**3.4.4 Color, power doppler**

114 Prostate Cancer – Diagnostic and Therapeutic Advances

they may supplement each other, will become important source of research endeavours in the future. HistoScanning manufacturer intends to use the technology also for other cancers, like ovary, thyroid and breast, which may be advantageous as prostate diagnosis may benefit from multidisciplinary team. On the other side, C-TRUS ANNA was developed by urologists for urologists, can be used in almost any setting (any digital ultrasound machine is good) and seems to have at present more peer reviewed data. HistoScanning is not aiming only towards prostate biopsy guidance, but also aims at other potentially useful predictions regarding prostate cancer and seems to have larger research base with groups from different countries (UK, Germany) who study its potential applications. Whether one or both

Real time transrectal ultrasonoelastograpy of the prostate is aimed at discrimination between harder and softer areas of prostate tissue. MRI elastography technology was also developed (S. Li et al., 2011), but here only ultrasound is described. Back-scattered ultrasound waves are displaced with compression or decompression of tissue (approximately 2%), harder areas showing less displacement compared to softer (Salomon et al., 2008). Elastography is performed in real-time, at the time of biopsy – no previous transrectal ultrasound examination (as for C-TRUS ANNA) is necessary. By subjectively observing US elastography picture, operator aims at evaluating symmetry of stiffness, focal areas of hardness and persistence of stiffness with probe tilting, aiming at stiff nodule more than 5 mm in diameter and persistence of stiffness after probe tilting (Giurgiu et al., 2011). There are different scoring systems (Salomon et al., 2009), some focus on identifying smaller lesions and potentially showing increased sensitivity (Kamoi et al., 2008). Technique of elastography is still improving, better differentiation markers are being developed constantly (Zhang et al., 2011). Further, standardization of compression with idea of leaving this part to the machine is also in testing (Tsutsumi et al., 2010). Regarding companies which provide elastography equipment, most studies have been performed using Hitachi machine, which is commercially available for prostate applications and most tested, although other manufacturers also offer this technology. Among target-biopsy techniques elastograpy seems at present most widely spread as technology is also in use for breast cancer (primarily) and investment needed is only in US machine and probe, there are no perinvestigation charges as for C-TRUS ANNA. Elastography procedure is also much simpler compared to MRI-US fusion. Another advantage of elastography is in its compatibility with power/color doppler techniques for image guidance, which can be performed simultaneously, therefore gaining from two sources. There are quite a few published studies describing experience with prostate elastograpy from different parts of the world. Study results are positive and seem to support claims that elastography improves cancer detection rate. One of the very appealing studies, from USA, analyzed help of elastograpy in biopsy of men with PSA values between 1.25 and 4 and free/total PSA ratio less than 18% (Aigner et al., 2010). They were able to detect 24% of cancers using 5 cores with elastography guidance compared to 5.1% cancers using 10 systematic biopsies. Another study, from Romania, used and compared in the same set of patients gray scale, doppler and elastograpyh data (Giurgiu et al., 2011). They found, in a series of 65 patients and 43% of them with identified cancer on biopsy, sensitivity of elastograpy to be 68% and specificity 62%. Particularly promising was elastography in a subgroup of older than 70 years, where sensitivity

techniques will stand the test of time and what role they will play remains open.

**3.4.3 Elastography** 

Angiogenesis is important in development of cancer and increased vascularity was detected in tumors in general and in radical prostatectomy specimens, therefore use of ultrasound to detect those changes was proposed. Color doppler imaging estimates mean frequency shift of doppler signal to determine velocity and direction of flow. Power doppler shows total energy of the signal by integrating it, therefore resulting in sig`nal with homogenous background and more precise detection of smaller and low flow vessels (Remzi et al., 2004). Study of usefulness of power and color doppler for evaluation of hypoechoic lesions showed 80% sensitivity and 82% specificity for detecting prostate cancer (Cho et al., 2000). Standardized criteria for scoring different degrees and distributions of prostatic vascularity were developed and also subjective scales seem to work well (Mitterberger et al., 2010), however this points to high subjectivity of the method, which is its drawback.

Power doppler was used for evaluation of peripheral prostatic capsular vessels, parenchymal vessels and vessels anastomosing with extraprostatic vessels (Sauvain et al., 2003). Criteria for suspicion of cancer in this study were increase in number of intra-lesional vessels, disoriented vessels or verticalized vessels in peripheral gland, asymmetrical blood flow, mass effect on the intraprostatic perilesional vessels and vessels in peripheral margins. Analyzing all those criteria, they aimed at estimation of prostate cancer stage by dividing lesions into three groups: absent extracapsular involvement, undetermined extracapsular involvement and presumably present extracapsular involvement. In this series, 55.7% patients had cancer and sensitivity of power doppler ultrasound was claimed to be 92%, specificity 72% (compared to 88% and 58% for ultrasound only). Group with ultrasound estimated lack of extracapsular involvement had this found in final pathology in 11%, while group with ultrasound suspicious for extracapsular involvement had it confirmed in 87%. Authors (Sauvain et al., 2003) conclude power doppler ultrasound improves accuracy of ultrasound imaging in the diagnosis of cancer, can increase detection rate, optimize number of biopsy cores and also predict extracapsular invasion by identification of capsule perforating vessels.

When using ultrasound for evaluation of minor differences in prostate blood flow between cancerous and benign areas, many factors can interfere with the results – for example position of the patient – it was shown left decubitus position caused flow asymmetry resulting in more biopsies directed toward left side without improving detection rate (Halpern et al., 2002).

Future of Prostate Biopsy: Who Will Get It and How? 117

nomogram (Remzi et al., 2005), as it is obvious higher number of cores gives better sampling and improves detection. Later, while some still questioned Vienna nomogram's usefulness (Lecuona & Heyns, 2010), it became obvious number of biopsy detected cancers is related to sampling density, which is a quotient between prostate size and number of cores taken. A lot of nomograms, which predict probability of positive prostate biopsy, take sampling density into account (Chun et al., 2007). Regarding number of cores, it went up from six at first to eight, later ten, later twelve (a lot of us still using this number at present for majority of patients for first biopsy), fifteen, eighteen... up to twenty-one (Guichard et al., 2007) core per biopsy session. This number seems to be highest present routine extended systematic biopsy scheme, simply because twenty-four or more cores is called saturation biopsy (Ahyai et al., 2010). Many have also argued they were unable to increase their cancer detection rate after increasing number of cores from for example 12 to 18. This underscores importance not only of

**3.6 Free hand systematic biopsy, targeted biopsy, prostatic mapping or combination**  Goal of prostate biopsy is not only to find "some" cancer in the prostate, as it was in the past. Now, it has not only to provide representative sample of DIL (dominant intraprostatic lesion), but also to show all "important" cancer areas in the prostate, describe precisely where they are and ensure other regions are cancer free. This is in contrast to efforts of targeted biopsies which claim they may reduce pain and burden of biopsy by reducing

Prostate-mapping biopsy approaches, for example TargetScann, have different approach – they aim at precisely sampling predefined sections of prostate with larger number of cores. Electronic doppler ultrasound probes are becoming increasingly complex and sensitive to detect blood flow signals in the prostate to help guiding biopsy. TargetScan's device ultrasound probe is sector and at present can not be used for image-guided approaches, but seems to provide relatively reliable results regarding prostate mapping, which is very important for all targeted therapy approaches (Andriole et al., 2007). "Robotic" probes (ultrasound systems, which are just inserted into rectum by physician and then guided by

We have therefore a mix of partly competing, some probably complementary and some excluding technologies aiming at improving prostate cancer detection and staging. Which will find its way into every-day practice and to what extent, remains open. It seems at present repeat biopsy yield is about 20%-40% and targeted biopsy methods claim, in repeat, previously negative setting, yield of 50%. All those new approaches need evaluation and confirmation. One way may be showing significantly better performance of targeted or mapping approaches compared to prediction of nomograms for repeat biopsy setting (Chun

Overall, it seems at present first biopsy should be 10-18 laterally directed cores (depending on prostate size, for prostates larger than 50 ml minimum 14). Targeted biopsy only, with less than 6 cores, may generally not be appropriate for the first biopsy, as it is far from 100%

For second and later biopsies, as targeted opinions are becoming more and more widespread and therefore accessible and are not untested technical glitches any more, we may in 2011 suggest any of the recently developed opinions, depending on local availability,

pressing buttons, are being developed also by other manufacturers.

number, but also direction of cores.

number of cores.

et al., 2007).

as follows.

and we need to assess whole prostate.

Different pharmaceutical interventions were proposed to increase difference between cancer and benign tissue: improved view with contrast agent, increased flow with phosphodiesterase inhibitor (vardenafil) (Morelli et al., 2011) or decreased flow with 5 alpha reductase inhibitor or combination of 5-alpha reductase inhibitor with contrast agent (Mitterberger et al., 2008).

Contrast enhanced transrectal prostate ultrasound was extensively evaluated in multiple research projects (Wink et al., 2008). Microbubbles act as additional reflectors in bloodstream and increase sensitivity of color and power doppler imaging. Newer techniques, for example harmonic imaging, were also tested. Use of ultrasound contrast agent is associated with only minimal side effects, like alterations in taste, flush or pain at the injection site. However, it costs additional money for contrast. It should be performed in 4 minutes after contrast injection (half life of bubbles). Further drawback is strong operator-dependence of the technique. Contrast enhanced ultrasound enables visualisation of prostate cancer (in up to 78% of cases), but sensitivity and specificity are not enough to avoid systematic biopsies. Targeted biopsies using this technique are claimed to allow lower number of cores per session without decrease in detection rate (Wink et al., 2008).

Use of 5-alpha reductase inhibitor was proposed in two staged approach: first color/power doppler evaluation of prostate is followed by 1-3 week of dutasteride and than reevaluation and biopsy guided to areas, where vascular signals have not decreased after treatment. Additional sextant systematic sample was also taken. Researchers claimed increased yield in targeted cores (20%) compared to sextant cores (8%) (Ives et al., 2005).

#### **3.5 Biopsy schemes and number of cores**

After finger guided biopsy strategies were replaced with ultrasound guided, it soon became clear (group around dr. Stamey, Stanford) 6 cores, taken in a systematic fashion, finds more cancer than aiming at hypo-echoic areas or randomly (Hodge et al., 1989). Standard approach, which hold for more than 10 years, was established: six cores were taken in parasagittal plane, one at the base, one mid-gland and one at apex. However, patients with negative biopsies and still suspicious for cancer, had repeat biopsies, which were almost as often positive as first biopsy – therefore it was obvious the system was not perfect. Aim should be – perform biopsy – if it is negative, then there is no cancer. Reality was – perform classic sextant scheme biopsy – if it is negative, then there is almost the same probability for cancer as before biopsy. So – search has begun for improvement of systematic biopsy scheme (mainly searching for optimal number of cores and location of cores) and this search has not settled yet. As this text aims at the future, not past, only some examples will be pointed out. Inadequacy of sextant scheme was proven many times, for example (Norberg et al., 1997) and also recent larger and longer retrospective data analyzes still turn to this question, for example regarding sextant biopsy's ability to predict unilateral disease (Mayes et al., 2011). First it became clear biopsies should be directed more laterally in the peripheral zone of the prostate (Eskew et al., 1997). Later, it seemed transitional zone inclusion may improve cancer detection, however this was abandoned for initial biopsy, because of inferior gain from transitional zone directed cores compared to more sampling toward far lateral mid-gland and anterior-apical areas. A lot of cancers are located on anterior horn of prostate. With repeat biopsy, of course, anterior transitional zone is also sampled (Chun et al., 2010). Innumerous analyzes have shown – more cores – more cancer. Prostate size has a role (Taneja, 2006). Nomogram was developed to optimize number of cores needed in relation to prostate size – so called Vienna

Different pharmaceutical interventions were proposed to increase difference between cancer and benign tissue: improved view with contrast agent, increased flow with phosphodiesterase inhibitor (vardenafil) (Morelli et al., 2011) or decreased flow with 5 alpha reductase inhibitor or combination of 5-alpha reductase inhibitor with contrast

Contrast enhanced transrectal prostate ultrasound was extensively evaluated in multiple research projects (Wink et al., 2008). Microbubbles act as additional reflectors in bloodstream and increase sensitivity of color and power doppler imaging. Newer techniques, for example harmonic imaging, were also tested. Use of ultrasound contrast agent is associated with only minimal side effects, like alterations in taste, flush or pain at the injection site. However, it costs additional money for contrast. It should be performed in 4 minutes after contrast injection (half life of bubbles). Further drawback is strong operator-dependence of the technique. Contrast enhanced ultrasound enables visualisation of prostate cancer (in up to 78% of cases), but sensitivity and specificity are not enough to avoid systematic biopsies. Targeted biopsies using this technique are claimed to allow lower number of cores per

Use of 5-alpha reductase inhibitor was proposed in two staged approach: first color/power doppler evaluation of prostate is followed by 1-3 week of dutasteride and than reevaluation and biopsy guided to areas, where vascular signals have not decreased after treatment. Additional sextant systematic sample was also taken. Researchers claimed increased yield in

After finger guided biopsy strategies were replaced with ultrasound guided, it soon became clear (group around dr. Stamey, Stanford) 6 cores, taken in a systematic fashion, finds more cancer than aiming at hypo-echoic areas or randomly (Hodge et al., 1989). Standard approach, which hold for more than 10 years, was established: six cores were taken in parasagittal plane, one at the base, one mid-gland and one at apex. However, patients with negative biopsies and still suspicious for cancer, had repeat biopsies, which were almost as often positive as first biopsy – therefore it was obvious the system was not perfect. Aim should be – perform biopsy – if it is negative, then there is no cancer. Reality was – perform classic sextant scheme biopsy – if it is negative, then there is almost the same probability for cancer as before biopsy. So – search has begun for improvement of systematic biopsy scheme (mainly searching for optimal number of cores and location of cores) and this search has not settled yet. As this text aims at the future, not past, only some examples will be pointed out. Inadequacy of sextant scheme was proven many times, for example (Norberg et al., 1997) and also recent larger and longer retrospective data analyzes still turn to this question, for example regarding sextant biopsy's ability to predict unilateral disease (Mayes et al., 2011). First it became clear biopsies should be directed more laterally in the peripheral zone of the prostate (Eskew et al., 1997). Later, it seemed transitional zone inclusion may improve cancer detection, however this was abandoned for initial biopsy, because of inferior gain from transitional zone directed cores compared to more sampling toward far lateral mid-gland and anterior-apical areas. A lot of cancers are located on anterior horn of prostate. With repeat biopsy, of course, anterior transitional zone is also sampled (Chun et al., 2010). Innumerous analyzes have shown – more cores – more cancer. Prostate size has a role (Taneja, 2006). Nomogram was developed to optimize number of cores needed in relation to prostate size – so called Vienna

agent (Mitterberger et al., 2008).

session without decrease in detection rate (Wink et al., 2008).

**3.5 Biopsy schemes and number of cores** 

targeted cores (20%) compared to sextant cores (8%) (Ives et al., 2005).

nomogram (Remzi et al., 2005), as it is obvious higher number of cores gives better sampling and improves detection. Later, while some still questioned Vienna nomogram's usefulness (Lecuona & Heyns, 2010), it became obvious number of biopsy detected cancers is related to sampling density, which is a quotient between prostate size and number of cores taken. A lot of nomograms, which predict probability of positive prostate biopsy, take sampling density into account (Chun et al., 2007). Regarding number of cores, it went up from six at first to eight, later ten, later twelve (a lot of us still using this number at present for majority of patients for first biopsy), fifteen, eighteen... up to twenty-one (Guichard et al., 2007) core per biopsy session. This number seems to be highest present routine extended systematic biopsy scheme, simply because twenty-four or more cores is called saturation biopsy (Ahyai et al., 2010). Many have also argued they were unable to increase their cancer detection rate after increasing number of cores from for example 12 to 18. This underscores importance not only of number, but also direction of cores.

### **3.6 Free hand systematic biopsy, targeted biopsy, prostatic mapping or combination**

Goal of prostate biopsy is not only to find "some" cancer in the prostate, as it was in the past. Now, it has not only to provide representative sample of DIL (dominant intraprostatic lesion), but also to show all "important" cancer areas in the prostate, describe precisely where they are and ensure other regions are cancer free. This is in contrast to efforts of targeted biopsies which claim they may reduce pain and burden of biopsy by reducing number of cores.

Prostate-mapping biopsy approaches, for example TargetScann, have different approach – they aim at precisely sampling predefined sections of prostate with larger number of cores. Electronic doppler ultrasound probes are becoming increasingly complex and sensitive to detect blood flow signals in the prostate to help guiding biopsy. TargetScan's device ultrasound probe is sector and at present can not be used for image-guided approaches, but seems to provide relatively reliable results regarding prostate mapping, which is very important for all targeted therapy approaches (Andriole et al., 2007). "Robotic" probes (ultrasound systems, which are just inserted into rectum by physician and then guided by pressing buttons, are being developed also by other manufacturers.

We have therefore a mix of partly competing, some probably complementary and some excluding technologies aiming at improving prostate cancer detection and staging. Which will find its way into every-day practice and to what extent, remains open. It seems at present repeat biopsy yield is about 20%-40% and targeted biopsy methods claim, in repeat, previously negative setting, yield of 50%. All those new approaches need evaluation and confirmation. One way may be showing significantly better performance of targeted or mapping approaches compared to prediction of nomograms for repeat biopsy setting (Chun et al., 2007).

Overall, it seems at present first biopsy should be 10-18 laterally directed cores (depending on prostate size, for prostates larger than 50 ml minimum 14). Targeted biopsy only, with less than 6 cores, may generally not be appropriate for the first biopsy, as it is far from 100% and we need to assess whole prostate.

For second and later biopsies, as targeted opinions are becoming more and more widespread and therefore accessible and are not untested technical glitches any more, we may in 2011 suggest any of the recently developed opinions, depending on local availability, as follows.

Future of Prostate Biopsy: Who Will Get It and How? 119

AUA guidelines (www.auanet.org, 2008 edition, reviewed 2010) also confirm prophylaxis is indicated in all patients as randomized controlled trials have confirmed significantly lower rates of complications in antibiotic groups. They also claim single dose may be adequate. A lot depends on local antibiotic resistance patterns. For example, if TMP+SMX regimen is not used even for non-complicated urinary tract infections in one area, one would not use it for prostate biopsy prophylaxis either. One can never predict for sure future development of antibiotic resistance. Therefore, constant vigilance is needed and monitoring rates of infectious complications is necessary. Special attention should focus on repeat biopsies and this setting may sometimes deserve different antibiotic scheme or previous culture and susceptibility analysis. Later may be performed in two ways – patients with catheters or other urinary tract insertions may be screened using urine culture (Bruyere et al., 2010), but all who need screening should have their stools sample cultured for resistant strains. Resistant strains do occur and may significantly contribute to complications (Liss et al., 2011). Due to high probability of E.coli resistance to quinolones in cases of patients returning to hospital after prostate biopsy with quinolone prophylaxis, it is wise to use another antibiotic before cultures are known (although it seems obvious, people do often get prescribed flouroquinolone again). If there is no or low risk for ESBL, cephalosporines

(probably third generation) may be the best initial guess (Zaytoun et al., 2011).

accepting single dose only approach.

the environment for longer time.

flouroquinolone resistance or intolerance is present.

gentamicin may be method of choice for single dose regimens.

Although single dose is claimed useful, in our and many other situations most patients can be considered not low risk regarding infectious risk classifications (more than 65 years of age, concomitant diseases, like diabetes and lower urinary tract symptoms, incomplete bladder emptying). Therefore typical scheme (as we use it and others, for example (Campos-Fernandes et al., 2009), uses ciprofloxacin 500 mg twice daily started before biopsy and continued for three days. It was shown to decrease rate of complications after biopsy (Schaeffer et al., 2007). As every single infectious complication, even most minor, requiring any health-service contact, even only consultation, is seen as a big problem and aim is to avoid any complication, there are many patients who probably benefit from short course and not single dose antibiotic and this may be further reason why urologists are reluctant in

Metronidazol is added in some centers routinely, but most do not use it at present. However, it might be useful for specific patients, with specific predisposing conditions and in combination with other antibiotics (for example cephalosporins, although subjective experience shows more complications with their use for this purpose), when

Instead of 1-2 hour prior to procedure fluoroquinolone orally, same use parenteral aminogylcoside (gentamicin or amikacin) or aminopenicilline with betalactamase inhibitor (co-amoxiclav) at the time of biopsy, which is followed by oral antibiotic (often fluoroquinolone, but also others) at home. This scheme is used in some centers and may be helpful when compliance with oral regimen prior to biopsy is questionable or for allergy and non-tolerance to quinolones or in areas with high resistance to quinolones (Kehinde et al., 2008). Combination of periprocedural oral dose of ciprofloxacine with iv dose of

Additional important recent problem regarding fluoroquinolones was finding significantly different serum concentrations of active drug comparing different generic manufacturers (Kehinde et al., 2010). Apart from probable reason for higher complication rate, substandard antibiotics preparations also contribute to resistance development as longer courses are needed and as a consequence low concentrations of drug are present in

