Alternative Local Treatments

1. Introduction:

Cryosurgery of the prostate (ACSC) and focused high-intensity ultrasound (HIFU) are currently considered as alternative therapeutic options in patients with PCa, especially if clinically localized (1-4).
Although HIFU is still considered an experimental treatment, ACSC has been recognized as a true therapeutic alternative, according to the guidelines of the American Urological Association. Both, HIFU and ACSC, were developed as minimally invasive procedures, with therapeutic efficacy, constituting important therapeutic alternatives associated with less morbidity.

2 - Prostate surgery (CSAP)

The first principle of cryosurgery is the use of freezing techniques to induce cell death by:
• dehydration resulting in protein denaturation;
• direct disruption of cell membranes by ice crystals;
• vascular stasis and microthrombi, resulting in stagnation of microcirculation and ischemia;
• promotion of apoptosis (1-4).
The second principle of successful cryosurgery is related to the procedural factors that maximize neoplastic cell death, such as freezing rate, freezing time or repetition of freeze-heat cycles.
The historical evolution of cryosurgery shows us that:
– there is evidence of clinical benefit
- the morbidity associated with the procedure has greatly decreased with the emergence of new improvements in the technique.

Freezing of the prostate is ensured by several 12-15 gauge needles placed perineally and guided by transrectal echo (TRUS). Thermal sensors are also placed at the level of the external sphincter and bladder neck, and a urethral heater is also inserted. Two freeze-thaw cycles are used under the guidance of TRUS.

2.1 - Indication for ACSC

Cryosurgery can be used as primary therapy or as a salvage therapy for prostate cancer.

2.1.1 - Cryosurgery as primary therapy

ACSC is an option in the primary treatment of organ-confined prostate cancer of any grade without evidence of metastasis (1-3). High-risk patients may undergo multimodal therapy. There are some studies concerning locally invasive disease (cT3), but the role of cryosurgery is still undetermined.
The volume and configuration of the prostate are factors to be taken into account, since the larger the volume, the more difficult it is to obtain uniform cooling of the gland, or even to have access to the entire organ through the interposition of the pubic arch. Ideally, the volume should be less than 40cc. In the case of larger prostates, patients can be submitted to neoadjuvant hormone therapy for their reduction (4a;4b).
Although many patients with elevated PSA are treated with cryosurgery, the best results were obtained with PSA below 10 ng/ml (4a,4b).
A previous TURP may be a relative contraindication, especially if the prostatic location is large, due to difficulty in heating the urethra, with a greater risk of urethral necrosis and acute urinary retention due to clots and debris (4a,4b).
Cryosurgery is therefore a minimally invasive option for men who refuse radical prostatectomy or who are not good candidates for radical prostatectomy (comorbidities, previous pelvic surgery, obesity or narrow pelvis) and who cannot undergo radiation therapy (previous radiation therapy, inflammatory bowel disease or rectal pathology).

2.1.2 - Cryosurgery as salvage therapy

Cryosurgery can be considered as a therapeutic option with curative intent in patients with radiotherapy failure (external or brachytherapy). The most appropriate candidates are those with a positive biopsy for persistent organ-confined disease, no metastases and no evidence of seminal vesicle invasion, a PSA of less than 10 ng/ml, a long PSA doubling time, and a life expectancy greater than 10 years. (4c,4d,4e). Prostate volume is not as important a factor as in the case of primary therapy, but prior TURP with a large location remains a relative contraindication.
Although there are no established parameters to define success after salvage cryosurgery, non-persistence of disease diagnosed by biopsy and a stable PSA value of less than 0.5 ng/ml are generally used to define the technique's effectiveness.
In conclusion, cryosurgery is an option for the recurrence of organ-confined prostate cancer after radiotherapy and should be considered early in these patients. Refinements in technique and equipment have resulted in a significant reduction in morbidity and encouraging short-term results.

2.2 - The results of cryosurgery

When comparing treatment modalities, it is important to keep in mind that in patients with clinically organ-confined RP, there is a very low risk (2.4%) of dying from PCa 10 years after surgery (5). Therapeutic outcomes have improved over time with refinement of the technique, such as new probes and the placement of transperineal probes, as used in third-generation cryosurgery (6-11).
With regard to the second generation of ACSC, if a PSA nadir Long et al. (6) performed a retrospective analysis of the results of 975 patients undergoing ACSC, subdivided into three risk groups. Using PSA thresholds of 1.0 ng/mL and • 76% and 60%, respectively, for the low-risk group;
• 71% and 45%, respectively, for the intermediate risk group;
• 61% and 36%, respectively, for the high-risk group.
Cryosurgery showed progression-free survival (PFS) of 36-92% (projected 1-7 years). Negative biopsies were observed in 72-87% of cases, but there are no biopsy data for the third generation of cryotherapy.
Bahn et al. (9) analyzed 590 patients undergoing ACSC due to clinically localized and locally advanced PCa. Using a PSA level Unfortunately, we do not yet have long-term data on this technique.

2.3 - Complications of CSAP

Short-term complications (one week to four months) include acute urinary retention, genital swelling, and penile paresthesia.
Long-term complications include rectal fistula, urinary incontinence and erectile dysfunction.
Erectile dysfunction occurs in approximately 80% (49-93%) of patients and remains a consistent complication of the procedure, regardless of the generation of the system used. Complication rates reported in third-generation cryosurgery include tissue shedding in about 3%, incontinence in 4.4%, pelvic pain in 1.4%, and urinary retention in about 2% of patients (6-11). Fistula development is generally rare, being less than 0.2% in recent series. About 5% of patients require transurethral resection of the prostate (TURP) for obstruction.

3 – HIFU

HIFU consists of the use of ultrasound waves emitted from a transducer, which cause tissue damage by mechanical and thermal effects, causing prostate cavitation (16). The purpose of HIFU is to heat malignant tissues above 65°C so that they are destroyed by coagulation necrosis.
HIFU is performed under general or locoregional anesthesia, with the patient lying in the lateral position. The procedure is time-consuming, with about 10 g of treated prostate tissue per hour.

3.1 The HIFU results

As with ACSC, it appears to be difficult to interpret oncological results in patients undergoing HIFU because the criteria for biochemical failure are heterogeneous and there is no international consensus.
According to a recent review (12), HIFU showed PFS (based on PSA ± biopsy) of 63-87% (projected to 3-5 years), but mean follow-up time in the studies ranged from 12-24 months only.
In one of the largest known studies, the results of 227 patients were analyzed after a mean follow-up of 27 months (range: 12-121 months) (17). At 5 years the BDFS was 66%, or only 57% if patients had displayed a pre-therapy PSA value of 4-10 ng/ml.
Due to the lack of long-term follow-up, the procedure is still considered experimental. As a primary therapy, HIFU is indicated in patients over 70 years of age with organ-confined disease, although it has been used with encouraging results as a first-line salvage therapy after definitive treatment, particularly in patients with low/medium risk disease. , or in locally advanced disease (T3,T4).

3.2 - Complications of HIFU

Morbidity is low and includes acute urinary retention, urethral stricture, urinary incontinence, erectile dysfunction and urethrorectal fistula.
Urinary retention appears to be one of the most common side effects of HIFU, developing in almost all patients between 12 and 35 days (16-18). Stress urinary incontinence occurs in about 12%. A subsequent TURP or bladder neck incision to treat the obstruction is common, and is sometimes performed at the time of HIFU. Erectile dysfunction occurs in 55-70% of patients.
Eltherman et al. (27) treated 95 patients using the Sonablate-500 device, and assessed the type and frequency of treatment-associated complications. With a minimum follow-up of 6 months, 17% (7/41) of men had significant incontinence and 2% had erectile dysfunction. Early and late obstruction requiring surgical treatment occurred in 17 (17.9%) and 20 (21.1%) patients, respectively.

4 - Focal therapy

During the last two decades, there has been a trend towards early diagnosis of PC due to greater public and professional awareness, leading to the adoption of both formal and informal screening strategies. The effect of this has been to identify men with early-stage tumors that occupy only 5-10% of the prostate volume, with a greater propensity for unifocal or unilateral disease (28-30).
Focal therapies, to date, have been achieved with ablative technologies such as cryotherapy, HIFU or photodynamic therapy. Some groups have proposed a more localized therapy, in the expectation that the genitourinary functions will be preserved and the tumor treated properly (31-33). Although focal therapy is not currently the standard for men with organ-confined PCa, it is a therapeutic approach with future potential. Although it is a conceptually attractive technique, clinical experience is limited and long-term results are unknown.

4.1 Pre-therapeutic assessment of patients

The current standard for characterization is prostate biopsy using a model-guided mapping approach. A 5 mm sampling frame is used to discard foci > 0.5 and 0.2 ml volume, with a 90% certainty (36). Thus, the exact location of the anatomical lesion defined as the most biologically aggressive can be accurately determined.

4.2 Selection of patients for focal therapy

The main goal of treatment should be the eradication of the measurable and biologically aggressive disease. However, although treatment is generally intended to be one-time, patients should know that treatment may still be necessary in the future.(34,35)
Patient selection criteria are not defined, but candidates are likely to be men with an indication for active surveillance but who prefer to be treated, or men with unilateral organ confined disease.
Based on published data, the following criteria are useful in identifying potential candidates for trials currently undergoing focal treatment:

• Candidates for focal therapy should ideally have transperineal mapping biopsies. MRI-guided biopsies may be used alternatively.
• Focal therapy should be limited to patients at low to moderate risk. The clinical stage of the tumor should be • Patients with previous prostate surgery should be advised carefully, as there is little data on functional and oncological outcomes available.
Patients should be informed that the therapy is still experimental and that there is a possibility of repeat treatment.

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