Abstract
In one-third of patients, prostate cancer (PCa) is monofocal. These patients can undergo focal high-intensity focused ultrasound (HIFU) therapy of the tumor without damage to surrounding structures and not compromising uro-oncologic safety. Robot-assisted HIFU coagulates the entire targeted volume within the prostate transrectally, in one session, without direct tumor contact and without adjuvant endourologic therapy. It is performed with the patient receiving spinal anesthesia and without blood loss; negative immunologic influence can be excluded. Heat-destroyed cancer cells that act as tumor vaccination are discussed. Right now, the limitation of focal therapy is caused by the lack of diagnostic accuracy to determine multifocal stages of PCa reliably. Discussions of tumor development, triggering primary lesion monotherapy, do not overcome skepticism about leaving invisible tumor foci untreated. This explains why PCa therapy today treats always the entire gland. Furthermore, the thought that the problem could be solved “radically, once forever,” ignores the fact that in all PCa therapies, local recurrence rates are between 10% and 50%. Considering the longer survival of men in industrialized countries, a structured multimodal therapy concept should be created and evaluated in studies and should replace the competition between classic therapies. Focal therapy in most cases should be the first approach in cancer therapy because it is noninvasive, has low side effects, and is a single-session therapy. It does not exclude but may delay other, more invasive therapies in cases of cancer recurrence. Focal therapy should not be misunderstood as substitution for existing classic therapies but as a therapeutic first choice in monofocal, low-aggressive PCa cases.
Introduction
None of the urologic organs is essential for survival and can therefore be resected in cases of tumor. Because surgery and radiation have been, up to now, the only effective local therapies, they became the guideline-supported classic therapies with longtime experience. In bladder as in kidney cancer, new concepts of organ-preserving therapies have been researched and supported by new technologies.
Not so in prostate cancer (PCa), although it is the most common cancer in men in industrialized countries. Of course, also in PCa therapy, new technologies have been evaluated and are used routinely, but the concept of total radical tumor therapy remains unchanged. Nerve-sparing techniques have been developed in radical prostatectomy, leaving parts of the capsule in place.
Local ablation techniques started to follow the same concept with the same indications, excluding contralateral areas of tissue from direct energy application. Protagonists of this concept were cryosurgeons who were propagating the “male lumpectomy” in prostate cancer. This concept allows reduced treatment volume to a predicted target area, minimizing tissue destruction and therapy-related side effects. Because more and more young men are receiving a diagnosis with low Gleason scores and low volume tumors, this is an understandable approach. The discussion was thematized by a task force inaugurated by the American Urological Association. One can assume that a concept, applied in many other organs, is valid also in PCa.
Meanwhile, technologic development implemented a new, radiation-free, non-invasive, and even contact-free robot-assisted, highly precise technology: Robot-assisted high-intensity focused ultrasound“ (rHIFU), which fulfills all conditions of modern focal PCa therapy.
Clinical History
High-intensity focused ultrasound (HIFU) has been used clinically in studies in Europe, Japan, and the United States since the early 1990s. 1 –5 Starting as therapy for benign prostatic hyperplasia, it proved its safety and efficacy in precise local tissue destruction. It showed clearly, however, that it also induces a significant shrinkage process within the treated organ, which then causes therapy-related side effects.
HIFU was effective in tissue destruction but not effective for infravesical deobstruction. It created even more obstruction by shrinkage and from necrotic tissue.
A relation between HIFU coagulated prostate volume and obstruction was seen, and analysis of prospective studies underlined this by the necessity for 34% transurethral resection of the prostate (TURP) after HIFU, as well as a high rate of urinary tract infections in this necrotic tissue. Because the concept of complete organ therapy was the target of these studies, HIFU was combined in 2000 with an adjuvant TURP, 6,7 debulking the adenoma part and radically resecting middle lobes, calcifications, abscesses, and bladder neck. 8
Treatment course, hospitalization, and side-effect profile are, since then, equal to those of a classic radical TURP—oncologic efficacy (5y no evidence of disease rate) at 77% 9 –11 for localized low and medium risk PCa. Tables 1 and 2 summarize published data regarding efficacy and side effects of HIFU.
PSA = prostate-specific antigen; NR = not reported.
INC = incontinence; ED = erectile dysfunction; FIS = fistula; S&S = stricture and stenosis; PR = postoperative retention; UTI = urinary tract infection; CA = postoperative catheter duration in days; NR = not reported; SP = suprapubic catheter; G1 = incontinence grade I, ie, loss of urine under heavy exercise necessitating 0–1 pad/day; G2 = incontinence grade II, ie, loss of urine under light exercise necessitating >1 pad/day; G3 = incontinence grade III, ie, loss of urine under any exercise necessitating >2 pads/day; TURP = transurethral resection of the prostate.
Ongoing prospective studies and two large databases (Harlaching HIFU database and @registry) will show in 2010 10-year data for local PCa and all therapy groups.
Focal Therapy
The newest topic of urologic discussion about local therapy of prostate cancer is the concept of focal therapy. 12 –20 The discussion—initiated in the United States by the problem of increasing low Gleason score, low volume PCa in young men—excluded until now “palliative HIFU” as focal therapy in already systemic PCa. Nevertheless, treating only a part of a systemic tumor disease deserves also to be categorized as focal therapy.
Muto and associates 21 have compared focal therapy with whole-gland ablation in a series of 70 patients. Of the 29 patients with unilateral disease, focal therapy involved ablation of the total peripheral zone and a half portion of transitional zone and resulted in a 77% negative biopsy rate at 12 months. Of the remaining 41 patients with bilateral disease, whole-gland ablation resulted in a 84% negative biopsy rate at 12 months. Two-year biochemical recurrence-free survival rates were 91% and 50% for low- and intermediate-risk groups who were undergoing whole-gland ablation compared with 83% and 54%, respectively, for the focal therapy equivalents. Morbidity with the two forms of HIFU was comparable. Focal therapy has to be defined clearly as to whether it should be organ and/or disease related.
The ongoing discussion about focal therapy in PCa is about local therapy in localized low Gleason score, low volume disease, searching the ideal focal therapy technology and application mode. The arguments for focal HIFU are preservation of potency and fertility, maybe the induction of an immunologic response, and avoiding overtreatment-induced side effects collateral to classic therapies. Counterarguments have to be considered, because there is the unclear situation of secondary foci, limited accuracy of staging tools, and multifocality in two-thirds of the cases. 16,22,23
An ideal focal therapy should meet certain criteria. 24 –26 Medically, it should be a single session therapy without blood loss or cut, there should be no cancer contact, and it should be repeatable. It should not increase tumor aggressiveness in case of recurrence and not exclude other therapeutic options. Technically, highest precision (<1 mm) should be guaranteed, as well as fast and precise computerized planning and operator independent application.
HIFU: Physics and Action Mode
HIFU can be delivered pulsed or as a continuous beam. The latter process includes solar waves, microwaves, and radar technology, whereas pulsed HIFU is applied as medical HIFU and extracorporeal shock wave lithotripsy. The high-frequency vibration (0.5–10 MHz) of a piezoelectric or piezoceramic transducer generates ultrasound waves, which are focused into a focal point by a concave or parabolic energy source. Degassed colored liquid as interface between transducer and rectum generates cooling of the rectal wall. There is minimal absorption or reflection of the ultrasound waves because of the similar physical properties of water and tissue, as well as the broad flat coupling surface. The power density of the converging ultrasound waves increases toward the focal point to build up the specificity of tissue destruction. 23
HIFU works in two ways to destroy tissue: Thermal effects and mechanical effects. The ultrasound energy that is produced by HIFU is absorbed by the tissue and converted into heat. The increase in temperature depends on the absorption coefficient of the tissue as well as size, shape, and thermal response of the tissue. The generated temperature and the length of exposure to that temperature (the thermal dose) affect the biologic changes that are induced. When the energy is higher than the specific threshold, this dose causes irreversible tissue damage through coagulative necrosis. There is a steep temperature gradient between the tissue in the focus of HIFU and the surrounding tissue, as evidenced in histologic samples of necrotic lesions.
Mechanically, the negative pressure of the ultrasound wave forms cavitation bubbles in the tissue. The cells increase in size to the point at which resonance is achieved. High pressure of 20,000 to 30,000 bars develops when the bubbles suddenly collapse, resulting in instant cell death.
rHIFU Application by Ablatherm®
The treatment module includes the treatment table, the probe positioning system, the ultrasound power generator, the cooling system for preservation of the rectal wall, and the computerized control module with specific software, and a treatment and imaging endorectal probe, which incorporates both a biplane imaging probe working at 7.5 MHz and a treatment transducer focused at a maximum of 45 mm, working at 3 MHz. There is variable focusing (19–26 mm) and rectum distance length (3–8 mm) adjustable for each single treatment slice. Real-time rectal wall control is present; automatic applicator adjustment toward the rectal wall and multiple security circuits exclude accidental focusing on the rectal wall, thus avoiding rectal injury. Since 2005, integrated imaging has been introduced, which allows transrectal ultrasound (TRUS)-based visual real-time control.
Software
Treatment parameters, important for effective tissue coagulation, include the power setting (<50W), the piezoelectric frequency (3 MHz), shot duration (5–7 sec), as well as the delay between shots (5–7 sec) and number of shots per prostate volume (dose). Delay between shots is necessary to avoid overwhelming accumulation of cavitation bubbles in adjacent lesions. Length and diameter of lesions within the prostate need to be considered in treatment planning, as well as the possibility of adapting the technology to different tissue types (untreated, preirradiated, or HIFU pretreated). Three types of software can be selected that involve the application of different levels of energy. The rationale is that irradiated prostate tissue has a higher uptake of HIFU energy, and, therefore, a lower level is equally efficient and reduces the risk of rectal wall injury to almost zero.
Safety issues
Safety was increased by introduction of real-time imaging through a new electronic probe. Less local movement has also been achieved through fixation of this new probe that allows greater accuracy in delivery of HIFU. Precise control of energy delivery is very important from the safety and efficacy perspective, and this is optimized through the use of the Ablapak® transducer fluid.
Ablatherm also has inbuilt controls that correct or stop the treatment automatically as well as adjust the endorectal position of the probe three-dimensionally when the probe is too close/far from the rectal wall. This control compares the three-dimensional (3D) position of the applicator to the treatment plan and allows the device to fire with a ±1-mm accuracy. In addition, an external motion sensor as well as internal safety circuits detect any technical malfunction or patient movement and consequently stop the procedure instantly (robot-assisted HIFU). The probe itself is covered and the rectum is held by a fluid (Ablasonic®) filled coupling balloon.
rHIFU preparation
Treatment commences with an enema to cleanse the rectum, administration of prophylactic antibiotics, and insertion of an urethral catheter for bladder control and visual planning. Spinal anesthesia with analgesic sedation is the preferred method for the procedure. The patient is positioned on his right side with inclined legs, and external warming is applied to counteract the cooling of the rectum. The transducer is covered with a balloon, which is inserted into the rectum and then filled with 150 mL degassed transmitter fluid (Ablasonic). A roller pump causes the liquid to circulate slowly through the balloon into a cooling unit and back to the rectum at a temperature of 15°C. The procedure of anesthesia administration, patient positioning, and device preparation takes about 20 minutes.
Treatment planning
After introducing the applicator manually into the rectum, the prostate is scanned by a 7.5 MHz transrectal ultrasound scanner from the base to the apex. A dynamic 3D TRUS-CT simulation is created that allows precise (<1 mm) virtual treatment planning, prostate volume calculation, and definition of apex and base. Prostatic apex definition is one of the most important aspects of treatment planning, involving a balance between preservation of continence and effective treatment. Vertical and lateral borders of the HIFU lesion to be generated are defined at this time. Based on these parameters, generated in just 5 minutes, treatment planning can then be carried out.
A TRUS image of the prostate in a longitudinal or transverse view is monitored on the computer screen. Depending on the results of the TRUS-guided biopsies and on the localization and volume of the prostate tumor, a complete treatment (95% of cases) is performed in a 2-hour single session. It is also possible to target only specific parts of the prostate, which results in focal therapy.
Complete Ablatherm treatment typically starts 5 mm cranially from the apex, moving toward the bladder, treating first the left lobe and then the right lobe of the prostate. The actual rHIFU will be controlled by the computer software. The treatment planning divides the prostate into 1.7-mm transverse sections that are subdivided into single lesions. The position of slices and lesions is defined by the operator on the control screen and adapted individually; slice by slice, up to 800 lesions in a few minutes may be defined, depending on the size of the prostate. Subsections (blocs) of the prostate (approximately 25% each) are targeted one after the other, to integrate the ongoing tissue edema into the consecutive planning process.
Treatment
The 5-minute planning process as well as rHIFU treatment is carried out by a single operator, making the process highly cost-efficient. He or she follows the treatment plan, going through all the predefined regions, whether focal or complete. For accuracy of the thermal effect, an absolutely stable position of the patient must be maintained. The treatment time is usually 95 (30–150) minutes for complete therapy, less than 1 hour for focal therapy. The treatment is automatically recorded and can be reviewed after the procedure. Postoperatively, there is minimum pain for the patient, making post-HIFU analgesic medication unnecessary.
HIFU's perioperative morbidity is low: No significant bleeding, no blood transfusion, no intensive care, no thrombosis or pulmonary embolism, and no analgesics. Antibiotic prophylaxis is usually continued until catheter removal, which, on average, occurs after transurethral resection and complete HIFU at 5 (3–10) days postoperatively. In focal HIFU without TURP, the catheter can be withdrawn the third day after the procedure.
Conclusion
rHIFU by Ablatherm allows contact-free, precise, repeatable focal therapy without compromising life quality or future oncologic per course or therapeutic possibilities.
It avoids overtreatment, delays the onset of more invasive therapies, and may be a curative treatment by itself. The critical counter-arguments, however, should be kept in mind: Focal therapy—because of missing precise diagnostic tools and studies—is still considered experimental. Experiences in focal cryotherapy encourage the introduction of rHIFU as ideal non-invasive, contact-free, precise tumor coagulation therapy.
Success of focal therapy will depend less on development of therapeutic tools than on diagnostic technologies that can pinpoint tumor lesions more specificcally. When this goal is reached, HIFU will be the most perfect therapeutic tool for focal PCa therapy.
Footnotes
Disclosure Statement
No competing financial interests exist.