The end goal of any cancer treatment is to control or cure the disease with minimal complications and side effects. To do this, the number of years of life gained should be balanced against the potential morbidity of a treatment, which in turn should be appropriately matched to the risk that a particular cancer poses to a patient. There is often innate difficulty in the decision-making process regarding the treatment of prostate cancer, given the long natural history of the disease without treatment and the treatment-related morbidities. Nonetheless, most men with low- and intermediate-risk prostate cancer elect curative therapy as opposed to active surveillance. The reasons given for this are related to psychological impact of active surveillance as well as physician concern over potential progression especially as around half of low-risk men go on to have radical therapy despite many actually having disease that was unlikely to cause any impact to their survival during their life.
Contemporarily, in surgical practice there is a movement toward combining cancer control with increasingly minimally invasive techniques. Within the field of prostate cancer, this is clearly demonstrated by the uptake of new techniques such as laparoscopic and robotic surgery as well as percutaneous brachytherapy, high-intensity focused ultrasonography, photodynamic therapy, and cryoablative therapies. Some of these techniques allow a more discrete delivery, treating the cancer and a margin of healthy tissue alone rather than the whole gland. Doing so reduces the potential complications or side effects seen following radical (whole-gland) treatments. These latter therapies represent an additional choice in men with low- and intermediate-risk diseases who are seeking a more balanced therapeutic ratio.
When used as focal therapies, these techniques are potentially very attractive. Although most prostate cancers are multifocal, around 20% are unifocal, allowing for treatment of a solitary area of disease. Additionally, the concept of an index lesion driving the metastatic process in prostate cancer has been explored. The risk of local and metastatic progression is potentially reduced and additionally they confer less morbidity than radical treatment. The Consensus Conference of Focal Treatment of Prostatic Carcinoma defined focal therapy as “an individualized treatment that selectively ablates known disease and preserves existing functions, with the overall objective of minimizing lifetime morbidity without compromising life expectancy.”
A universally accepted set of indications for focal treatment of prostate cancer is lacking. On the whole, suitability for treatment is based on the patient’s risk of bilateral or extraprostatic disease, with guidance—such as that proposed by the National Comprehensive Cancer Network and advocated by the 2015 consensus meeting on focal therapy (Donaldson 2015)—based on clinical, biopsy, and imaging findings.
In this chapter, we will outline the contemporary procedural techniques involved in administering effective focal therapy for prostate cancer. However, as focal therapies mandate accurate location of disease, a high-quality multiparametric MRI followed by an accurate biopsy technique is needed. Hence, we will start with the transperineal template biopsy, which is often used for accurate disease localization.
Transperineal Template Biopsy
Focal therapies demand good accuracy of disease location and diagnosis. The reasons for this are twofold. First, as the accuracy of tumor mapping falls, the greater the volume of healthy prostate that will inevitably be destroyed to ensure treatment efficacy. Second, visualizing and targeting the diseased area accurately increases the efficacy of treatment. Thus, accurate localization of disease is mandatory prior to contemplating focal therapy. The bimodal combination of transperineal mapping biopsies and multiparametric magnetic resonance imaging (mpMRI) has emerged, providing a good method to fill this essential role.
Increasingly, traditional office transrectal ultrasound-guided biopsies are shown to be deficient for localizing prostate cancer, and with some momentum they are being replaced with transperineal mapping biopsies and mpMRI. These latter modalities offer significant advantages in sensitivity and specificity over TRUS biopsies in their ability to exclude patients and areas of the prostate that harbor significant disease. This diagnostic combination is a requisite restaging protocol prior to the commencement of focal therapy.
The transperineal three-dimensional template-guided pathologic guided mapping (3D-TPM) approach is a popular choice for preoperative restaging and confirmation of disease severity. The advantages conferred include far easier access to the anterior apical region of the gland, a systematic sampling approach that is not subject to visual bias and the provision of a set of pathologic coordinates easy to use for disease mapping. Unfortunately, disadvantages include increased cost, increased burden and side effects for the patient, and the need for greater logistic and theatre support.
Preparation
The procedure can be performed as a day case unless medical reasons demand otherwise. Prior to or on the day of admission, the patient’s consent should be taken for the procedure. The reasons for the procedure and its complications should be discussed.
Indications
Indications for template mapping biopsies include previous repetitive inconclusive biopsies, anterior disease identified on imaging, restaging prior to focal therapy, and previous infections following rectal biopsies.
Anesthesia
The level of anesthesia required essentially depends on the number of cores being taken. For example, limited prostatic biopsies via the transperineal route may be performed with local anesthetic only or with the addition of a periprostatic block. However, full template mapping biopsies involve taking a large number of cores and such a method is unlikely to confer a sufficient level of anesthesia. As such, this procedure should be performed under general or spinal anesthetic. Commonly, a combination of long-acting local anesthetic with general and spinal anesthesia is used.
Antibiotic Prophylaxis
The transperineal route to the prostate passes directly through the skin and does not involve puncture of the rectum. Strictly speaking, this makes it a sterile procedure, thus negating any necessity for antimicrobial prophylaxis except in cases of immunosuppression, diabetes, implanted cardiac or neurological devices, heart valve pathologies, indwelling catheters, or patients with high postvoid residual volumes. In these patients, local antimicrobial advice should be sought; however, generally fluoroquinolones, aminoglycosides, or beta-lactams are sufficient. In practice prophylaxis is often started the day prior to the procedure and in some cases continued for 3–5 days postoperatively. Surgery should be postponed in patients with bacteruria and active urinary tract infection until it has been treated.
Antiplatelets and Anticoagulants
All patients taking these medications should have their risk of stopping them assessed prior to surgery. High-risk patients should be identified and discussed with the relevant specialty. If a patient is taking warfarin, they should stop it 3 days preoperatively and have their INR checked prior to the procedure to ensure it is less than 1.5. The use of aspirin does not preclude commencement of the procedure; however, clopidogrel should be stopped 7 days before the day of surgery. In patients taking new-generation anticoagulants such as dabigatran or apixaban, specialist advice should be sought.
Enema
A preoperative enema is not necessary as its role in reducing the rectal mucosal bacterial load holds less importance because the biopsy needle does not traverse the rectum. However, an enema performed prior to the procedure decreases patient discomfort and improves the quality of ultrasonographic images.
Technique
Patient Position
The patient should be positioned in either a standard dorsal lithotomy position or in the extended lithotomy position ( Fig. 81.1 ). The latter permits sampling of even the largest glands up to 80–100 mL. The scrotum is then held anteriorly with surgical adhesive tape and the perineum and surrounding skin cleaned with iodine-povidone solution.
Urethral Catheter
A urethral catheter is placed in the normal manner facilitating visualization of the urethra. Postoperatively the current practice is invariably to remove it prior to discharge unless there is a high risk for postoperative urinary retention.
Probe
A 4–10-MHz endorectal ultrasound probe allowing imaging in the sagittal and axial planes is suitable for the procedure (the higher the frequency the better the visualization). A water-inflatable condom is placed over the probe to improve the perioperative images. This is mounted in an articulated stepper adjoining the surgical bed ( Fig. 81.2 ). Local anesthetic gel may be inserted into the rectum to aid the insertion of the probe as well as provide additional anesthesia for cases under sedation/local anesthetic, and a digital rectal examination is performed. The probe should be inserted with minimal resistance until there is satisfactory visualization of the prostate gland in both axial and sagittal profiles. Once the position is satisfactory, the brachytherapy template device is attached to the rig above the probe in the midline ( Fig. 81.3 ).
Sampling
The perineal skin is cleaned with chlorhexidine or iodine-povidone solution and sterile drapes applied. Subsequently, 0.5% bupivacaine with adrenaline (1 : 200,000) (20 mL) is infiltrated into the perineum providing postoperative anesthesia and control of bleeding. A mixture of 0.5% bupivacaine with 1% lidocaine can additionally be used for periprostatic block for those under local anesthetic.
Using visual guidance from the ultrasound images and calibrated to the brachytherapy template, cores should be taken from each topographical zone of the prostate such as the 20-zone University College London group’s modified Barzell zones ( Fig. 81.4 ). Other protocols have been described. The greatest accuracy is achieved with 5-mm sampling. Once the operator selects a template column, the needle should be inserted under visual guidance from the ultrasonographic imaging in sagittal section. When one is mapping prior to focal therapy, care should be taken to ensure the midline biopsies posterior to the urethra are segregated to prevent false-positive sampling from the contralateral side to the treatment area. This is due to the bevel tracking of the needle causing it to enter the urethra on one side and exit on the other. Great care should be taken to avoid injury to the prostatic urethra during the procedure. The urethral catheter can be used to identify the urethra. There is a greater risk of urethral injury from anterior midline biopsies. In lesions that sit anteriorly in the midline cranial to the apex, the operator has no choice but to insert the needle through the urethra for accurate targeting. The large number of zones that are individually targeted leads to a large number of cores being taken. This can be as high as 90 cores taken for analysis. Each zone should be placed in its own individually labeled sample pot.
Complications
Common (greater than 1 in 10) complications include hematuria for up to 10 days, hematospermia for up to 6 weeks and perineal bruising with associated pain. It should be stated that the hematospermia poses no risk to the patient or their sexual partners. There is a 1% quoted risk of urinary infection, although sepsis is rare at 1 in 500–1000. There is a 2% risk of hemorrhage causing clot retention. Acute urinary retention occurs in about 5%–10% and often depends on sampling density, size of gland, and preexisting lower urinary tract symptoms. Alpha-blocker medication can reduce these risks but not eliminate them. Failure to detect disease in the prostate and subsequent repeated biopsies should also be discussed and occur at a rate of 5%–20% depending on the sampling density that the operator uses and on whether an mpMRI was carried out before the biopsy.
Focal Therapy Procedural Techniques
Several techniques have been proposed that offer the discrete tissue necrosis we demand of focal therapy.
High-Intensity Focused Ultrasound
Since Wood et al in the 1920s, high-intensity focused ultrasonography (HIFU) has been proposed as an ablative technique in a plethora of diseases. However, without the development of adequate imaging technologies such as ultrasonography, computed tomography, and magnetic resonance imaging, its ability to accurately localize and treat target lesions without damaging adjacent structures was simply not good enough. As such, research into the technique languished until these imaging modalities were established. At this time, clinicians began to look seriously again at the use of HIFU in the treatment of malignant disease, especially in urology. During the past 20 years, commercially available devices have been developed that deliver HIFU accurately, and in some centers its use in the noninvasive, focal treatment of prostatic carcinoma is common.
Diagnostic ultrasonography typically utilizes frequencies between 1 and 20 MHz. By comparison, HIFU generally uses frequencies of 0.8–4 MHz. The energy levels therefore delivered are about 10,000 times greater in a HIFU beam than a modern diagnostic ultrasound beam. This amount of energy can rapidly increase the temperature in the beam’s focus to 80°C or higher which is adequate for causing cell death. Outside of the focus little damage occurs to tissue with the resultant lesion size and shape dependent on the design of the transducer, the ‘on’ and ‘off’ time of the beam as well the power (W) delivered.
Ultrasound is an inaudible (to humans) high frequency wave vibration, which in clinical practice is emitted by a transducer. When precisely focused on a point the effect is tissue destruction in the form of coagulative necrosis by heat injury and cavitation. The ultrasound waves are absorbed by the tissue and agitate the molecules within. The subsequent friction generates heat and the temperature in the tissue affected can rise to 100°C in seconds. The heat denatures protein and lipoprotein structures in the cell membrane and the membranes of organelles contained within. The second destructive mechanism is through microbubble formation and collapse in the targeted tissue, causing further destruction (cavitation).
Intraoperative monitoring of HIFU therapy increases the safety and efficacy of the procedure by targeting disease and monitoring the effects of the treatment, both of which are essential. Currently, it is possible to monitor HIFU with either ultrasonography or MRI. Given the significant cost difference between these modalities, diagnostic ultrasonography is the more popular choice. Additionally, it is mobile and invariably more accessible. Usually, the imaging ultrasound transducer is mounted in a treatment probe, so real-time monitoring is possible. In real time, the gray-scale images can be monitored for gray-scale hyperechoic changes. The hyperechoic areas represent microbubble formation from heated tissue (in effect, steam). The operator can react to these changes accordingly. Unfortunately, this is also a disadvantage as the bubbles inevitably cause artifacts, which when added to the already poor images, add difficulty to their interpretation. This is of particular note when tissue in front of the target zone is heated. MRI has been used to guide focal HIFU in renal carcinomas; however, it is not currently widely used in the treatment of prostate cancer in the same manner.
HIFU Treatment Devices
There are currently 2 commonly used commercial devices available for purchase for the treatment of prostate cancer. First, there is the Sonablate system developed by Sonacare Inc (Indiana, IL, USA). Secondly, there is the Ablatherm HIFU device developed by EDAP TMS (Lyon, France).
The Sonablate is a mobile, minimally invasive HIFU device developed to treat prostate cancer via an endorectal probe. The probe confers the advantages of real-time imaging of the prostate and gives the added option of fusion imaging with mpMRI. This also allows for accurate treatment planning. Prostates up to 40 mL in volume may be treated. Each lesion produced by the delivered energy is 10–12 mm in diameter. This small size in conjunction with the robotic transducer that can target the whole gland allows accurate treatment of disease throughout the gland. Additionally, the system allows for real-time monitoring of conditions within the tissue being treated. A color-coded system allows the operator to objectively monitor the temperature in both the treatment areas and surrounding structures such as the rectal wall and neurovascular bundles. The probe also is fitted with a cool water pumping system to protect the rectum.
The Ablatherm is a semiautomated HIFU device that treats prostate cancer with an endorectal probe with the patient in the right lateral cubitus position. It consists of a treatment module, a control module, and an endorectal probe with both treatment and imaging ultrasound transducers. The system allows for accurate treatment planning and offers real-time intraoperative imaging with adjustments of energy delivery. The transducer allows precise energy delivery to tissue creating lesions 19–26 mm in diameter through predefined power protocols. A rectal cooling system is incorporated within the device as well as real-time rectal wall monitoring and patient movement detection. These safety features help to prevent damage to adjacent vital structures.
Indications
Indications for HIFU include focal treatment of localized disease or whole-gland ablation for multifocal disease. The lesion should be visible on mpMRI and concordant with the histologic analysis. The disease should be clinically significant, generally meaning a Gleason score of 3+4 or higher and a volume greater than 0.2 mL ( Fig. 81.5 ).
Preparation
As with all focal therapies for prostate cancer, all men who are to be considered for HIFU must undergo accurate zonal and risk assessment.
The procedure can be performed as a day case unless medical reasons demand otherwise. Prior to or on the day of admission, the patient’s consent should be taken for the procedure. The reasons for the procedure and its complications should be discussed. Patients taking antiplatelet or anticoagulant medications should be managed in the manner described for transperineal template biopsies.
Bowel Preparation
Bowel preparation in some form is justified to optimize the perioperative ultrasonographic imaging. In some centers, patients are admitted the evening before surgery for full bowel preparation; however, an enema 1 hour prior to surgery can be sufficient.
Antimicrobial Prophylaxis
Antimicrobial prophylaxis is guided by local policy. Intravenous administration of broad-spectrum, gram-negative, and anaerobic covering antibiotics such as metronidazole, cefuroxime, and gentamicin is generally acceptable. Surgery should be postponed in patients with bacteruria and active urinary tract infection until it has been treated. A postoperative course of oral antibiotics is recommended. As always, this should be guided by local policy; however, in our practice, we use ciprofloxacin for 7 days postoperatively.
Anesthesia
This procedure should be performed under general or spinal anesthetic. If the latter, heavy sedation is required because any movement will be problematic. If significant abdominal breathing movements occur and these can be seen to move the prostate, then the patient should be paralyzed and ventilated. Nitrous oxide should not be used during a HIFU procedure as it has been reported to cause microbubble formation in the prostate with significant widespread artifactual changes seen that impact the safe delivery of the HIFU therapy.
Technique
When under anesthesia, the patient is placed in the extended lithotomy (Sonablate) or right lateral decubitus position (Ablatherm), exposing the perineum, and a warming blanket is placed over them to prevent hypothermia. A urethral catheter can be inserted for planning. Some users will carry out a mini-TURP 4–6 weeks prior to the HIFU to reduce risk of stricture formation with whole-gland therapy. Others will insert a suprapubic catheter to reduce this risk. A digital rectal examination is performed to ensure an empty rectum and the endorectal HIFU probe is introduced to the rectum using lubricating jelly. The prostate is mapped with the ultrasonographic imaging and the desired treatment area is defined. If fusion imaging is being used, it is calibrated at this point. The cooling system is then started and the energy delivered. The operator ensures safe delivery of the energy by monitoring the treatment area. Treatment can be stopped if structures such as the rectum are in danger of injury. Depending on the device, the power is either set (Ablatherm) or can be individually changed dependent on the tissue changes seen (Sonablate). The urethral catheter is usually left in place for 5–10 days ( Fig. 81.6 ).
Postoperative Management
Patients are usually discharged on the day of surgery. Up to 7 days of oral antimicrobials are given; however, this should be guided by local policy. Fluoroquinolones or beta-lactams will usually be suitable. Alpha-blockers are given for up to 14 days post procedure. Postoperative pain is usually mild and analgesic requirements are generally fulfilled with simple oral analgesics. Follow-up protocols may vary between centers; however, a suitable regime is 3-monthly for a year, 6-monthly for the following year, and then yearly. PSA monitoring should be performed as well as their lower urinary tract function, which should be monitored with the IPSS score and their erectile function. PSA values should be treated with caution as it can take several months for it to reach its nadir. If there is concern regarding incomplete treatment or recurrence, biopsies and mpMRI can be performed. Usually an mpMRI at 12 months is required ( Fig. 81.7 ).
