Version May 2024
INTRODUCTION — Ablation techniques, including cryotherapy, high-intensity focused ultrasound (HIFU), photodynamic therapy (PDT), and focal laser ablation (FLA), have been used to destroy prostate tissue, either by freezing or by generating local thermal energy, and thereby treat the cancer. These ablation techniques can be applied to the entire prostate gland or to only the part of the gland thought to be involved with cancer.
The role of ablation techniques as an alternative to radical prostatectomy or radiation therapy (RT) for the definitive treatment of prostate cancer remains uncertain. Potential advantages in men with localized disease include the ability to destroy cancer cells using a relatively noninvasive procedure, as well as sparing normal tissue. These procedures are associated with minimal blood loss and less pain than surgery, and there is a more rapid posttreatment convalescence.
Whether the long-term outcomes are equivalent to those with definitive surgery or RT is uncertain, however. Additional experience and longer follow-up are required to compare the rate of disease control and side effects profiles with other treatment modalities [1].
The role of ablative techniques for the initial treatment of localized prostate cancer as well as its use in the salvage setting is discussed here. Standard treatment options for early prostate cancer and the approach to patients with local recurrence after RT are discussed separately. (See "Initial approach to low- and very low-risk clinically localized prostate cancer" and "Rising serum PSA after radiation therapy for localized prostate cancer: Salvage local therapy".)
CRYOTHERAPY — The precise role of cryotherapy in the management of patients with localized disease remains uncertain despite the technologic advances that have been made. Even among men with low-risk disease (table 1), it is not clear that results with cryotherapy are comparable with those that can be achieved with other therapeutic approaches. Prospective comparative trials using "third-generation" cryotherapy devices and methods are needed to evaluate the long-term efficacy of primary cryotherapy, as well as to define its precise role in the management of clinically localized disease.
Until then, we suggest that cryotherapy not be used routinely as an alternative to standard treatment approaches (ie, radical prostatectomy, external beam radiation therapy [RT], brachytherapy, or active surveillance) for localized prostate cancer. Consistent with guidelines from the American Society of Clinical Oncology (ASCO) [2], whole-gland cryosurgery should be limited to men with low-risk (table 1), clinically localized prostate cancer who are not suitable for either radical prostatectomy or RT due to comorbidities, yet who have a >10-year life expectancy.
Cryotherapy is a treatment modality for localized prostate cancer in which freezing is used to destroy tumor cells. Potential advantages of cryoablation compared with other therapeutic options in men with localized prostate cancer include:
●The ability to destroy cancer cells using a relatively noninvasive procedure. Cryotherapy is associated with minimal blood loss and pain, is much better tolerated than an open radical prostatectomy, and has a more rapid posttreatment convalescence. These differences may be less pronounced compared with minimally invasive (robotic or laparoscopic) prostatectomy.
●Cryotherapy can be performed under spinal rather than general anesthesia and therefore can be offered to men who are not candidates for surgery because of advanced age or comorbidities.
●Cryotherapy can be used to treat men with localized disease or locally recurrent cancer following initial RT. Cryoablation can be performed more than once; if necessary, it can be followed by either RT or radical prostatectomy. (See "Rising serum PSA after radiation therapy for localized prostate cancer: Salvage local therapy", section on 'Cryotherapy'.)
In early studies, cryotherapy was associated with unacceptably high complication rates, and it was largely abandoned. Improvements in tumor demarcation, instrumentation, and treatment delivery systems have led to a resurgence of interest in cryotherapy to treat prostate cancer.
One of the major advances facilitating the use of prostate cryotherapy was the application of high-precision transrectal ultrasound (TRUS) imaging. Using this approach, the extent of freezing can be precisely controlled and tissue destruction is monitored with real-time visualization of the prostate and surrounding structures [3]. In addition, "third-generation" systems for prostate cryotherapy use smaller cryoprobes that are placed via a percutaneous transperineal approach with a brachytherapy template. Argon, rather than liquid nitrogen, is used to facilitate rapid freezing using ultrathin probes. Helium gas is used to actively thaw the prostate.
Biology — The biology underlying tissue injury by freezing is complex and incompletely understood. During cryotherapy, argon gas is used to cool the cryoprobes that have been inserted into the prostate, thus rapidly extracting heat from the gland. This cooling facilitates rapid development of ice crystals in the extracellular compartment with freezing of intracellular water, resulting in cell death.
The rapid development of intracellular ice crystals produces shearing and rupture of cell membranes, organelles, and the cytoskeleton [4]. Tissue damage also occurs because ice crystallization extracts free water from the intracellular solutes, resulting in protein denaturation. These complex mechanisms of cell death are further enhanced by damage to the microvascular circulation, which results in secondary anoxia and hemorrhagic necrosis [5]. These mechanisms of cellular injury have been well described in tissue rapidly frozen to -40ºC once or to -10ºC twice.
The two parameters that correlate best with the magnitude of cell destruction are the lowest temperature achieved and the rate of cooling during freezing [6]. Cell death requires temperatures lower than -20ºC, but temperatures as low as -40ºC may be necessary to ensure complete freezing of the intracellular compartment [7]. This fact has important implications for the urologist performing the procedure. The hyperechoic visualized edge of the ice ball as seen on TRUS has a temperature of 0 to -2ºC, while temperatures are as low as -20 to -40ºC inside this edge. Thus, the ice ball must extend beyond the edge of the prostatic tumor to ensure adequate tissue ablation [8].
Rapid freezing is crucial to ensure cell destruction because with time, cells initiate fluid shifts, becoming relatively hyperosmolar and cryoresistant. Because rapid freezing is associated with minimal loss of intracellular water, it is associated with a maximal chance of intracellular ice formation. Passive warming, which occurs over 15 to 20 minutes after the cryoprobes are allowed to thaw, results in the formation of larger ice crystals (termed recrystallization), which results in further tissue destruction [8].
After one episode of freezing, the cells are highly vulnerable to additional hypothermic injury with a second freeze-thaw cycle, resulting in the destruction of many of the previously surviving cells [7]. The increased effectiveness of the "double freeze-thaw" technique appears to occur without appreciably higher rates of side effects [9].
Technique — Perioperative preparation consists of a Fleet enema prior to the procedure. Crossmatching of blood is unnecessary. Prophylactic antibiotics are given intravenously on the day of surgery, and in our practice we use an oral fluoroquinolone for prophylaxis for one week following cryotherapy.
Cryotherapy can be performed under either regional or general anesthesia with the patient placed in the lithotomy position. Careful cystoscopic inspection of the urethra, bladder, prostate, and ureteral orifices should be accomplished at the beginning of the procedure. Urethral and suprapubic catheters are placed to permit a continuous flow of warm irrigant through the urethra to protect its mucosa from freezing and sloughing [4,10].
The freezing of the prostate is carried out using multiple cryoprobes that are placed approximately 1 cm apart [11,12]. Using high-precision TRUS imaging, these probes are placed within the prostatic tumor via a percutaneous transperineal approach. Generally, two probes are placed anteromedially, two posterolaterally, and one posteriorly, although in one series, the use of six to eight cryoprobes appeared to provide better glandular ablation compared with the five probe technique [13]. Modern or "third-generation" techniques employ a higher number of ultrathin needles which are inserted through a brachytherapy template [14,15]. Multiple thermocouples are distributed both within the gland and outside the gland to measure temperature during the procedure.
After the cryoprobes and thermocouples are in place, argon gas is used to cool the cryoprobes, creating freezing temperatures in the gland and destroying the exposed tissue. The extent of freezing is precisely controlled and tissue destruction is monitored using real-time visualization of the prostate and surrounding structures by TRUS [3]. When the ice ball has reached the posterior aspect of the prostate capsule, helium gas is used to actively thaw the prostate. Two freeze-thaw cycles are generally administered in order to optimize cell killing.
Following therapy, the majority of patients are discharged home with a urethral catheter in place for at least two weeks. This appears to be associated with a lower likelihood of urethral sloughing and/or urinary retention compared with the use of a suprapubic catheter or with shorter periods of urethral catheterization [8].
Indications — Standard approaches to the management of men with localized prostate cancer include radical prostatectomy, RT (external beam and/or brachytherapy), and active surveillance. (See "Initial approach to low- and very low-risk clinically localized prostate cancer".)
There are three clinical settings in which prostate cryoablation may be considered as an alternative to standard therapy:
●Cryotherapy can be used as primary therapy in patients who have not undergone previous local therapy (eg, RT, surgery). If cryotherapy is administered as a primary treatment with curative intent, it should be limited to men with clinical stage T1 or T2 tumors and no evidence of metastatic disease (table 2 and table 3). (See 'Primary therapy' below.)
●Cryotherapy can be used as a form of salvage therapy for men with locally recurrent disease following external beam RT or interstitial therapy. This can be used as an alternative option to salvage radical prostatectomy. (See "Rising serum PSA after radiation therapy for localized prostate cancer: Salvage local therapy".)
●Palliative cryotherapy may be an option to relieve symptoms in a small subset of men who have extensive local tumor involvement with concomitant lower urinary tract symptoms, even if they have advanced extraprostatic disease [16].
Contraindications to prostate cryotherapy include the following:
●Men who have had an abdominal perineal resection, either for rectal cancer or some other reason.
●The inability to visualize the prostate with a TRUS probe.
●Extensive local tumor volume that cannot be adequately treated with cryoablation without an excess risk to surrounding structures. The limitations of cryotherapy for the treatment of larger tumors were illustrated by a randomized trial in which 64 patients with clinical stage T2c or T3 lesions were randomly assigned to cryotherapy or external beam RT (table 2) [17]. Biochemical disease-free survival at four years was significantly worse with cryotherapy (13 versus 47 percent with RT).
Primary therapy — Standard approaches to the management of men with localized prostate cancer include radical prostatectomy, RT, and active surveillance. (See "Initial approach to low- and very low-risk clinically localized prostate cancer".)
Efficacy — Cryotherapy to ablate the prostate gland has been compared with external beam RT in two small randomized trials:
●In one trial, 244 men with localized prostate cancer (82 percent T2 and 18 percent T3) were randomly assigned to treatment with external beam RT or cryotherapy [18]. Patients received three to six months of androgen deprivation therapy (ADT) prior to RT or cryotherapy. Treatment failure was based on a rising serum prostate-specific antigen (PSA), radiologic evidence of disease progression, or the need for further treatment. Using the Phoenix criteria to define PSA progression, treatment failure was observed in 24 percent of each treatment group at 36 months. At 36 months there was a higher incidence of positive biopsies in patients treated with RT (29 versus 8 percent), but longer follow-up of these patients is needed to determine the significance of this finding. (See "Rising serum PSA following local therapy for prostate cancer: Definition, natural history, and risk stratification", section on 'After radiation therapy'.)
●In a smaller trial conducted between 1999 and 2002, 63 men with T2c or T3 prostate cancer received neoadjuvant ADT and were then randomly assigned to RT or cryotherapy [17,19]. With a median follow-up of 105 months, the eight-year biochemical disease-free survival was significantly longer for RT compared with cryotherapy (59 versus 17 percent). There was no significant difference in disease-specific or overall survival.
Cryotherapy was compared with low dose rate brachytherapy in a retrospective series of 359 men with low- or intermediate-risk prostate cancer [20]. Cryotherapy was less efficacious based on five-year biochemical progression-free survival using a criterion for failure of PSA nadir +2 ng/mL. However, these results should be interpreted with caution, since the study patients were treated over a 22 year period, and significant biases associated with patient selection, the use of ADT, and changes in diagnosis, treatment, and imaging techniques may have affected patient outcomes.
Factors limiting the interpretation of these data include the relatively short follow-up and the lack of accepted criteria to define biochemical treatment failure after treatment with cryotherapy. In addition, the doses of radiation used in both trials with external beam RT were low by contemporary standards (114 of 119 patients receiving ≤70 Gy in one trial [18], and all patients were treated with 66 Gy in the other trial [17]). (See "External beam radiation therapy for localized prostate cancer".)
Multiple observational series have also reported on outcomes when cryotherapy is used as the primary therapy to ablate the whole prostate gland for localized prostate cancer. Interpretation of these results is hampered by the lack of uniform tumor staging and grading, variable follow-up duration, and inconsistencies in the use of neoadjuvant androgen ablation. Posttreatment biopsies of the primary tumor have been the used to evaluate local tumor control, but the absence of a rise in the posttreatment serum PSA is increasingly accepted as a surrogate endpoint. Cryotherapy does not result in complete ablation of all prostatic tissue. As such, defining the specific value of posttreatment serum PSA which best predicts treatment outcome is difficult.
The most extensive data with the longest follow-up on cryotherapy to the whole prostate gland to treat localized prostate cancer come from the COLD (Cryo-On-Line Data) registry [21]. This database is supported and maintained by the manufacturers of the cryotherapy equipment, but the data are maintained by an entirely separate company to maintain scientific integrity. The following reports are available:
●A report from this registry incorporated pre- and posttreatment information from 1198 patients. The mean follow-up was two years, and 11 percent of men were followed for five years or more. Biochemical disease-free survival was assessed using both the American Society for Radiation Oncology (ASTRO) criteria and the Phoenix revision of those criteria, although both were developed for patients managed with RT rather than cryotherapy. The five-year rates of biochemical disease-free survival for the entire data set were 77 and 73 percent, using these two sets of criteria. Based on risk of relapse, the five-year biochemical disease-free survival rates according to the ASTRO and Phoenix criteria were 85, 73, and 75 percent and 91, 78, and 62 percent, respectively, for low, intermediate, and high-risk patients. (See "Rising serum PSA following local therapy for prostate cancer: Definition, natural history, and risk stratification", section on 'After radiation therapy'.)
●In a study of 1111 men derived from the registry, a nadir PSA <0.4 ng/mL correlated with five-year progression-free survival rates of 90, 81, and 74 percent in low, intermediate, and high-risk prostate cancer, respectively. In contrast, the 24 month biochemical failure rates were 29, 46, and 49 percent for low, intermediate, and high-risk cases, respectively [22].
Results were reported for posttreatment prostate biopsies in 326 cases. When there was no specific indication for a biopsy, 30 of 207 (14 percent) were positive, while 49 of 129 (38 percent) were positive among those in whom there was a suspicion of residual or recurrent disease.
Other retrospective series suggest favorable long-term oncologic and functional outcomes from whole gland cryotherapy. In this report of 260 men undergoing primary whole gland cryotherapy and followed for a median of 107 months, failure-free survival rates at years 1, 3, 5, 7, and 9 years were 98, 90, 83, 79, and 71 percent, respectively [23]. Patients with high-risk disease were twice as likely to recur.
Those who have positive posttreatment biopsies following cryotherapy may be eligible for further treatment that has the potential to render them pathologically free of disease (pT0) [24,25]. This was illustrated in a series of 76 men undergoing primary prostate cryoablation, in which 10 of 73 assessable patients had positive postcryotherapy biopsies. After repeated treatment, all 10 had negative biopsy results, although two required further treatment.
The term therapeutic "bifecta" has been defined as a measure of the ability of a salvage therapy to achieve a post-treatment nadir PSA <0.6 ng/mL and preserving urinary control [3]. The therapeutic "bifecta" serves as a surrogate benchmark to assess the impact of salvage therapies on a patient's quality of life in addition to enabling a direct comparison of various local salvage therapy modalities. Within the COLD registry, a therapeutic "bifecta" rate of 73 percent was observed in a cohort of 183 patients undergoing prostate cancer salvage cryotherapy [26].
Focal cryotherapy
Rationale — Ablation techniques have been advocated as a way to target only those areas of the prostate that harbor tumor, rather than the entire gland [27-29]. Based on this rationale, normal segments of the gland and the neurovascular bundles can be preserved in most cases. Thus, focal therapy may avoid some of the complications of radical prostatectomy or RT.
Focal therapy assumes that the prostate cancer can be localized to a defined region in the prostate gland and that limited treatment can eradicate disease [30]. Patient selection for this approach has been based on extended biopsy schemes to define the area of the gland that is involved with tumor. However, pathologic involvement as defined in the radical prostatectomy specimen is often substantially more extensive than what had been predicted. Magnetic resonance imaging (MRI) of the prostate and both systematic and targeted biopsies should be considered to optimize cancer detection; focal ablation of areas of MRI-suspected intraprostatic recurrence preserves continence in the majority of cases, with good early cancer control [31]. (See "The role of magnetic resonance imaging in prostate cancer", section on 'Males considering focal therapy'.)
The frequency of multifocal, bilateral disease is illustrated by a series of 100 consecutive radical prostatectomy specimens examined histologically with serial sections [32]. Based on the preoperative evaluation, all cases had favorable prognosis disease limited to one side of the prostate gland (less than three positive cores, ≤50 percent involvement of any core, and Gleason score ≤6). Despite these favorable preoperative parameters, 65 cases had contralateral involvement, as discrete nodules and/or tumor crossing the midline from the side with known involvement. In six cases, the contralateral tumor had a Gleason score of 7. Similar results have been seen in other studies [28,33-35], emphasizing the need for careful patient selection based on estimated life expectancy and a thorough pretreatment biopsy scheme.
For those patients with higher volume or multifocal cancer, more complete ablation of the prostate corresponding to tumor location can be performed. Such treatments take longer and are associated with more urinary morbidity and higher rates of erectile dysfunction. Complete gland ablation usually implies destruction of both neurovascular bundles.
Results — Depending on the volume of cancer and number of positive biopsies, focal cryotherapy can be tailored to the patient's individual clinical features such that one complete lobe of the prostate (including the ipsilateral neurovascular bundle) may be treated, particularly in those men with large volume unilateral disease or multiple positive cores involving one lobe only. Focal cryotherapy can also be limited to the specific region/location of the previously positive prostatic biopsy in those with a single positive core for cancer.
A report from the COLD registry identified 1160 patients who had been treated with focal cryotherapy [36]. The safety profile appeared favorable. However, further experience and longer follow-up are needed to define the role of focal cryotherapy in men with localized prostate cancer. At this time, patients best suited for such focal therapy include those with low-risk features (pretreatment serum PSA <10 ng/mL, Gleason grade <6, and clinical stage T2a or lower) and unilateral disease.
Patients who are treated with focal cryotherapy will continue to have a detectable serum PSA since the entire prostate has not been treated. A rising PSA following focal cryotherapy is most often related to persistent localized disease (either a new focus of cancer or incomplete destruction of the original focus) and should promptly repeat prostate biopsy of both sides of the gland. If the biopsy is positive, men may be candidates for repeat cryotherapy or external beam RT as second-line treatments.
Cryotherapy for rising PSA after RT — The role of cryotherapy in the management of patients with a rising serum prostate-specific antigen (PSA) after definitive radiation therapy (RT) for localized prostate cancer is discussed separately. (See "Rising serum PSA after radiation therapy for localized prostate cancer: Salvage local therapy", section on 'Cryotherapy'.)
Complications — Complications of cryotherapy are discussed in this section. No therapy-related deaths have been reported to date, and the incidence of serious complications with prostatic cryoablation with modern techniques is low.
Pain and swelling — In one series, patient-reported complications after primary cryoablation for prostate cancer included scrotal swelling, penile tingling, and pelvic pain in 18, 15, and 12 percent of men, respectively; in most cases, symptoms spontaneously resolved within three months [37]. In other reports, the incidence of perineal pain has ranged from 0.4 to 12 percent [25,38,39]. The routine use of a urethral warming catheter during cryoablation appears to reduce the likelihood of postoperative perineal pain.
Incontinence and outflow obstruction — The incidence of damage to the urethra from cryotherapy has been markedly diminished by the routine use of a warming catheter. This has been associated with a decrease in the incidence of obstruction and tissue sloughing.
In the COLD Registry report, incontinence was reported in 4.8 percent of patients, and 2.9 percent required pads [21]. However, registry reports of this complication may underestimate the frequency of such complications.
Urinary retention was reported in 43 cases (3.6 percent). In 18 of the 43, this was successfully managed with further catheterizations, while transurethral resection of sloughed tissue was required in the others.
Fistulas and strictures — Although fistula formation initially occurred in as many as 4 percent of patients [3], the current incidence with contemporary techniques is believed to be less than 1 percent. In the COLD Registry, rectal fistulas were reported in 0.4 percent of cases [21]. Similarly, urethral stricture formation is uncommon following cryoablation, developing in less than 1 percent of men treated for localized disease [40].
Impotence — In the COLD registry, 30 percent of men were potent prior to treatment with cryotherapy [21]. Of these, 89 of 354 (25 percent) resumed having intercourse following treatment, although only 28 (8 percent) were able to do so without drug or device assistance.
Guidelines from expert groups — Guidelines for management of clinically localized prostate cancer are available from several groups, and they differ with regard to the role of cryotherapy and other forms of focal ablation:
●Guidelines for management of clinically localized prostate cancer from the American Urological Association (AUA), ASTRO, the National Comprehensive Cancer Network (NCCN), the European Association of Urology (EAU), ASCO, and the European Society for Medical Oncology all recommend only radical prostatectomy, RT (external beam or brachytherapy), or active surveillance as standard approaches for the treatment of clinically localized prostate cancer [1,2,41-43].
●An updated joint guideline from the AUA/ASTRO states that clinicians should inform patients with intermediate risk prostate considering whole gland or local ablation that there are a lack of high quality data comparing ablation outcomes to RT, surgery, and active surveillance [44]. Clinicians may consider whole-gland ablation for men with intermediate-risk (but not high-risk) disease (table 1) in select appropriately informed patients, with clinical trial participation preferred.
●On the other hand, ASCO did not endorse the use of cryotherapy for men with intermediate-risk prostate cancer, concluding that there was insufficient evidence to support its use in this setting [2].
●German guidelines that are specific to focal therapy in localized prostate cancer have been published and provide a benchmark for appropriate pre-treatment selection criteria, follow-up diagnostic pathways and an extended overview of focal therapy techniques with current supportive evidence [45]. Notably, the guidelines state that education about focal therapy should state that the equivalence of focal therapy to standard therapies for localized prostate cancer is not proven. They recommend that focal therapy, including focal cryotherapy, be limited to patients with unilateral, localized, low-risk prostate cancer who refuse both standard therapies and active surveillance.
Links to these and other professional guidelines are provided elsewhere. (See 'Society guideline links' below.)
Salvage therapy — Cryotherapy may also be useful in the management of patients with a local recurrence following definitive RT for localized prostate cancer. The application and results of cryotherapy in this setting are discussed separately. (See "Rising serum PSA after radiation therapy for localized prostate cancer: Salvage local therapy".)
HIGH-INTENSITY FOCUSED ULTRASOUND — High-intensity focused ultrasound (HIFU) uses sonic waves to create thermal energy that destroys the target tissue within the prostate. HIFU has not been compared with other standard treatment approaches in randomized trials, nor is it included in guidelines for the initial management of men with prostate cancer. Clinicians should inform patients considering HIFU that this treatment option lacks robust evidence of efficacy, and that even though HIFU is approved by the US Food and Drug Administration (FDA) for destruction of prostate tissue, it is not approved explicitly for the treatment of prostate cancer. If HIFU is performed, limiting apical treatment to minimize morbidity increases the risk of cancer persistence.
HIFU uses externally generated sonic waves to create a sharply delineated area of thermal energy that destroys the target tissue [46,47]. Various devices are available for HIFU in different areas (ie, Ablatherm, Sonablate). HIFU has not been compared with standard treatment approaches in randomized trials, nor is it included in guidelines for the initial management of men with prostate cancer [48,49]. The FDA has approved prostate HIFU as a minimally invasive treatment approach to ablate prostate tissue.
The results with HIFU are illustrated by a single institution series of 1002 patients treated from 1997 to 2009 [50]. Approximately 96 percent of patients had T1 or T2 lesions, 90 percent were Gleason 6 or 7, and 81 percent were classified as low or intermediate risk. Median follow-up was 6.4 years. The eight-year biochemical-free survival rates for low, intermediate, and high-risk prostate cancer were 76, 63, and 57 percent, respectively, based on the Phoenix criteria [51]. However, the Phoenix criteria were explicitly developed for use with radiation therapy (RT), and the appropriateness of this endpoint with HIFU therapy is uncertain [52]. (See "Rising serum PSA following local therapy for prostate cancer: Definition, natural history, and risk stratification", section on 'Definition of biochemical progression'.)
In a literature review on the use of HIFU as primary treatment in men with prostate cancer, common side effects included impotence, bladder outlet obstruction, urethral stricture, and urinary incontinence (44, 17, 12, and 8 percent, respectively) [46]. However, the incidence of side effects was substantially higher in men who had received prior radiation therapy. Rectourethral fistulas are a rare but particularly severe complication, since major abdominal surgery is required for definitive repair [53]. Although the incidence was only 1 percent after a single treatment, this complication was substantially more frequent when repeat treatment was required.
Although HIFU most commonly has been used to treat the whole prostate gland, it has also been used for partial gland ablation (limiting apical treatment) in an effort to minimize potential complications [54-58]. However, this may increase the risk of cancer persistence [59]. Longer term follow-up is required to assess both functional and oncologic outcomes before this can be considered a standard approach.
At least some reports would suggest focal HIFU maybe less effective in treating anterior prostate cancer lesions as compared with posterior tumors [60]. One approach to ensuring that all disease is included in the treated field is MRI-guided focal HIFU. While one early report of 101 individuals with intermediate-risk prostate cancer is promising, follow-up is limited, and additional studies are needed to evaluate the long-term functional and oncologic outcomes from this approach [61].
Guidelines from expert groups — Although the FDA has approved prostate HIFU as a minimally invasive treatment approach to ablate prostate tissue, HIFU is not included in several international guidelines for the initial management of men with prostate cancer [44,48,49]. One of these, a joint guideline from the American Urological Association (AUA)/American Society for Radiation Oncology (ASTRO)/Society of Urologic Oncology (SUO) [62], which was endorsed by the American Society of Clinical Oncology (ASCO) [2], states that clinicians should inform patients considering HIFU that this treatment option lacks robust evidence of efficacy, and that even though HIFU is approved by the FDA for destruction of prostate tissue, it is not approved explicitly for the treatment of prostate cancer. Furthermore, if HIFU is performed, limiting apical treatment to minimize morbidity increases the risk of cancer persistence.
Similarly, as noted above, a German guideline on focal therapy for prostate cancer [45] states that education about focal therapy, including HIFU should state that the equivalence of focal therapy to standard therapies for localized prostate cancer is not proven. They recommend that focal therapies, including HIFU, be limited to patients with unilateral, localized, low-risk prostate cancer who refuse both standard therapies and active surveillance.
PHOTODYNAMIC THERAPY — Vascular-targeted photodynamic therapy (PDT) using padeliporfin, also referred to as light-activated focal therapy for early prostate cancer and marketed as TOOKAD vascular-targeted photodynamic (VTP) therapy, has been studied for the treatment of low-risk prostate cancer as an alternative to active surveillance. However, longer follow-up and comparisons with other treatment modalities are required to assess the role of this approach in men with early prostate cancer. PDT currently remains experimental and not approved by the US Food and Drug Administration (FDA) in the United States, although it has received approval for treatment of low-risk prostate cancer in 31 European countries, Israel, and Mexico.
PDT entails the intravenous administration of a photodynamic sensitizer, padeliporfin, which is then activated by local exposure to near-infrared laser light into nitric oxide, resulting in localized blood vessel destruction. The infrared laser light is directed to the tissue by optical fibers inserted into the region of the prostate to be ablated.
This approach was compared with active surveillance in a single, randomized, open-label phase III trial in which 413 men were randomly assigned to PDT or active surveillance [63]. At a median follow-up of 24 months, significantly fewer patients had progressed to medium- or high-risk disease in the PDT group (28 versus 58 percent, hazard ratio [HR] 0.34, 95% CI 0.24-0.46). In addition, more men treated with PDT had a negative biopsy at 24 months compared with those on active surveillance (49 versus 14 percent, adjusted risk ratio 3.67, 95% CI 2.53-5.33). Treatment was generally well tolerated. In a later update, conversion to radical therapy was less likely in the PDT group (7 versus 32 percent) [64].
FOCAL LASER ABLATION — Focal laser ablation (FLA) is performed transrectally under MRI guidance using a 980 nm diode laser. Emerging data suggest promise for this approach, with a negligible effect on urinary or sexual function, although experience is limited, and significantly longer follow-up is mandatory to fully assess this novel treatment.
In the largest series of 120 men with low- to intermediate-risk prostate cancer (table 1) who underwent FLA, only 20 (17 percent) required additional oncologic therapy one year following the procedure (mostly reablation) [65]. A significant decrease in prostate-specific antigen (PSA) was noted at 12 and 24 months. There was one complication of urinary tract infection and 15 other complications, two of which were rectourethral fistulas. At a median follow-up of 34 months, there were no significant changes in urinary or sexual function.
SURVEILLANCE AFTER TREATMENT — Few specific guidelines address follow-up strategies after focal therapy. A year 2022 German guideline suggests a targeted plus systematic prostate biopsy 6 to 12 months after focal therapy utilizing MRI guidance, but does not address the role of PSA monitoring or radiologic monitoring after month 12 [45].
A general discussion of surveillance strategies after treatment for localized prostate cancer is provided separately. (See "Follow-up surveillance after definitive local treatment for prostate cancer".)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Diagnosis and management of prostate cancer".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.
●Beyond the Basics topics (see "Patient education: Treatment for advanced prostate cancer (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
●Standard treatment for organ-confined prostate cancer – The three standard therapies for men with organ-confined prostate cancer are radical prostatectomy, radiation therapy (RT) administered either as external beam RT and/or brachytherapy, and active surveillance. (See "Initial approach to low- and very low-risk clinically localized prostate cancer".)
●Cryosurgery
•Cryosurgery is an evolving technology that may be an alternative for the initial treatment of clinically localized prostate cancer. The best estimate of the five-year biochemical disease-free survival rate with this approach is approximately 75 percent. Optimal results have been seen in patients with low-risk disease, although active surveillance remains the preferred treatment option within this patient subset. (See 'Efficacy' above.)
•In the absence of adequate long-term data on local control and survival, we suggest that cryotherapy not be used routinely as an alternative to standard treatment approaches for localized prostate cancer (Grade 2C). Whole-gland cryosurgery should be limited to men with low-risk (table 1), clinically localized disease who are not suitable for either radical prostatectomy or RT due to comorbidities, yet who have a >10-year life expectancy. (See 'Efficacy' above and "Initial approach to low- and very low-risk clinically localized prostate cancer", section on 'Summary and recommendations'.)
Cryotherapy may also have a role in the management of patients with a rising serum prostate-specific antigen (PSA) and local recurrence following definitive RT for localized prostate cancer. (See "Rising serum PSA after radiation therapy for localized prostate cancer: Salvage local therapy", section on 'Cryotherapy'.)
●HIFU
•High-intensity focused ultrasound (HIFU) uses sonic waves to create thermal energy that destroys the target tissue within the prostate. HIFU has not been compared with other standard treatment approaches in randomized trials, nor is it included in guidelines for the initial management of men with prostate cancer.
•Clinicians should inform patients considering HIFU that this treatment option lacks robust evidence of efficacy, and that even though HIFU is approved by the US Food and Drug Administration (FDA) for destruction of prostate tissue, it is not approved explicitly for the treatment of prostate cancer. If HIFU is performed, limiting apical treatment to minimize morbidity increases the risk of cancer persistence. (See 'High-intensity focused ultrasound' above.)
ACKNOWLEDGMENT — We are saddened by the death of Nicholas Vogelzang, MD, who passed away in September 2022. UpToDate gratefully acknowledges Dr. Vogelzang's role as Section Editor on this topic, and his dedicated and longstanding involvement with the UpToDate program.
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