostate cancer. A total of 20 consecutive patients suspicious of prostate cancer at the multi-parametric MRI scan were recruited prospectively. Targeted biopsies were carried out for each cancer-suspicious lesion, and 12 systematic biopsies using the BioJet system. Pathological findings of targeted and systematic biopsies were analyzed. The median age of the patients was 70 years (range of 52 to 83 years). The median pre-operative PSA value was 7.4 ng/ml (range of 3.54 to 19.9 ng/ml). Median pre-operative prostate volume was 38 ml (range of 24 to 68 ml). The number of cancer-detected cases was 14 (70 %). The median Gleason score was 6.5 (range of 6 to 8). Cancer-detected rates of the systematic and targeted biopsy cores were 6.7 and 31.8 %, respectively (p < 0.0001). In 6 patients who underwent radical prostatectomy, the geographic locations and pathological grades of clinically significant cancers and index lesions corresponded to the pathological results of the targeted biopsies. The authors concluded that prostate cancers detected by targeted biopsies with manually controlled targeted biopsy using real-time multi-parametric MRI and TRUS fusion imaging have significantly higher grades and longer length compared with those detected by systematic biopsies. Moreover, they stated that further studies and comparison with the pathological findings of whole-gland specimens have the potential to determine the role of this biopsy methodology in patients selected for focal therapy and those under active surveillance.

An UpToDate review on “Prostate biopsy” (Benway and Andriole, 2014) states that “The limitations of MR-targeted biopsy are its long examination time and that it requires radiologic expertise, and thus, is not generally available. The best of the MR-targeted biopsy options listed above for urologists, who perform the majority of prostate biopsies, may be biopsy with MR/TRUS image fusion technique (e.g., Koelis Urostation). However, the technique needs further validation”.

The American urological Association (2000) stated that “PSA is currently the best single test for early prostate cancer detection, but the combination of PSA and DRE is better -- because DRE will detect some of the tumors in patients who have prostate cancer despite a normal PSA of less than 4.0 ng/ml. Transrectal ultrasonography is not a useful test for early prostate cancer detection; it adds little to the combination of PSA and DRE”.

The Ontario’s Ministry of Health and Long-Term Care (2012) stated that “A PSA value of greater than 4 ug/L (ng/ml) has often been defined in the literature as abnormal and is frequently used as a cut-off point by some jurisdictions including Ontario and the United States. However, a man's PSA level increases steadily as he ages, and some -- not all -- urologists advocate the use of age-related "normal" PSA cut-points, rather than using greater than 4 ug/L (ng/ml)for all. It is recommended that men should talk with their doctor in regards to PSA levels”.

The Canadian Cancer Society (2016) states that “TRUS is done if the doctor suspects cancer because of an increased prostate-specific antigen (PSA) level, abnormalities felt during digital rectal examination (DRE) or certain symptoms are present …. “.

Tornblom et al (1999) retrospectively investigated the use of percent free prostate-specific antigen (PSA) compared with total PSA in serum as predictor of prostate cancer in men selected randomly from the general population who underwent biopsy on the basis of abnormal findings on digital rectal examination (DRE) or transrectal ultrasound (TRUS) and/or serum PSA levels greater than 10 ng/ml. A single intervention, population-based screening study was undertaken in 1988 and 1989. Of the 2,400 men aged 55 to 70 years invited to participate, 1,782 men responded and were examined with DRE, TRUS, and PSA testing (Tandem-Hybritech). In 1995, frozen serum samples from 1,748 men were analyzed for percent free PSA (Prostatus, Wallac OY); 5-year follow-up data on new cancers in the screened population were obtained from the Swedish Cancer Registry (SCR). Of the 1,748 men, 367 underwent TRUS-guided biopsies because of abnormal findings on either DRE or TRUS or serum PSA levels of greater than 10 ng/ml. This resulted in the diagnosis of 64 cases of prostate cancer (3.7 %). PSA levels of 3.0 ng/ml or greater were found in 55 (86 %) of 64 cancer cases and in 399 (24 %) of the 1,684 benign cases. Among the 1,294 men with PSA less than 3.0 ng/ml, 9 prostate cancers were diagnosed (14 % of all prostate cancers). All 9 patients with cancer and with PSA less than 3.0 ng/ml had a percent free PSA of 18 % or less. In the group of 1,109 patients with PSA less than 3.0 ng/ml and a percent free PSA greater than 18 %, 159 biopsies were performed because of abnormal DRE or TRUS. However, no prostate cancer was diagnosed in this category of patients; 5 years after the screening intervention, 7 more cases of prostate cancer were clinically diagnosed in the screened population according to the SCR. The authors concluded that the combination of PSA levels less than 3.0 ng/ml and percent free PSA greater than 18 % defined a large part of the population at a very low risk of cancer of the prostate both at the time of screening and during the following 5 years. Men in this group may be spared DRE, and longer screening intervals may be considered. However, the risk of having prostate cancer is not negligible in men with PSA less than 3.0 ng/ml and percent free PSA of 18 % or less. The authors stated that the findings of this study indicated that biopsy should be recommended to men fulfilling these criteria, although these results should be confirmed in larger prospective studies because of the limited number of patients with prostate cancer in the present series.

Men et al (2001) evaluated the effectiveness of various diagnostic tests including TRUS, TRUS-guided biopsy, DRE, PSA, and prostate specific antigen density (PSAD) in detecting prostatic carcinomas. A total of 134 men underwent TRUS guided random, or directed and random sonographic biopsies of the prostate. The mean age was 64.67 (range of 31 to 88) years. Indications for biopsy were abnormal findings suggesting prostatic carcinoma on DRE or increased levels of PSA, defined as 4.0 ng/ml or greater in a monoclonal antibody assay. PSAD was calculated by dividing the serum PSA in ng/ml to the volume of the entire prostate in cm3. The biopsy results were grouped as benign, malign and, prostatitis. The patients were also divided into 3 groups according to their PSA values. Of the 134 patients evaluated, 31 (23.1 %) had prostate adenocarcinoma, 89 (66.4 %) had benign prostatic tissue, hyperplasia or prostatic intraepithelial neoplasia, and 14 (10.4 %) had prostatitis. The mean PSA and PSAD of the carcinoma group were significantly higher than those of the non-cancer group. In the group of patients with PSA levels between 4 and 10 ng/ml, abnormal TRUS or DRE increased cancer detection rate, where neither PSA nor PSAD was capable of discriminating the patients with and without cancer. PSAD did not prove to be superior to the other diagnostic tests in this study. The authors recommended biopsy when either TRUS or DRE is abnormal in patients with PSA levels between 4 and 10 ng/ml. In the patients with PSA levels greater than 10 ng/ml, biopsy is indicated whatever the findings on TRUS or DRE are, since cancer detection rate is high.

Cancer Research UK (2014) states that “A reading higher than these values but less than 10 ng/ml is usually due to a non-cancerous (benign) enlargement of the prostate gland. A reading higher than 10 ng/ml may also be caused by benign prostate disease, but the higher the level of PSA, the more likely it is to be cancer. Sometimes a cancer may be diagnosed in a man with a PSA reading within the normal range. But usually, the higher the reading, the more likely it is to be cancer”.

An UpToDate review on “Measurement of prostate specific antigen” (Freedland, 2015) states that “Serum PSA levels overlap considerably in men with BPH and those with prostate cancer. As an example, one report retrospectively examined preoperative serum PSA in 187 men with a histologic diagnosis of BPH on a transurethral resection of the prostate (TURP) specimen and 198 men with organ-confined prostate cancer as determined by step-section analysis of a radical prostatectomy specimen. The median serum PSA concentrations were 3.9 (range 0.2 to 55) and 5.9 ng/ml (range 0.4 to 58), respectively. Although this difference was statistically significant, the distribution of serum PSA values in both groups overlapped considerably with a clustering of PSA values below 10.0 ng/ml (90 and 73 %, respectively) …. For men with total PSA in the diagnostic gray zone (4.0 and 10.0 ng/ml), the use of cPSA alone would have missed one of the 36 men with cancer who would be identified using total PSA, and 34 biopsies could be avoided. By contrast, f/t PSA alone would also have missed one cancer, but eliminated biopsy in only 20 men. The utility of cPSA in men with a lower total PSA (2 to 4 ng/ml) is under study; there are conflicting data as to whether cPSA improves specificity compared with f/t PSA”.

Hoffman (2015) recommended that men with a PSA level above 7 ng/mL be referred; the interventional specialist can decide whether to proceed directly to biopsy or perform additional testing. Hoffman (2015) suggested that men with a PSA level between 4 ng/mL and 7 ng/mL undergo repeat testing several weeks later. Before repeating PSA testing, men should abstain from ejaculation and bike riding for at least 48 hours. Men with symptomatic prostatitis should be treated with antibiotics before retesting. Men with a repeat PSA level above 4 ng/mL should be referred for biopsy.

National Comprehensive Cancer Network’s clinical practice guideline on “Prostate cancer” (Version 1.2016) indicates that PSA less than 10 ng/ml can be classified as very low risk or low risk; PSA between 10 to 20 ng/ml is classified as intermediate risk; PSA over 20 ng/ml is classified as high risk.

Multiparametric MRI/US Fusion Biopsy

Vourganti and colleagues (2012) noted that patients with negative TRUS biopsies and a persistent clinical suspicion are at risk for occult but significant PCa. The ability of multi-parametric MRI/US fusion biopsy to detect these occult prostate lesions may make it an effective tool in this challenging scenario. Between March 2007 and November 2011, all men who underwent prostate 3T endorectal coil MRI in the authors’ institution were selected for this study. All concerning lesions were targeted with MRI/US fusion biopsy. In addition, all patients underwent standard 12-core TRUS biopsy. Men with 1 or more negative systematic prostate biopsies were included in this cohort. Of the 195 men with previous negative biopsies, 73 (37 %) were found to have cancer using the MRI/US fusion biopsy combined with 12-core TRUS biopsy. High grade cancer (Gleason score 8+) was discovered in 21 men (11 %), all of whom had disease detected with MRI/US fusion biopsy. However, standard TRUS biopsy missed 12 of these high grade cancers (55 %). Pathological upgrading occurred in 28 men (38.9 %) as a result of MRI/US fusion targeting versus standard TRUS biopsy. The diagnostic yield of MRI/US fusion platform was unrelated to the number of previous negative biopsies and persisted despite increasing the number of previous biopsy sessions. On multivariate analysis only PSA density and MRI suspicion level remained significant predictors of cancer. The authors concluded that multi-parametric MRI with a MRI/US fusion biopsy platform is a novel diagnostic tool for detecting PCa and may be ideally suited for patients with negative TRUS biopsies in the face of a persistent clinical suspicion for cancer. The main drawbacks of this study included:

as the authors’ center is a specialty referral center, the very act of primary urologist referral in the face of negative biopsy suggests some clinical suspicion of cancer, resulting in selection bias. The true “denominator” of those men with negative results and who were not referred cannot be assessed, and
it is likely that a number of factors contribute to this clinical suspicion (including PSA, PSAV, PSAD, DRE, age specific PSA thresholds, and patient anxiety).

The applicability of these data to the larger screening population will require more testing. The authors stated that formal randomized prospective trial is the best methodology to clarify this issue.

Siddiqui et al (2013) stated that Gleason scores from standard, 12-core prostate biopsies are upgraded historically in 25 to 33 % of patients. Multi-parametric prostate MRI (MP-MRI) with US-targeted fusion biopsy may better sample the true gland pathology. These researchers compared the rate of Gleason score upgrading from an MRI/US-fusion-guided prostate-biopsy platform with a standard 12-core biopsy regimen alone. There were 582 subjects enrolled from August 2007 through August 2012 in a prospective trial comparing systematic, extended 12-core TRUS biopsies to targeted MRI/US-fusion-guided prostate biopsies performed during the same biopsy session. The highest Gleason score from each biopsy method was compared. An MRI/US-fusion-guided platform with electromagnetic tracking was used for the performance of the fusion-guided biopsies. A diagnosis of PCa was made in 315 (54 %) of the patients. Addition of targeted biopsy led to Gleason upgrading in 81 (32 %) cases. Targeted biopsy detected 67 % more Gleason greater than or equal to 4+3 tumors than 12-core biopsy alone and missed 36 % of Gleason less than or equal to 3+4 tumors, thus mitigating the detection of lower-grade disease. Conversely, 12-core biopsy led to upgrading in 67 (26 %) cases over targeted biopsy alone but only detected 8 % more Gleason greater than or equal to 4+3 tumors. On multivariate analysis, MP-MRI suspicion was associated with Gleason score upgrading in the targeted lesions (p < 0.001). The authors concluded that MRI/US-fusion-guided biopsy upgrades and detects PCa of higher Gleason score in 32 % of patients compared with traditional 12-core biopsy alone. Targeted biopsy technique preferentially detected higher-grade PCa while missing lower-grade tumors. The main drawbacks of this study were

study compared 2 biopsy modalities to each other. Ideally, the addition of final prostatectomy pathology as an end-point arbitrated which lesions were most important to detect; definitive pathology from radical prostatectomy was not available,
the referral population in this study usually presented with an elevated PSA level that had prompted prior negative biopsies. Thus, the population was skewed to patients who would be more likely to benefit from targeted biopsies. This selection bias suggested that these findings may not be generalizable to the general population of men undergoing biopsy, and
the inclusion criteria of the trial specified patients with MRI-visible lesions, thus excluding patients with no lesions seen on MRI.

Siddiqui et al (2015) noted that targeted MR/US fusion prostate biopsy has been shown to detect PCa. The implications of targeted biopsy alone versus standard extended-sextant biopsy or the 2 modalities combined are not well understood. These investigators evaluated targeted versus standard biopsy and the 2 approaches combined for the diagnosis of intermediate- to high-risk PCa. These researchers performed a prospective cohort study of 1,003 men undergoing both targeted and standard biopsy concurrently from 2007 through 2014 at the National Cancer Institute. Patients were referred for elevated level of PSA or abnormal DRE results, often with prior negative biopsy results. Risk categorization was compared among targeted and standard biopsy and, when available, whole-gland pathology after prostatectomy as the "gold standard". Patients underwent multi-parametric prostate MRI to identify regions of prostate cancer suspicion followed by targeted MR/US fusion biopsy and concurrent standard biopsy. The primary objective was to compare targeted and standard biopsy approaches for detection of high-risk PCa (Gleason score greater than or equal to 4 + 3); secondary end-points focused on detection of low-risk PCa (Gleason score 3 + 3 or low-volume 3 + 4) and the biopsy ability to predict whole-gland pathology at prostatectomy. Targeted MR/US fusion biopsy diagnosed 461 PCa cases, and standard biopsy diagnosed 469 cases. There was exact agreement between targeted and standard biopsy in 690 men (69 %) undergoing biopsy. Targeted biopsy diagnosed 30 % more high-risk cancers versus standard biopsy (173 versus 122 cases, p < 0.001) and 17 % fewer low-risk cancers (213 versus 258 cases, p < 0.001). When standard biopsy cores were combined with the targeted approach, an additional 103 cases (22 %) of mostly low-risk PCa were diagnosed (83 % low risk, 12 % intermediate risk, and 5 % high risk). The predictive ability of targeted biopsy for differentiating low-risk from intermediate- and high-risk disease in 170 men with whole-gland pathology after prostatectomy was greater than that of standard biopsy or the 2 approaches combined (area under the curve, 0.73, 0.59, and 0.67, respectively; p < 0.05 for all comparisons). The authors concluded that among men undergoing biopsy for suspected PCa, targeted MR/US fusion biopsy, compared with standard extended-sextant US-guided biopsy, was associated with increased detection of high-risk PCa and decreased detection of low-risk PCa. Moreover, they stated that future studies will be needed to assess the ultimate clinical implications of targeted biopsy. The major drawbacks of this study included:

the majority of the 1,003 patients had 1 or more previous biopsies. The study population consisted of patients referred to a single institution, which could have introduced selection bias. Future validation of these findings in a large biopsy-naïve screening population may clarify the implications of this paradigm for screening,
patients with no lesions visible on MP-MRI were excluded from the study,
all of the MP-MRIs in this study cohort were read by 2 highly experienced genitourinary radiologists.

Reproducing these findings may be challenging until sufficient experience in the interpretation of these studies has been attained at centers newly adapting this technology.

Mendhiratta et al (2015) noted that in recent years, mpMRI of the prostate has shown promise as a modality to identify areas of suspicion within the gland which correlate with cancer location and disease extent. However, optimal individualization of prostate biopsy using mpMRI relies on aligning the relative benefits of MRI-targeted approaches with the goals of biopsy. For men with prior negative biopsies, mpMRI allows improved detection of occult high-grade cancers missed by repeat systematic biopsy but also has the potential to identify men who will not benefit from repeat biopsy due to a low likelihood of significant disease. For men with prior low-grade cancer diagnosis, the addition of MRI-targeted biopsy may identify those who are poor candidates for active surveillance by detecting high-risk disease without serial biopsies. For men without prior biopsy, mpMRI and targeted biopsy may help improve high-grade cancer diagnosis and significantly limit the detection of low-risk disease. The authors concluded that mpMRI of the prostate is a promising tool to address many of the shortcomings of traditional systematic prostate biopsy. Biopsy history plays a critical role in determining how to assess the potential advantages and disadvantages of prostate mpMRI in the context of each patient. They stated that although these benefits have been suggested by published clinical outcomes data, there is a need for prospective validation of mpMRI and MRI-targeted biopsy in comparison with the current approach of systematic biopsy for all men, to define new paradigms for PCa detection and risk stratification.

Hamoen and colleagues (2015) stated that in 2012, an expert panel of the European Society of Urogenital Radiology (ESUR) published the Prostate Imaging Reporting and Data System (PI-RADS) for PCa detection with mpMRI. These researchers reviewed the diagnostic accuracy of PI-RADS for PCa detection with mpMRI. They searched Medline and Embase up to March 20, 2014. They included diagnostic accuracy studies since 2012 that used PI-RADS with mpMRI for PCa detection in men, using prostatectomy or biopsy as the reference standard. The methodological quality was assessed using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tool by 2 independent reviewers. Data necessary to complete 2×2 contingency tables were obtained from the included studies, and test characteristics including sensitivity and specificity were calculated. Results were pooled and plotted in a summary receiver operating characteristics plot. A total of 14 studies (1,785 patients) could be analyzed. The pooled data showed sensitivity of 0.78 (95 % CI: 0.70 to 0.84) and specificity of 0.79 (95 % CI: 0.68 to 0.86) for PCa detection, with negative predictive values (NPV) ranging from 0.58 to 0.95. Sensitivity analysis revealed pooled sensitivity of 0.82 (95 % CI: 0.72 to 0.89) and specificity of 0.82 (95 % CI: 0.67 to 0.92) in studies with correct use of PI-RADS (i.e., clear description in the methodology and no adjustment of criteria). For studies with a less strict or adjusted use of PI-RADS criteria, or unclear description of the methodology, had pooled sensitivity of 0.73 (95 % CI: 0.62 to 0.82) and specificity of 0.75 (95 % CI: 0.61 to 0.84). The authors concluded that in patients for whom PCa is suspected, PI-RADS appeared to have good diagnostic accuracy in PCa detection, but no recommendation regarding the best threshold can be provided because of heterogeneity.

Valerio et al (2015) compared the detection rate of clinically significant PCa with software-based MRI-US fusion targeted biopsy against standard biopsy. The 2 strategies were also compared in terms of detection of all cancers, sampling utility and efficiency, and rate of serious adverse events. The outcomes of different targeted approaches were also compared. These researchers performed a systematic review of PubMed/Medline, Embase (via Ovid), and Cochrane Review databases in December 2013 following the Preferred Reported Items for Systematic reviews and Meta-analysis statement. The risk of bias was evaluated using the Quality Assessment of Diagnostic Accuracy Studies-2 tool. A total of 14 papers reporting the outcomes of 15 studies (n = 2,293; range of 13 to 582) were included. These investigators found that MRI-US fusion targeted biopsies detected more clinically significant cancers (median of 33.3 % versus 23.6 %; range of 13.2 to 50 % versus 4.8 to 52 %) using fewer cores (median of 9.2 versus 37.1) compared with standard biopsy techniques, respectively. Some studies showed a lower detection rate of all cancer (median of 50.5 % versus 43.4 %; range of 23.7 to 82.1 % versus 14.3 to 59 %). MRI-US fusion targeted biopsy was able to detect some clinically significant cancers that would have been missed by using only standard biopsy (median of 9.1 %; range of 5 to 16.2 %). It was not possible to determine which of the 2 biopsy approaches led most to serious adverse events because standard and targeted biopsies were performed in the same session. Software-based MRI-US fusion targeted biopsy detected more clinically significant disease than visual targeted biopsy in the only study reporting on this outcome (20.3 % versus 15.1 %). The authors concluded that software-based MRI-US fusion targeted biopsy appeared to detect more clinically significant cancers deploying fewer cores than standard biopsy. They noted that because there was significant study heterogeneity in patient inclusion, definition of significant cancer, and the protocol used to conduct the standard biopsy, these findings need to be confirmed by further high-quality evidence (large multi-center validating studies) before current practice can be changed.

Schoots and associates (2015) performed a systematic review and meta-analysis of evidence regarding the diagnostic benefits of MRI-targeted biopsy (MRI-TBx) versus TRUS-guided biopsy (TRUS-Bx) in detection of overall PCa (primary objective) and significant/insignificant PCa (secondary objective). A systematic review of Embase, Medline, Web of Science, Scopus, PubMed, Cinahl, and the Cochrane library was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. Identified reports were critically appraised according to the Quality Assessment of Diagnostic Accuracy Studies criteria. Only men with a positive MRI were included. The included 16 studies used both MRI-TBx and TRUS-Bx for PCa detection. A cumulative total of 1,926 men with positive MRI were included, with PCa prevalence of 59 %. MRI-TBx and TRUS-Bx did not significantly differ in overall PCa detection (sensitivity 0.85, 95 % CI: 0.80 to 0.89, and 0.81, 95 % CI: 0.70 to 0.88, respectively). MRI-TBx had a higher rate of detection of significant PCa compared to TRUS-Bx (sensitivity 0.91, 95 % CI: 0.87 to 0.94 versus 0.76, 95 % CI: 0.64 to 0.84) and a lower rate of detection of insignificant PCa (sensitivity 0.44, 95 % CI: 0.26 to 0.64 versus 0.83, 95 % CI: 0.77 to 0.87). Subgroup analysis revealed an improvement in significant PCa detection by MRI-TBx in men with previous negative biopsy, rather than in men with initial biopsy (relative sensitivity 1.54, 95 % CI: 1.05 to 2.57 versus 1.10, 95 % CI: 1.00 to 1.22). Because of underlying methodological flaws of MRI-TBx, the comparison of MRI-TBx and TRUS-Bx needed to be regarded with caution. The authors concluded that in men with clinical suspicion of PCa and a subsequent positive MRI, MRI-TBx and TRUS-Bx did not differ in overall PCa detection. However, MRI-TBx had a higher rate of detection of significant PCa and a lower rate of detection of insignificant PCa compared with TRUS-Bx, suggesting that MRI-guided targeted biopsy benefits the diagnosis of PCa.

In a prospective, randomized trial, Arsov and co-workers (2015) compared PCa detection between targeted MRI-guided in-bore biopsy (IB-GB) alone and targeted MRI-US fusion-guided biopsy (FUS-GB) + TRUS-guided biopsy (TRUS-GB) in patients with at least 1 negative TRUS-GB and PSA greater than or equal to 4 ng/ml. Patients were prospectively randomized after mpMRI to IB-GB (arm A) or FUS-GB + TRUS-GB (arm B) from November 2011 to July 2014. The study was powered at 80 % to demonstrate an overall PCa detection rate of greater than or equal to 60 % in arm B compared to 40 % in arm A. Secondary end-points were the distribution of highest Gleason scores, the rate of detection of significant PCa (Gleason greater than or equal to7), the number of biopsy cores to detect 1 (significant) PCa, the positivity rate for biopsy cores, and tumor involvement per biopsy core. The study was halted after interim analysis because the primary end-point was not met. The trial enrolled 267 patients, of whom 210 were analyzed (106 randomized to arm A and 104 to arm B). Prostate cancer detection was 37 % in arm A and 39 % in arm B (95 % CI: -16 % to 11 %; p = 0.7). Detection rates for significant PCa (29 % versus 32 %; p = 0.7) and the highest percentage tumor involvement per biopsy core (48 % versus 42 %; p = 0.4) were similar between the arms. The mean number of cores was 5.6 versus 17 (p < 0.001). A drawback of this study was the limited number of patients because of early cessation of accrual. The authors concluded that this trial failed to identify an important improvement in detection rate for the combined biopsy approach over MRI-targeted biopsy alone. They stated that a prospective comparison between MRI-targeted biopsy alone and systematic TRUS-GB is justified.

Dwivedi et al (2016) stated that risk stratification, based on the Gleason score (GS) of a prostate biopsy, is an important decision-making tool in PCa management. As low-grade disease may not need active intervention, the ability to identify aggressive cancers on imaging could limit the need for prostate biopsies. These researchers evaluated the ability of mpMRI in pre-biopsy risk stratification of men with PCa. A total of 120 men suspected to have PCa underwent mpMRI (diffusion MRI and MR spectroscopic imaging) prior to biopsy; 26 had cancer and were stratified into 3 groups based on GS:

low grade (GS less than or equal to 6),
intermediate grade (GS = 7), and
high grade (GS greater than or equal to 8).

A total of 910 regions of interest (ROIs) from the peripheral zone (PZ, range of 25 to 45) were analyzed from these 26 patients. The metabolite ratio [citrate/(choline + creatine)] and apparent diffusion coefficient (ADC) of voxels were calculated for the PZ regions corresponding to the biopsy cores and compared with histology. The median metabolite ratios for low-grade, intermediate-grade and high-grade cancer were 0.29 (range of 0.16 to 0.61), 0.17 (range of 0.13 to 0.32) and 0.13 (range of 0.05 to 0.23), respectively (p = 0.004). The corresponding mean ADCs (×10-3 mm2 /s) for low-grade, intermediate-grade and high-grade cancer were 0.99 ± 0.08, 0.86 ± 0.11 and 0.69 ± 0.12, respectively (p < 0.0001). The combined ADC and metabolite ratio model showed strong discriminatory ability to differentiate subjects with GS less than or equal to 6 from subjects with GS greater than or equal to 7 with an area under the curve of 94 %. The authors concluded that these data indicated that pre-biopsy mpMRI may stratify PCa aggressiveness non-invasively. As the recent literature data suggested that men with GS less than or equal to 6, cancer may not need radical therapy, these data may help limit the need for biopsy and allow informed decision making for clinical intervention.

Gayet et al (2016) stated that despite limitations considering the presence, staging and aggressiveness of PCa, US-guided systematic biopsies (SBs) are still the “gold standard” for the diagnosis of PCa. Recently, promising results have been published for targeted prostate biopsies (TBs) using MRI/US-fusion platforms. Different platforms are FDA-registered and have, mostly subjective, strengths and weaknesses. To the authors’ knowledge, no systematic review exists that objectively compares PCa detection rates between the different platforms available. To examine the value of the different MRI/US-fusion platforms in PCa detection, these researchers compared platform-guided TB with SB, and other ways of MRI TB (cognitive fusion or in-bore MR fusion). They performed a systematic review of well-designed prospective randomized and non-randomized trials in the English language published between January 1, 2004 and February 17, 2015, using PubMed, Embase and Cochrane Library databases. Search terms included: “prostate cancer”, “MR/ultrasound(US) fusion” and “targeted biopsies”. Extraction of articles was performed by 2 authors and were evaluated by the other authors. Randomized and non-randomized prospective clinical trials comparing TB using MRI/US-fusion platforms and SB, or other ways of TB (cognitive fusion or MR in-bore fusion) were included. In all, 11 of 1,865 studies met the inclusion criteria, involving 7 different fusion platforms and 2,626 patients: 1,119 biopsy naïve, 1,433 with prior negative biopsy, 50 not mentioned (either biopsy naïve or with prior negative biopsy) and 24 on active surveillance (who were disregarded). The Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tool was used to assess the quality of included articles. No clear advantage of MRI/US fusion-guided TBs was seen for cancer detection rates (CDRs) of all prostate cancers. However, MRI/US fusion-guided TBs tended to give higher CDRs for clinically significant PCa in this analysis. Important limitations of the present systematic review included: the limited number of included studies, lack of a general definition of “clinically significant” PCa, the heterogeneous study population, and a reference test with low sensitivity and specificity. Today, a limited number of prospective studies have reported the CDRs of fusion platforms. The authors concluded that although MRI/US-fusion TB has proved its value in men with prior negative biopsies, general use of this technique in diagnosing PCa should only be performed after critical consideration. They stated that before bringing MRI/US fusion-guided TB into general practice, there is a need for more prospective studies on PCa diagnosis.

In a randomized controlled trial (RCT), Baco and colleagues (2016) compared the rate of detection of clinically significant PCa (csPCa) between prostate biopsy guided by computer-assisted fusion of MRI and TRUS images (MRI group) and the traditional 12-core random biopsy (RB; control group). This study included 175 biopsy-naïve patients with suspicion for PCa, randomized to an MRI group (n = 86) and a control group (n = 89) between September 2011 and June 2013. In the MRI group, 2-core TB guided by computer-assisted fusion of MRI/TRUS images of MRI-suspicious lesions was followed by 12-core RB. In the control group, both 2-core TB for abnormal DRE and/or TRUS-suspicious lesions and 12-core RB were performed. In patients with normal MRI or DRE/TRUS, only 12-core RB was performed. The detection rates for any cancer and csPCa were compared between the 2 groups and between TB and RB. Detection rates for any cancer (MRI group 51/86, 59 %; control group 48/89, 54 %; p = 0.4) and csPCa (38/86, 44 % versus 44/89, 49 %; p = 0.5) did not significantly differ between the groups. Detection of csPCa was comparable between 2-core MRI/TRUS-TB (33/86, 38 %) and 12-core RB in the control group (44/89, 49 %; p = 0.2). In a subset analysis of patients with normal DRE, csPCa detection was similar between 2-core MRI/TRUS-TB (14/66, 21 %) and 12-core RB in the control group (15/60, 25 %; p = 0.7). Among biopsy-proven csPCas in MRI group, 87 % (33/38) were detected by MRI/TRUS-TB. The definition of csPCa was only based on biopsy outcomes. The authors concluded that overall csPCa detection was similar between the MRI and control groups; 2-core MRI/TRUS-TB was comparable to 12-core RB for csPCa detection.

In a single-center, prospective RCT, Tonttila et al (2016) compared mpMRI/TRUS-fusion targeted biopsy with routine TRUS-guided random biopsy for overall and clinically significant PCa detection among patients with suspected PCa based on PSA values. This study included 130 biopsy-naive patients referred for prostate biopsy based on PSA values (PSA less than 20 ng/ml or free-to-total PSA ratio less than or equal to 0.15 and PSA less than 10 ng/ml). Patients were randomized 1:1 to the mpMRI or control group. Patients in the mpMRI group underwent pre-biopsy mpMRI followed by 10- to 12-core TRUS-guided random biopsy and cognitive MRI/TRUS fusion targeted biopsy. The control group underwent TRUS-guided random biopsy alone. The primary outcome was the number of patients with biopsy-proven PCa in the mpMRI and control groups. Secondary outcome measures included the number of positive prostate biopsies and the proportion of clinically significant PCa in the mpMRI and control groups. Between-group analyses were performed. Overall, 53 and 60 patients were evaluable in the mpMRI and control groups, respectively. The overall PCa detection rate and the clinically significant cancer detection rate were similar between the mpMRI and control groups, respectively (64 % [34 of 53] versus 57 % [34 of 60]; 7.5 % difference [95 % CI: -10 to 25], p = 0.5, and 55 % [29 of 53] versus 45 % [27 of 60]; 9.7 % difference [95 % CI: -8.5 to 27], p = 0.8). The PCa detection rate was higher than assumed during the planning of this single-center trial. The authors concluded that mpMRI/TRUS-fusion targeted biopsy did not improve PCa detection rate compared with TRUS-guided biopsy alone in patients with suspected PCa based on PSA values.

NCCN’s clinical practice guideline on “Prostate cancer” (Version 3.2016) states that “Although mpMRI is not recommended for routine use, it may be considered if PSA rises and systemic prostate biopsy is negative to exclude the presence of an anterior cancer”. NCCN guideline on prostate cancer screening (2017) notes that "emerging data" suggest that, in men undergoing initial biospy, targeting using MRI/ultrasound fusion may significantly increase the detection of clinically significant, higher-risk disease while lowering the detection of lower-risk disease.

Wegelin and colleagues (2017) stated that the introduction of MRI-guided biopsies (MRI-GB) has changed the paradigm concerning prostate biopsies; 3 techniques of MRI-GB are available:

in-bore MRI target biopsy (MRI-TB),
MRI-TRUS fusion (FUS-TB), and
cognitive registration (COG-TB).

These researchers examined if MRI-GB has increased detection rates of (clinically significant) PCa compared with TRUS-GB in patients at risk for PCa, and which technique of MRI-GB has the highest detection rate of (clinically significant) PCa. They performed a literature search in PubMed, Embase, and CENTRAL databases. Studies were evaluated using the Quality Assessment of Diagnostic Accuracy Studies-2 checklist and START recommendations. The initial search identified 2,562 studies and 43 were included in the meta-analysis. Among the included studies 11 used MRI-TB, 17 used FUS-TB, 11 used COG-TB, and 4 used a combination of techniques. In 34 studies concurrent TRUS-GB was performed. There was no significant difference between MRI-GB (all techniques combined) and TRUS-GB for overall PCa detection (relative risk [RR] 0.97 [0.90 to 1.07]). MRI-GB had higher detection rates of clinically significant PCa (csPCa) compared with TRUS-GB (RR 1.16 [1.02 to 1.32]), and a lower yield of insignificant PCa (RR 0.47 [0.35 to 0.63]). There was a significant advantage (p = 0.02) of MRI-TB compared with COG-TB for overall PCa detection. For overall PCa detection there was no significant advantage of MRI-TB compared with FUS-TB (p = 0.13), and neither for FUS-TB compared with COG-TB (p = 0.11). For csPCa detection there was no significant advantage of any one technique of MRI-GB. The impact of lesion characteristics such as size and localization could not be assessed. The authors concluded that MRI-GB had similar overall PCa detection rates compared with TRUS-GB, increased rates of csPCa, and decreased rates of insignificant PCa. MRI-TB had a superior overall PCa detection compared with COG-TB. FUS-TB and MRI-TB appeared to have similar detection rates. They stated that head-to-head comparisons of MRI-GB techniques are limited and are needed to confirm these findings.

Ahmed, et al. (2017) reported on a multicenter, paired-cohort, confirmatory study to test diagnostic accuracy of MP-MRI and TRUS-biopsy against a reference test (template prostate mapping biopsy [TPM-biopsy]). Men with prostate-specific antigen concentrations up to 15 ng/mL, with no previous biopsy, underwent 1·5 Tesla MP-MRI followed by both TRUS-biopsy and TPM-biopsy. The conduct and reporting of each test was done blind to other test results. Clinically significant cancer was defined as Gleason score ≥4 + 3 or a maximum cancer core length 6 mm or longer. Between May 17, 2012, and November 9, 2015, the investigators enrolled 740 men, 576 of whom underwent 1·5 Tesla MP-MRI followed by both TRUS-biopsy and TPM-biopsy. On TPM-biopsy, 408 (71%) of 576 men had cancer with 230 (40%) of 576 patients clinically significant. For clinically significant cancer, MP-MRI was more sensitive (93%, 95% CI 88-96%) than TRUS-biopsy (48%, 42-55%; p<0·0001) and less specific (41%, 36-46% for MP-MRI vs 96%, 94-98% for TRUS-biopsy; p<0·0001). 44 (5·9%) of 740 patients reported serious adverse events, including 8 cases of sepsis. The investigators stated that, using MP-MRI to triage men might allow 27% of patients avoid a primary biopsy and diagnosis of 5% fewer clinically insignificant cancers. The investigators stated that, if subsequent TRUS-biopsies were directed by MP-MRI findings, up to 18% more cases of clinically significant cancer might be detected compared with the standard pathway of TRUS-biopsy for all. MP-MRI, used as a triage test before first prostate biopsy, could reduce unnecessary biopsies by a quarter. The investigators stated that MP-MRI can also reduce over-diagnosis of clinically insignificant prostate cancer and improve detection of clinically significant cancer.

Pepe and associates (2017) evaluated the detection rate for csPCa after mpMRI/TRUS fusion biopsy versus extended biopsy or saturation prostate biopsy (SPBx) in men enrolled on active surveillance (AS). From May 2013 to January 2016, a total of 100 men with very low-risk PCa were enrolled on AS. Eligible criteria were: life expectancy greater than 10 years, cT1c, PSA below 10 ng/ml, PSA density less than 0.20 ng/ml², 3 or fewer unilateral positive biopsy cores, GS equal to 6 and greatest percentage of cancer in a core 50 % or lower. All patients underwent 3.0 T pelvic mpMRI before confirmatory transperineal extended biopsy (20 cores) and SPBx (median 30 cores) combined with mpMRI/TRUS fusion targeted biopsy (median 4 cores) of suspicious lesions [Prostate Imaging Reporting and Data System (PI-RADS) 3-5]; csPCa was defined as the presence of at least 1 core with a GS of 4 or higher. After confirmatory biopsy, 16 out of 60 (26.6 %) patients showed significant PCa. Targeted biopsy of PI-RADS 4-5 versus PI-RADS 3-5 lesions diagnosed 6 out of 16 (37.5 %) and 12 out of 16 (87.5 %) significant PCa, respectively, with 2 false positives (5 %). The detection rate for significant PCa was equal to 68.8 % on mpMRI/TRUS fusion biopsy, 75 % on extended biopsy and 100 % on SPBx. mpMRI/TRUS targeted biopsy and extended biopsy missed 5 out of 16 (31.2 %) and 4 out of 16 (25 %) PCa, respectively. The authors concluded that although mpMRI may improve the diagnosis of significant PCa in men under AS, SPBx had a higher detection rate for clinically significant PCa.

Ristau and co-workers (2017) noted that mpMRI/ultrasound targeted prostate biopsy (TB) is touted as a tool to improve prostate cancer care. Yet, the true clinical utility of TB over TRUS-B has not been systematically analyzed. These researchers introduced 2 metrics to better quantify and report the deliverables of TB. These investigators reviewed their prospective database containing patients who underwent simultaneous TB/TRUS-B. Actionable Intelligence Metric (AIM) was defined as the proportion of patients for whom TB provided actionable information over TRUS-B. Reduction Metric (ReM) was defined as the proportion of men in whom TRUS-B could have been omitted. They compared metrics within their cohort and prior reports. A total of 371 men were included. AIM and ReM were 22.2 % and 83.6 % for biopsy naïve, 26.7 % and 84.2 % for prior negative TRUS-B, and 24 % and 77.5 % for AS patients. No significant differences among groups were observed (p = 0.89 for AIM; p = 0.27 for ReM). AIM was 25.0 % for PIRADS 3, 27.5 % for PIRADS 4 and 21.7 % for PIRADS 5 (p = 0.73) lesions. TRUS-B could have been avoided in more patients with PIRADS 3 compared to PIRADS 4/5 lesions (ReM 92.0 % versus 76.7 %, p < 0.01). These findings compared favorably to other reported series. The authors concluded that AIM and ReM are novel, clinically relevant quantification metrics to standardize reporting of TB deliverables; TB afforded actionable information (AIM) in about 25 % of men; ReM assessment highlighted that TRUS-B may only be omitted after carefully considering the risk of missing clinically significant cancers.

Intraoperative MRI/US Fusion Optimization for Low-Dose-Rate Prostate Brachytherapy

Abel and colleagues (2017) stated that intraoperative planning with TRUS is used for accurate seed placement and optimal dosimetry in prostate brachytherapy. However, prostate MRI has shown superiority in delineation of prostate anatomy. Accordingly, MRI/US fusion may be useful for accurate intraoperative planning. These researchers analyzed planning with MRI/US fusion to compare differences in dosimetry and volume to that derived from the post-operative CT. A total of 20 patients underwent pre-operative prostate MRI, which was fused intraoperatively with US during prostate brachytherapy. Intraoperative 125-I or 103-Pd seed placement was modified by the use of MRI fusion when indicated. Following implantation, dose comparisons were made between data derived from MRI/US and that from post-operative CT scans. Plan parameters analyzed included the D90 (dose to 90 % of the prostate), rectal D30, V30 (volume of the rectum receiving 30 % of dose), and prostate V100. The median number of seeds implanted per patient was 76. The MRI measured prostate volume, which was on average 4.47 cc larger than the CT measured prostate volume. In 9 patients, the apex of the prostate was better identified under MRI with the fusion protocol, and an average of 4 fewer seeds were needed to be placed in the apex/urinary sphincter region. Both MRI and US individually showed a reduced intraoperative prostate D90 in comparison to the post-operative CT, with a larger mean difference for MRI in comparison with US (9.71 versus 4.31 Gy, p = 0.007). This was also true for the prostate V100 (5.18 versus 2.73 cc, p = 0.009). Post-operative CT under-estimated rectal D30 and V30 in comparison to both MRI and US with MRI showing a larger mean difference than US for D30 (40.64 versus 35.92 Gy, p = 0.04) and V30 (50.20 versus 44.38 cc, p = 0.009). The authors concluded that the MRI/US fusion demonstrated greater prostate volume compared to standard CT/US based planning likely due to the better resolution of the prostate apex. Furthermore, rectal dose was under-estimated with CT versus MRI based planning. They stated that additional larger scale studies are needed to evaluate the long-term clinical implications of disease control and normal tissue morbidity, especially as related to the rectum and urinary sphincter. They stated that MRI/US intraoperative fusion is feasible and may improve prostate dosimetry while sparing the rectum and urethra, potentially impacting disease control and late toxicity.

Photoacoustic Imaging for Prostate Cancer Angiogenesis

In a pilot study, Horiguchi and colleagues (2017) investigated a link between the appearance of photo-acoustic imaging (PAI) and microvasculature in PCa and examined the feasibility of PAI for angiogenesis imaging in PCa. These researchers have developed a PAI system equipped with a TRUS-type probe. A total of 3 patients who underwent PAI just before prostate biopsy and subsequently underwent radical prostatectomy were included. The PAI appearance was retrospectively reviewed, and in each patient, 4 representative areas were selected: 1 with high PAI signal intensity, 1 with low PAI signal intensity, 1 peripheral to the index tumor, and 1 inside the index tumor. The correlation of PAI intensity with 3 microvascular parameters-microvascular density, total vascular area (TVA), and total vascular length (TVL)-assessed by CD34-immunostaining in resected specimens was analyzed. In all 3 patients the PAI intensity, TVA, and TVL in areas with high-intensity PAI signals were significantly higher than those in areas with low-intensity PAI signals, suggesting that PAI appearance described the distribution of microvasculature in prostatic tissue correctly. All index tumors showed a ring-like PAI appearance consisting of a peripheral area of high signal intensity completely or partially surrounding an area with low signal intensity. The PAI intensity, TVA, and TVL in the periphery of the index tumors were significantly higher than those inside of the index tumors. The authors concluded that the intensity of PAI signals might reflect the microvascularity in normal prostatic tissues and index tumors. They stated that PAI could be a novel modality for imaging PCa angiogenesis.

Positron Emission Tomography (PET) Image-Directed, Three-Dimensional US-Guided Biopsy

Fei and colleagues (2017) provided a review on molecular imaging with positron emission tomography (PET) and MRI for PCa detection and its applications in fusion targeted biopsy of the prostate. Literature search was performed through the PubMed database using the keywords "prostate cancer", "MRI/ultrasound fusion", "molecular imaging", and "targeted biopsy". Estimates in autopsy studies indicated that 50 % of men older than 50 years of age have PCa. Systematic TRUS-guided prostate biopsy is considered the standard method for PCa detection and has a significant sampling error and a low sensitivity. Molecular imaging technology and new biopsy approaches are emerging to improve the detection of PCa. Molecular imaging with PET and MRI showed promising results in the early detection of PCa. MRI/TRUS fusion targeted biopsy has become a new clinical standard for the diagnosis of PCa. PET molecular image-directed, 3-D US-guided biopsy is a new technology that has great potential for improving PCa detection rate and for distinguishing aggressive PCa from indolent disease. The authors concluded that molecular imaging and fusion targeted biopsy are active research areas in PCa research.

Furthermore, National Comprehensive Cancer Network’s clinical practice guideline on “Prostate cancer” (Version 2.2017) does not mention PET/US-guided biopsy as a management tool.

Multi-Parametric MRI for Diagnosis of Prostate Cancer

In a prospective study, Boesen and colleagues (2017) compared the PCa detection rate of systematic TRUS-guided biopsies (TRUS-bx) and mpMRI targeted biopsies (mpMRI-bx) in a repeat biopsy setting and evaluated the clinical significance following an "MRI-targeted-only" approach. Patients with prior negative biopsies underwent prostatic mpMRI that was scored using the Prostate Imaging Reporting and Data System (PI-RADS) classification. All underwent both repeated TRUS-bx and mpMRI-bx using image fusion of any PI-RADS greater than or equal to 3 lesion. Biopsy results from TRUS-bx, mpMRI-bx, and the combination were compared. PCa was detected in 89 out of 206 (43 %) patients. Of these, 64 (31 %) and 74 (36 %) patients were detected using mpMRI-bx and TRUS-bx, respectively. Overall, mpMRI-bx detected fewer patients with low-grade (Gleason score [GS] 3 + 3) cancers (14/64 versus 41/74) and more patients with intermediate/high-grade cancers (GS greater than or equal to3 + 4) (50/64 versus 33/74) using fewer biopsy cores compared with TRUS-bx (p < 0.001). Using an "MRI-targeted-only" approach in men with PI-RADS of greater than or equal to 3 lesions reduced the number of men requiring repeated biopsies by 50 %, decreased low-grade cancer diagnoses by 66 %, and increased intermediate/high-grade cancer diagnoses by 52 %. The authors concluded that mpMRI/TRUS fusion biopsies had a high detection rate for significant PCa in patients with prior negative TRUS-bx and preferentially detected intermediate/high-grade compared with low-grade tumors. In patients with prior negative TRUS-bx and moderate to highly suspicious lesions on mpMRI, an mpMRI “targeted-only” biopsy strategy may be most beneficial. However, more comprehensive, multi-center studies are needed before recommending an mpMRI “targeted-only” biopsy strategy for widespread adoption.

The authors stated that this study had several drawbacks. TRUS-bx and mpMRI results were interpreted by 1 highly experienced TRUS-operator and 1 dedicated mpMRI physician. Less experienced operators might not achieve the same diagnostic yield. The TRUS-bx technique for patients with prior negative TRUS-bx was modified to target the medial cores more anteriorly to sample a greater proportion of the anterior prostate, where tumors undetected by initial biopsies often reside. However, the repeated TRUS-bx scheme comprised the same prostatic sextant zones used in the initial biopsy setting and did not include extended cores (greater than 10 to 12 samples) or saturation-biopsies. Routinely increasing the number of cores might have improved the diagnostic rates at repeat TRUS-bx. However, it would not change the utility of mpMRI-bx and insignificant PCa would still be detected. The patients in this study were also selected as good candidates for targeted biopsies because many presented with rising PSA levels and clinical suspicion warranting a repeat biopsy. Therefore, these results may not be directly applicable to biopsy-naïve men, who constitute a different patient population. As a result, future studies in biopsy-naïve men such as the PRECISION trial are evolving to clarify the implications of mpMRI-bx and a “targeted-only” approach in the initial biopsy setting. Additionally, because biopsy results were used comparatively in this study, the true rate of false negative readings could not be assessed for patients with negative biopsies. A further analysis of patients who subsequently underwent RP following diagnosis might identify some cases, although this was a selected patient group. Using biopsy results as comparing reference allowed the comparison of 2 biopsy approaches in a repeat biopsy setting. Furthermore, previous studies have shown a good correlation between mpMRI and the RP specimen, even though some report that mpMRI failed to detect significant tumors in 5 to 28 % of cases. Thus, there was an unknown proportion of significant cancers that were difficult to detect using mpMRI. In addition, prostate biopsies are still necessary to confirm the presence of PCa in a suspicious lesion, as mpMRI findings are not cancer-specific. Furthermore, targeted mpMRI-bx could not always be accurate due to mis-registration using image-fusion and PCa lesions may therefore be missed. Conversely, unnecessary targeted biopsies may be conducted due to false-positive mpMRI readings. Moreover, the cost-effectiveness of a diagnostic mpMRI and the additional use of mpMRI-bx have not been fully explored. Thus, cautions should be made about recommending “targeted-only” biopsies over a systematic approach. Nevertheless, these findings indicated that cancers that are not detected by mpMRI followed by mpMRI-bx in a repeat biopsy setting are unlikely to be significant higher-grade tumors that are detected using systematic repeated TRUS-bx cores. Finally, the criterion for significant PCa was based solely on the GS from histopathological assessment of the biopsies and the authors chose not to include patient-specific static risk factors such as age, PSA, or number of visible MRI lesions, as they did not change between biopsy modalities. A number of definitions of insignificant and significant PCa including clinical findings, GS, and tumor volume (number of positive cores and maximum cancerous core length) have been proposed. Including these parameters might have changed these results. However, there is still no clear consensus on the definition of significant PCa in targeted biopsies, although incorporating the maximum cancerous core length has been recommended for risk stratification. Including only GS findings in the definition of significant PCa led to a more strict comparison between the 2 biopsy modalities.

Kasivisvanathan and colleagues (2018) stated that mpMRI, with or without targeted biopsy, is an alternative to standard TRUS-guided biopsy for PCa detection in men with a raised PSA level who have not undergone biopsy. However, comparative evidence is limited. In a multi-center, randomized, non-inferiority trial, these researchers assigned men with a clinical suspicion of PCa who had not undergone biopsy previously to undergo MRI, with or without targeted biopsy, or standard TRUS-guided biopsy. Men in the MRI-targeted biopsy group underwent a targeted biopsy (without standard biopsy cores) if the MRI was suggestive of PCa; men whose MRI results were not suggestive of PCa were not offered biopsy. Standard biopsy was a 10- to 12-core, TRUS-guided biopsy. The primary outcome was the proportion of men who received a diagnosis of clinically significant (CS) cancer; secondary outcomes included the proportion of men who received a diagnosis of clinically insignificant cancer. A total of 500 men underwent randomization. In the MRI-targeted biopsy group, 71 of 252 men (28 %) had MRI results that were not suggestive of PCa, so they did not undergo biopsy; CS cancer was detected in 95 men (38 %) in the MRI-targeted biopsy group, as compared with 64 of 248 (26 %) in the standard-biopsy group (adjusted difference, 12 percentage points; 95 % CI: 4 to 20; p = 0.005). MRI, with or without targeted biopsy, was non-inferior to standard biopsy, and the 95 % CI indicated the superiority of this strategy over standard biopsy. Fewer men in the MRI-targeted biopsy group than in the standard-biopsy group received a diagnosis of CS cancer (adjusted difference, -13 percentage points; 95 % CI: -19 to -7; p < 0.001). The authors concluded that the use of risk assessment with MRI before biopsy and MRI-targeted biopsy was superior to standard TRUS-guided biopsy in men at clinical risk for PCa who had not undergone biopsy previously.

The authors stated that this study had several drawbacks. First, despite the use of standardized reporting of MRI results, the central quality-control review of mpMRIs showed moderate agreement (78 %) between the site and the central radiologist reading, a finding that highlighted that there is still room for improvement in attaining consistency in the reporting of the results of mpMRI. Regardless, the degree of agreement with central interpretation was similar to the inter-rater agreement that has been oberved in other studies involving expert readers of mpMRIs. This finding highlighted the need for further research regarding improvements to the standardization, reproducibility, and reporting of mpMRIs. Second, a small proportion of the pathological test results were up-graded or down-graded on central pathological review. However, the differences were not substantial between groups, and the agreement that was observed on central review was consistent with that seen in the literature. Third, there were concerns regarding the men with negative results on mpMRI who do not undergo biopsy. It has been shown that these men had a low risk of clinically significant cancer, but nonetheless, follow-up with monitoring of the PSA level was routine, reasonable and safe. Participants provided consent for long-term follow-up in national registries. Moreover, this trial showed that, among men with negative results on initial tests, a far greater proportion of the participants in the standard biopsy group underwent further diagnostic tests than did those in the MRI-targeted biopsy group, a finding that confirmed that a negative result on mpMRI was more reassuring to the participants and clinicians than a negative result on standard TRUS-guided biopsy. Fourth, it was possible that clinically significant cancers may have been missed by the omission of standard biopsy cores in men in the MRI-targeted biopsy group. Previous well-designed studies have highlighted that the percentage of cases of clinically significant cancer that were missed by MRI-targeted biopsy but detected by standard TRUS-guided biopsy was low, between 0 % and 10 %. Despite more than 25 % of the men avoiding a biopsy, this trial showed that when clinicians limited themselves to the use of MRI-targeted biopsies only, the rates of detection of clinically significant cancer were higher than those seen with the standard of care. Furthermore, because systematic biopsy was avoided, clinically insignificant cancer was detected in fewer men, which may have a substantial benefit in reducing the over-treatment of men with PCa. If both systematic biopsy and MRI-targeted biopsy were performed in the same man at the same time, the performance of one test could be influenced by the other, which would make it difficult to evaluate the unbiased performance of each test individually.

In an editorial that accompanied the afore-mention study by Kasivisvanathan et al (2018), Barry and Rosenkrantz (2018) stated that the findings of the PRECISION trial represented intermediate outcomes, whereas outcomes such as PCa morbidity and mortality will take large numbers of men and many years to assess. Moreover, they noted that the findings suggested that mpMRI may have a place in decisions regarding prostate biopsy. The editorialists stated that because of the major implications for wider use of mpMRI in evaluating men with elevated PSA levels, including the need for additional MRI equipment and personnel and the effect on total costs. these findings should be replicated and extended.

Di Campli and associates (2018) noted that MRI plays a crucial role to identify men with a high likelihood of CS PCa who require immediate biopsy. The added value of dynamic contrasted-enhanced imaging (DCE) MRI in combination with T2-weighted imaging and DWI is controversial (risks related to gadolinium administration, duration of MR examination, financial burden, effects on diagnostic performance). A comparison of a bi-parametric and a standard mpMRI protocol, taking into account the different experience of the readers, may help to choose the best MR approach regarding diagnostic performance. These investigators determined the added value of DCE over T2-weighted imaging (T2-WI) and DWI for the detection of CS PCa, and examined how it affected the diagnostic performance of 3 readers with different grade of experience in prostate imaging. A total of 85 patients underwent prostate MR examination at 1.5 T MR scanner performed because of elevated PSA level and/or suspicion of PCa at DRE. Two MR images sets (Set 1 = bi-parametric, Set 2 = multi-parametric) were retrospectively and independently scored by 3 radiologists with 7, 3 and 1 years of experience in prostate MR imaging respectively, according to PI-RADS v2. Sensitivity, specificity, positive predictive value (PPV), and NPV were calculated by dichotomizing reader scores; ROC analysis was performed and areas under the curve (AUCs) were calculated for each reader and image set. A comparison of ROC curves was performed to test the difference between the areas under the ROC curves among the 3 readers. There was no significant difference regarding the detection of CS tumor among the 3 readers between the 2 image sets. The AUC for the bi-parametric MRI and mpMRI protocol was 0.68 to 0.72 (Reader 1), 0.72 to 0.70 (Reader 2), and 0.60 to 0.54 (Reader 3). Respectively; ROC curve comparison revealed no statistically significant differences for each protocol among the most experienced (Reader 1) and the other readers (Readers 2 and 3). The authors concluded that the diagnostic accuracy of a bi-parametric MRI protocol consisting of T2-weighted imaging and DWI was comparable with that of a standard mpMRI protocol for the detection of CS PCa. Furthermore, the experience of the reader did not significantly modify the diagnostic performance of both MR protocols.

Faira and co-workers (2018) stated that the current recommendation of using TRUSB to diagnose PCa misses CS cancers. More sensitive biopsies (e.g., TPMB) are too resource intensive for routine use, and there is little evidence on mpMRI. These investigators identified the most effective and cost-effective way of using these tests to detect CS PCa. Cost-effectiveness modeling of health outcomes and costs of men referred to secondary care with a suspicion of PCa prior to any biopsy in the United Kingdom National Health Service (NHS) using information from the diagnostic Prostate MR Imaging Study (PROMIS). Interventions included combinations of mpMRI, TRUS-guided biopsy (TRUSB), and TPMB, using different definitions and diagnostic cut-offs for CS cancer. Outcome measures and statistical analysis included strategies that detect the most CS cancers given testing costs, and incremental cost-effectiveness ratios (ICERs) in quality-adjusted life years (QALYs) given long-term costs. The use of mpMRI first and then up to 2 MRI-targeted TRUSBs detected more CS cancers per pound spent than a strategy using TRUSB first (sensitivity = 0.95 [95 % CI: 0.92 to 0.98] versus 0.91 [95 % CI: 0.86 to 0.94]) and was cost-effective (ICER = £7,076 [€8,350/QALY gained]). The authors concluded that an under certain assumptions, the use of mpMRI first and then up to 2 TRUS-guided biopsy was better than the current clinical standard. However, these findings were sensitive to the test costs, sensitivity of MRI-targeted TRUSB, and long-term outcomes of men with cancer, which warrant more empirical research.

Brown and associates (2018) noted that men with suspected PCa usually undergo TRUS-guided prostate biopsy; TRUS-guided biopsy can cause side effects and has relatively poor diagnostic accuracy; mpMRI used as a triage test might allow men to avoid unnecessary TRUS-guided biopsy and improve diagnostic accuracy. In a validating paired-cohort study and an economic evaluation using a decision-analytic model, these investigators evaluated the ability of mpMRI to identify men who can safely avoid unnecessary biopsy, assessed the ability of the mpMRI-based pathway to improve the rate of detection of CS cancer compared with TRUS-guided biopsy, and estimated the cost-effectiveness of a mpMRI-based diagnostic pathway. This study was carried out in 11 NHS hospitals in England; participants were men at risk of PCa undergoing a 1st prostate biopsy. Subjects underwent 3 tests: mpMRI (the index test), TRUS-guided biopsy (the current standard), and TPM biopsy (the reference test). Diagnostic accuracy of mpMRI, TRUS-guided biopsy and TPM-biopsy were measured by sensitivity, specificity, PPV and NPV using primary and secondary definitions of CS cancer. The percentage of negative MRI scans was used to identify men who might be able to avoid biopsy. Diagnostic study -- a total of 740 men were registered and 576 underwent all 3 tests. According to TPM-biopsy, the prevalence of any cancer was 71 % [95 % CI: 67 % to 75 %]. The prevalence of CS cancer according to the primary definition (a Gleason score of greater than or equal to 4 + 3 and/or cancer core length of greater than or equal to 6 mm) was 40 % (95 % CI: 36 % to 44 %). For CS cancer, TRUS-guided biopsy showed a sensitivity of 48 % (95 % CI: 42 % to 55 %), specificity of 96 % (95 % CI: 94 % to 98 %), PPV of 90 % (95 % CI: 83 % to 94 %) and NPV of 74 % (95 % CI: 69 % to 78 %). The sensitivity of mpMRI was 93 % (95 % CI: 88 % to 96 %), specificity was 41 % (95 % CI: 36 % to 46 %), PPV was 51 % (95 % CI: 46 % to 56 %) and NPV was 89 % (95 % CI: 83 % to 94 %). A negative mpMRI scan was recorded for 158 men (27 %). Of these, 17 were found to have CS cancer on TPM-biopsy. Economic evaluation -- the most cost-effective strategy involved testing all men with mpMRI, followed by MRI-guided TRUS-guided biopsy in those patients with suspected CS cancer, followed by re-biopsy if CS cancer was not detected. This strategy was cost-effective at the TRUS-guided biopsy definition 2 (any Gleason pattern of greater than or equal to 4 and/or cancer core length of greater than or equal to 4 mm), mpMRI definition 2 (lesion volume of greater than or equal to 0.2 ml and/or Gleason score of greater than or equal to 3 + 4) and cut-off point 2 (likely to be benign) and detected 95 % (95 % CI: 92 % to 98 %) of CS cancers. The main drivers of cost-effectiveness were the unit costs of tests, the improvement in sensitivity of MRI-guided TRUS-guided biopsy compared with blind TRUS-guided biopsy and the longer-term costs and outcomes of men with cancer. The authors concluded that incorporating mpMRI into the diagnostic pathway as an initial test prior to prostate biopsy may reduce the proportion of men having unnecessary biopsies, improve the detection of CS PCa, and increase the cost-effectiveness of the PCa diagnostic and therapeutic pathway. The PROMIS data set will be used for future research; this is likely to include modeling prognostic factors for CS cancer, optimizing MRI scan sequencing and biomarker or translational research analyses using the blood and urine samples collected. Better-quality evidence on long-term outcomes in PCa under the various management strategies is needed to better assess cost-effectiveness. The value-of-information analysis should be developed further to assess new research to commission.

The authors stated that this study had several drawbacks. First, TPM-biopsy was limited by the size of the template grid equipment and interference with needle insertion from the bony pubic arch. This meant that some men with very large prostates (greater than 100 ml) had to be excluded from the study, which may result in a slight decrease in the proportion of true negatives in the study population. However, although it was too invasive for routine use in the clinic, TPM-biopsy offered the precision required for a highly accurate reference test by virtue of its uniform 5-mm sampling density over the entire prostate. Second, these investigators acknowledged that PROMIS represented a selected group, although it was encouraging that men who were subsequently withdrawn from the study did not differ from those who completed it in terms of the baseline data collected. The authors also acknowledged that these men may differ in terms of other characteristics that these investigators did not measure. Third, some systematic error may have been introduced into the standard test by the sequence in which TPM-biopsy and TRUS-guided biopsy were performed, and these researchers were unable to control for this. Carrying out TPM-biopsy before TRUS-guided biopsy may have contributed to the poor accuracy of the standard test because of swelling, distortion and tissue disruption. The sequencing was based on patient safety considerations and on the need to preserve the integrity of the reference test. Infection was a major risk associated with TRUS-guided biopsy because of breaching of the rectal mucosa. Participants might have been exposed to excess risk if bacteria had been introduced into the prostate prior to multiple needle deployments of an inherently sterile TPM-biopsy. Fourth, because of the need for blinding, the targeting of suspicious lesions identified in MRI was not possible, and these researchers could not accurately assess the clinical utility of a MRI-targeted biopsy approach. Fifth, although the authors included some measurements of inter-observer variability, these were between 2 expert readers. Further work is needed to measure the inter-observer variability of expert and non-expert reporters. Last, these researchers acknowledged that likelihood ratios and area under the ROC curves were not part of the pre-specified analysis plan. These metrics provided an overall measure of test performance and clarified the relative strengths and weaknesses of each test, particularly as likelihood ratios were independent of disease prevalence. The mpMRI scans were performed using a magnetic field strength of 1.5 T. This was chosen because it was widely available and because the authors assumed that any benefit shown was likely to be at least maintained at higher magnetic field strengths, where it was possible to achieve greater signal-to-noise ratios. Finally, the authors acknowledged the benefits of communicating risk using the 1 to 5 ordinal scale conferred by the Gleason grade group. The end-points could not, unfortunately, be re-classified using Gleason grade group as they incorporated histopathology for the primary end-point (Gleason grade 4 + 3 or Gleason grade group 3) and secondary end-point (Gleason grade 3 + 4 or Gleason grade group 2), and the cancer core length thresholds, which were not part of the Gleason grade group definitions. One of the principal outcomes of PROMIS was that a normal MRI result was not associated with any Gleason grade group of greater than or equal to 3.

An UpToDate review on “The role of magnetic resonance imaging in prostate cancer” (Tempany et al, 2018) states that “The potential role of multiparametric MRI was illustrated by the PRECISION trial, which included 500 men with a clinical suspicion of prostate cancer (elevated serum PSA, abnormal digital rectal examination, or both). Study participants were randomly assigned to either standard TRUS-guided 10- to 12-core biopsy or to multiparametric MRI. If the MRI detected areas that were equivocal or suggestive (PI-RADS version 2 score ≥3) of clinically significant prostate cancer (Gleason score 3+4 or greater), patients underwent an MR-targeted biopsy (to a maximum of three sites and a maximum of four cores per site) … There is good evidence that multiparametric MRI prior to radical prostatectomy can be used to verify organ-confined status and thus support the decision to perform nerve-sparing radical prostatectomy. However, this practice has not been incorporated as a standard of care in major practice guideline … Multiparametric MRI may also be helpful in differentiating between residual local disease and distant metastatic spread … ”.

Transrectal Ultrasonography (TRUS) plus Ultrasonic Elastosonography and Contrast-Enhanced US for Staging of Rectal Cancer

Feng and colleagues (2020) examined biplane TRUS plus ultrasonic elastosonography (UE) and contrast-enhanced US (CEUS) in tumor (T) staging of rectal cancer. Between March 2016 and January 2019, a total of 66 rectal cancer patients who completed biplane TRUS plus UE and CEUS for pre-operative work-up and were treated by primary total mesorectal excision (TME) were retrospectively analyzed. The accuracy of TRUS plus UE and CEUS in all T staging of rectal cancer was 69.7 %. The highest accuracy was achieved in the T3 stage (87.5 %), while it was 71.4 % and 50.0 % in the T1 and T2 stage, respectively. The mean sizes of uT1-T2 lesions and uT3-T4 lesions were 30.0 ± 10.6 mm (range of 10.0 to 55.0) and 40.2 ± 11.2 mm (range of 14.0 to 57.0), respectively (p < 0.001). According to the receiver operating characteristic (ROC) curve to predict pT stages (pT1,2 versus pT3), the optimal cut-off value of lesions in greatest dimension was 28.5 mm by TRUS with areas under the curve (AUC) of 0.769, and the optimal cut-off values of peak systolic velocity (PSV) and resistive index (RI) were 18.8 cm/sec and 0.645, respectively. The AUCs of PSV and RI were 0.588 and 0.555, respectively. The authors concluded that diagnostic accuracy of TRUS plus UE and CEUS in T staging of rectal cancer did not reach the excellent published study results, especially for patients with early rectal cancer. Tumor sizes, PSV and RI are useful additions for TRUS in T staging of rectal cancer.

The authors stated that this study had several drawbacks, including the retrospective nature of the study design, a single-center experience, and the limited number of patients (n = 66), which could have affected the outcomes. Nevertheless, this report was noteworthy because this was the 1st study to examine biplane TRUS plus UE and CEUS in T staging of rectal cancer after primary TME. Ultrasonography based radiomics has been used to improve prediction of lymph node metastasis of rectal cancer. The role of UE and CEUS based radiomics for rectal cancer should be elucidated in the future.

Furthermore, National Comprehensive Cancer Network’s clinical practice guideline on “Rectal cancer” (Version 6.2020) does not mention transrectal ultrasonography plus ultrasonic elastosonography and contrast-enhanced US as a management tool.

Table: CPT Codes / HCPCS Codes / ICD-10 Codes
Code	Code Description
*Information in the [brackets] below has been added for clarification purposes. Codes requiring a 7th character are represented by "+"*:
CPT codes covered if selection criteria are met:
45341	Sigmoidoscopy, flexible: with endoscopic ultrasound examination
76872	Ultrasound, transrectal [TRUS combined with USG elastosonography plus contrast-enhanced USG not covered for staging of rectal cancer]
76873	prostate volume study for brachytherapy treatment planning (separate procedure)
CPT codes not covered for indications listed in the CPB:
76376	3D rendering with interpretation and reporting of computed tomography, magnetic resonance imaging, ultrasound, or other tomographic modality with image postprocessing under concurrent supervision; not requiring image postprocessing on an independent workstation
76856	Ultrasound, pelvic (nonobstetric), real time with image documentation; complete
76978	Ultrasound, targeted dynamic microbubble sonographic contrast characterization (non-cardiac)
76979	each additional lesion with separate injection (List separately in addition to code for primary procedure)
76981 - 76983	Ultrasound, elastography
78812	Positron emission tomography (PET) imaging; skull base to mid-thigh
Other CPT codes related to the CPB:
45342	Sigmoidoscopy, flexible; with transendoscopic ultrasound guided intramural or transmural fine needle aspiration/biopsy(s)
76870	Ultrasound, scrotum and contents
77761 - 77778, 77789	Brachytherapy
ICD-10 codes covered if selection criteria are met:
C19 - C21.8	Malignant neoplasm of rectosigmoid junction, rectum, anus and anal canal
C61	Malignant neoplasm of prostate
C76.3	Malignant neoplasm of pelvis
C78.5	Secondary malignant neoplasm of large intestine and rectum
C79.82	Secondary malignant neoplasm of genital organs
D01.1 - D01.3	Carcinoma in situ of rectosigmoid junction, rectum, anus and anal canal
D07.5	Carcinoma in situ of prostate
D12.7 - D12.9	Benign neoplasm of rectosigmoid junction, rectum, anus and anal canal
D29.1	Benign neoplasm of prostate
D37.5	Neoplasm of uncertain behavior of rectum
D40.0	Neoplasm of uncertain behavior of prostate
K60.3 - K60.5	Fistula of anal and rectal regions
K61.0 - K61.4	Abscess of anal and rectal regions
K62.89	Other specified diseases of anus and rectum (to be used for anal sphincter dysfunction)
N46.01 - N46.9	Male infertility
R36.1	Hematospermia
R97.20	Elevated prostate specific antigen [PSA]
ICD-10 codes not covered for indications listed in the CPB:
Z03.89	Encounter for observation for other suspected diseases and conditions ruled out
Z12.12	Encounter for screening for malignant neoplasm of rectum
Z12.5	Encounter for screening for malignant neoplasm of prostate

The above policy is based on the following references:

Aarnink RG, Beerlage HP, De La Rosette JJ, et al. Transrectal ultrasound of the prostate: Innovations and future applications. J Urol. 1998;159(5):1568-1579.
Abel S, Renz P, Gayou O, et al. Evaluation of intraoperative magnetic resonance imaging/ultrasound fusion optimization for low-dose-rate prostate brachytherapy. J Contemp Brachytherapy. 2017;9(4):309-315.
Aboumarzouk OM, Ogston S, Huang Z, et al. Diagnostic accuracy of transrectal elastosonography (TRES) imaging for the diagnosis of prostate cancer: A systematic review and meta-analysis. BJU Int. 2012;110(10):1414-1423; discussion 1423.
Ahmad I, Krishna NS. Hemospermia. J Urol. 2007;177(5):1613-1618.
Ahmed HU, El-Shater Bosaily A, Brown LC, et al.; PROMIS study group. Diagnostic accuracy of multi-parametric MRI and TRUS biopsy in prostate cancer (PROMIS): A paired validating confirmatory study. Lancet. 2017;389(10071):815-822.
American Urologic Association (AUA). Early detection of prostate cancer and use of transrectal ultrasound. In: American Urologic Association 1992 Policy Statement Book. Linthicum, MD: AUA; 1992.
Anderson JE. Prostatic imaging: The role of transrectal ultrasound. Aust Fam Physician. 1995;24(4):557-558, 560-561.
Applewhite JC, Matlaga BR, McCullough DL, et al. Transrectal ultrasound and biopsy in the early diagnosis of prostate cancer. Cancer Control. 2001;8(2):141-150.
Arsov C, Rabenalt R, Blondin D, et al. Prospective randomized trial comparing magnetic resonance imaging (MRI)-guided in-bore biopsy to MRI-ultrasound fusion and transrectal ultrasound-guided prostate biopsy in patients with prior negative biopsies. Eur Urol. 2015;68(4):713-720.
Baco E, Rud E, Eri LM, et al. A randomized controlled trial to assess and compare the outcomes of two-core prostate biopsy guided by fused magnetic resonance and transrectal ultrasound images and traditional 12-core systematic biopsy. Eur Urol. 2016;69(1):149-156.
Badiozamani KR, Wallner K, Cavanagh W, et al. Comparability of CT-based and TRUS-based prostate volumes. Int J Radiat Oncol Biol Phys. 1999;43(2):375-378.
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Last Review 03/19/2021

Effective: 07/21/1995

Next Review: 01/13/2022
Review History
Definitions

Transrectal Ultrasound

Policy

Background

Multiparametric MRI/US Fusion Biopsy

Intraoperative MRI/US Fusion Optimization for Low-Dose-Rate Prostate Brachytherapy

Photoacoustic Imaging for Prostate Cancer Angiogenesis

Positron Emission Tomography (PET) Image-Directed, Three-Dimensional US-Guided Biopsy

Multi-Parametric MRI for Diagnosis of Prostate Cancer

Transrectal Ultrasonography (TRUS) plus Ultrasonic Elastosonography and Contrast-Enhanced US for Staging of Rectal Cancer

Information in the [brackets] below has been added for clarification purposes. Codes requiring a 7th character are represented by "+":

CPT codes covered if selection criteria are met:

CPT codes not covered for indications listed in the CPB:

Other CPT codes related to the CPB:

ICD-10 codes covered if selection criteria are met:

ICD-10 codes not covered for indications listed in the CPB:

The above policy is based on the following references:

Policy History

Additional Information

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