Editing Management of Localized Prostate Cancer (section)

==== Focal therapy ====

* Proposed as an alternative to active surveillance or radical treatment for localized prostate cancer
* Goal is to treat only those foci of cancer that will affect the patient’s survival or quality of life while preserving surrounding tissue and structures and in turn, the patient’s sexual and urinary function.
* '''Biologic basis for prostate focal therapy'''
** '''Cancer grade is an indication of cancer aggressiveness'''
*** Natural history studies suggest that tumor grade, serum PSA levels, and clinical stage are the best predictors of prostate cancer–related mortality. Among these phenotypic expressions of aggressivity, '''cancer grade remains the earliest indication of lethal potential in low-volume, localized prostate cancer.'''
** '''Multifocality of prostate cancer vs. the index lesion hypothesis'''
*** '''The majority of prostate cancer (50-91%) is multifocal'''
*** '''It is thought that the index lesion, the largest tumor focus within the prostate, determines the subsequent course of the cancer.''' This hypothesis is supported by:
***# Most of the time, the grade/stage is determined by the index lesion.
***# Most of the tumor volume is contributed by the index lesion.
***# The majority of satellite tumors are small and low grade.
***# Genetic studies suggest a monoclonal origin of metastatic or lethal prostate cancer.
*** If the index lesion can be accurately identified and ablated, the majority of tumor within the prostate, and its most aggressive components, can be treated, metastasis and death could theoretically be prevented by removing the lethal component of the prostate cancer.
**** Pathologic features of aggression such as largest tumor size, highest Gleason score, or highest stage, do not always occur in the same nodules, and in fact, may occur in satellite rather than index lesions; these biologic variations will contribute to treatment failures in focal therapy applied to the index lesion
* '''Clinical applications of focal therapy'''
** '''A successful focal strategy depends on:'''
**# '''Accurately determining the disease extent/location through advanced imaging and biopsy'''
**#* The aggressive lesion within the prostate must be identified and its extent carefully delineated to completely ablate it
**#* '''Advanced radiologic techniques such as mpMRI allow the entire prostate gland to be visualized''' and, in some cases, predict a more aggressive histology.
**#* '''However, because of the potential 10-15% false-negative rate with mpMRI, there remains consensus to histologically confirm the aggressiveness of the lesion through biopsy'''. Furthermore, current imaging studies remain imperfect in predicting the absence of aggressive cancer, and '''many experts would advocate a systematic biopsy to more comprehensively evaluate the gland.'''
**# Ascertain that the patient will benefit from treatment and be compliant to follow-up
**#* A 2016 consensus on patient selection for prostate focal therapy defined Gleason 3+4 lesions as the “sweet spot” for focal therapy.
**#* With higher-grade lesions, there is a concern about increasingly aggressive cancer portending a higher likelihood of EPE outside the image-guided target zone that may need to be met with more radical types of treatment.
**# Completely ablate the index lesion(s)
**#* A complementary strategy of treating intermediate or high-grade cancer foci with focal therapy, while monitoring the remainder of the gland having low-grade cancer with active surveillance. During surveillance, if any higher-grade cancers are detected, they could potentially be treated focally again.
**# Monitor the patient post-treatment utilizing advanced imaging and biopsy with a view to future targeted treatment of either persistent or de novo disease, or conversion to whole-gland treatment as necessary
** Advanced imaging techniques in prostate cancer
*** Multiparametric MRI
**** Developments have positioned mpMRI as a key enabler for prostate focal therapy and have been responsible for renewed interest in this area because of its ability to do the following:
****# Preferentially detect high-grade lesions.
****# Improve the detection of anterior zone prostate cancers.
****# Improve the detection of EPE.
****# Accurately identify the index lesion.
**** Historadiologic correlation studies consistently show that '''mpMRI underestimates histologic tumor volume by 5-30%''', after accounting for shrinkage and other artifacts; this poses significant challenges for lesion-based ablation, and complete ablation may ultimately require hemiablation or zonal ablation.
** '''Ablation patterns and current technologies'''
*** Approaches
**** The prostate can be accessed for ablation via a transrectal, transperineal, or less commonly, a transurethral approach. The approach chosen will depend largely on the following:
****# Location of the tumor
****# Desired ablative technology that is available
****# Any other anatomic consideration unique to the patient
**** Transrectal approaches allow for ease of access to the posterior zone, and transperineal approaches offer better access to the anterior zone of the prostate.
**** Treatment can be applied in various patterns (hemiablation, quadrant ablation, lesion ablation)
*** '''<span style="color:#ff0000">Modality</span>'''
**** '''<span style="color:#ff0000">Several different forms of thermal energy have been used for focal treatment of prostate cancer, including cryoablation, HIFU, laser ablation therapy, radiofrequency ablation, and photodynamic therapy</span>'''. Limited data on the long-term efficacy of these procedures.
**** '''Cryoablation'''
***** A thermal ablative modality achieving cell kill through extraction of heat producing lethal cold temperatures.
***** Can be used as primary whole-gland therapy, as a salvage treatment option after radical prostatectomy or radiotherapy
***** Has been advocated in elderly men who may have underlying comorbidity that precludes radical prostatectomy; there are no studies directly comparing focal cryotherapy to established treatments such as radical prostatectomy or radiation.
***** Better suited for less bulky prostate cancer; gross extracapsular tumor extension or seminal vesicle invasion are usually treated with neoadjuvant hormone therapy to reduce the tumor volume and allow for easier inclusion within the ice ball
***** '''No universally accepted definition for treatment failure after cryoablation'''
***** '''Complications of cryotherapy have include urinary incontinence, urethral sloughing, osteitis pubis, transient penile paresthesia, perineal and rectal pain, rectal fistula, need for a TURP for urinary obstruction, and erectile dysfunction'''
**** '''<span style="color:#ff0000">High-intensity Focused Ultrasound (HIFU)</span>'''
***** '''A transducer focuses multiple ultrasound beams onto a preset point, generating a temperature of at least 55°C, thus ablating focal lesions or the entire gland'''
***** Transrectal HIFU is well suited for treatment of posterior-zone lesions. However, the anterior gland may be more difficult to treat because of energy dissipation over the intervening prostate tissue and displacement of anterior zone targets with gradual edema of the prostate tissue as treatment progresses
***** Treatment is performed with use of general or spinal anesthesia and takes 1-4 hours, depending on the '''prostate volume, which should not exceed 40 mL'''
***** In-bore MRI-guided focused ultrasonography (MRgFUS) allows for monitoring of treatment temperatures within the target area using MR thermometry, as well as ensuring safe temperatures in the urethra and sphincter
***** '''Usually well tolerated; the most common side effect is acute urinary retention, occurring in ≈20% of patients. Other potential complications are urinary fistula (2%), incontinence (up to 10%), erectile dysfunction (20-60%), dysuria, urethral stricture, and perineal pain'''
***** '''<span style="color:#ff0000">Should be reserved for men with a life expectancy < 10 years and for whom sexual function is not an important issue</span>'''
***** '''Clinical studies have reported mixed results regarding the efficacy and safety of HIFU therapy'''
***** '''Focal HIFU: results are substantially worse than those of radical prostatectomy or radiotherapy'''
**** '''Laser'''
***** Focal laser ablation refers to the creation of coagulative necrosis using an interstitially placed laser fiber.
**** '''Irreversible Electroporation'''
***** A nonthermal ablative technique that uses short pulses of direct-current electricity to produce irreversible pores in the cell membrane, leading to cell death
**** '''Photodynamic therapy (PDT)'''
***** '''Based on tumor cell destruction by light emitted from a laser fiber interacting with a photosensitizing drug delivered to the tumor tissue.'''.
***** Photosensitizing agents accumulate preferentially in cancer cells; 2 types of photosensitizing agents:
****** '''Tissue-activated photosensitizers'''
******* Require hours to days to achieve therapeutic concentrations within the tumor
******* Can accumulate in the skin and eyes, and be activated within those organs for some time after administration; therefore, protection of the skin and eyes against light is required.
****** '''Vascular-activated photosensitizers'''
******* Advantage of having a short drug-light interval because they achieve peak concentrations in the vasculature within minutes. Because the clearance is also rapid, patients can be discharged on the day of treatment without light protection.
***** The laser fiber is inserted transperineally using a brachytherapy template under ultrasound guidance. After fiber placement, interstitial illumination must be conducted in a darkened room to prevent cutaneous photosensitization.
***** Treatment of anteriorly situated lesions may be limited by pubic arch anatomy.
***** Oncologic treatment outcomes and side effects have not been well documented because of the limited studies
**** Focal brachytherapy
***** The benefit of brachytherapy is the sharp falloff in radiation dose within a few millimeters of the radiation source.
**** Stereotactic radiotherapy
***** Dosimetric feasibility has been demonstrated in the use of stereotactic body radiotherapy for focal therapy though there has not been any clinical trial
** '''Post-focal therapy follow-up'''
*** With focal therapy, traditional markers of therapeutic success may be less relevant. After curative radical prostatectomy, PSA is expected to be undetectable, and after radiation therapy, a significant rise is needed to define biochemical recurrence. '''After focal therapy,''' however''', the expected fall in PSA has been variable''', with some studies reporting a 50-80% reduction. The PSA level would depend on the amount of residual prostate epithelium that may continue to grow and is thus less informative as an absolute marker.
*** Similarly, clinical examination of the prostate may be affected by post-treatment scarring and contraction of the original tumor site, making follow-up biopsy less reliable. These post-treatment findings are seen on mpMRI, TRUS, and contrast-enhanced ultrasonography (CEUS), with increasing ablation zone volume in the early post-treatment period followed by a gradual overall reduction in prostate volume caused by ablation zone fibrosis and deformation
*** In a 2015 Joint International Consultation on Urological Diseases (ICUD)/Society Internationale de Urologie (SIU) project on image-guided focal therapy, success was defined as the following
***# Within the treated or infield area as the:
***## Eradication of the tumor focus in the short term.
***## Absence of clinically significant cancer in the intermediate to long-term.
***#* Development of clinically significant cancer should be observed within the untreated or outfield area.
***#** In the short term, this outfield cancer focus likely represents selection failure, and in the intermediate- to long-term, this may represent de novo cancer.
**** This consultation '''recommended an mpMRI with mandatory targeted biopsy of 4-6 cores in the treated area at 3-6 months, then mpMRI at 1 to 2 years and 5 years with targeted biopsy as needed,''' especially if a new lesion should become manifest. A systematic biopsy was also recommended at 1 to 2 years and 5 years to provide further histologic evaluation of the untreated zone for potential outfield recurrence.
***** It should be noted that there is limited experience with mpMRI in the post–focal treatment arena, and it is unknown how posttreatment changes interact with mpMRI performance.