Anasayfa » Focal Therapies in Prostate Cancer
The ideal patient for FT has a well-defined lesion and a life expectancy less than 20 years for active surveillance, or other significant comorbidities, which condition the life expectancy. This strategy applies to low- and intermediate-risk cancer, and the patient should have a good prostate volume, and an initial PSA and PSA density suitable for these options. The patient should be appropriately informed, evaluated using MRI techniques and possibly targeted biopsies beforehand, and understand the potential complications and length of FT experiences.
It is critical to choose the right patient: young and fit patients are not candidates for FT. Those should be maintained under surveillance after therapy with periodic MRI. The biopsy should also be managed in a similar fashion as for active surveillance with the standard time points of biopsy. The oncologic outcomes are promising, but no definitive clinical trial has demonstrated their efficacy. The main candidates for FT appear to be eligible for whole-mapping strategies. The definition of the ideal patient and treatment is continuously evolving and recent advances in technology can contribute to the achievement of this goal. The main objective of the paper is to provide an overview of the current experience and evidence available about FT.
In recent years, the highly effective development of active surveillance has allowed a better understanding of the natural history of prostate cancer (PCa). Active surveillance and management are being increasingly considered as the first therapeutic option for patients with low-risk PCa. This approach aims to avoid complications related to radical treatments, but without increasing the risk of death from the disease. Focal therapy (FT) has appeared recently, mainly driven by the improvement in diagnostic techniques and the different tissue ablative modalities which minimize the risk of functional complications. FT has been defined by the American Urological Association as the primary treatment—organ-confined disease—of a pre-selected target within the prostate.
Initially, PC was underdetected, and many men were diagnosed after reaching the distant metastasis phase when they presented bone pain, pathological fracture, cord compression, or ureteral obstruction. In the past, the advent of systematic serologic analysis of Prostate Specific Antigen (PSA) allowed the detection of more primary prostate cancers than me.
Although tumors are restricted to the prostate and have not yet reached massive forms, and they have facilitated the patient’s use of the best treatment modalities and selection of the treatment decision. PSA staging and transrectal ultrasound provided stage-guided treatment approaches. In recent years, image changes have improved the scaling of tumors with higher degrees of detail.
In particular, magnetic resonance imaging (MRI) has contributed substantial and intense data about extracapsular cancer growth and the possibility of extraprostatic extension, not a few lesions ignored by traditional imaging. In histology, there are categories of tumors with less potential malignancy that are classified as active surveillance or tight surveillance. These histologies have a minor probability of progression or allow a controlled progression with simple interventions when tests show a laborious pathology. There are several modalities of primary therapy of PC.
Prostate cancer (PC) is a common cancer among men, but the impact is limited. In the United States, PC is responsible for 6.9% of cancer cases and 3.4% of cancer deaths—among men, however, it remains the most frequent infectious ton cancer and the second leading cause of death.
Human prostate cancer presents a broad spectrum, ranging from small foci of little clinical consequence to extensive tumors representing potential life-threatening cancer. PC follows a long natural history; it starts as prostatic intraepithelial neoplasia (PIN), evolves to a series of differentiated lesions that can become locally invasive into the prostate, spread to regional lymph nodes, and ultimately produce or receive distant metastases, mainly to bone. Bone metastases present when the tumor is disseminated; they often provoke osteoblastic reactions.
According to a recent report from the USA, the stage migration from metastatic to localized prostate cancer began in the early 1990s when prostate cancer was first reported as the most common type diagnosed in the USA.
A screening recommendation from the American Cancer Society was issued in 1992. The prostate-specific antigen (PSA) era was associated with a 74% detection rate increase during the early 1990s, which continued through the 2000s as the incidence of localized cancer increased approximately 14.7% per year. However, with the release of a 2012 United States Preventive Services Task Force report stating that the potential harms of PSA-based screening for prostate cancer outweighed the benefits, a reversal trend was observed. There is currently no consensus about the pros and cons of PSA-based screening.
General awareness of prostate-specific antigen or PSA screening has led to a stage migration and an increase in low-risk prostate cancer with considerable clinical significance worldwide. Over time, there has been an accumulation of expertise in imaging modalities, biopsy devices, histopathological diagnostics, and an increasing number of active surveillance strategies.
Currently, minimally invasive therapies for small, low-risk prostate cancer have evolved under the umbrella term of focal therapy strategies, which are mainly based on techniques developed to destroy the entire gland in radical therapies. The rise in efficacy and focal therapy strategies, along with increasing experience and exact disease localization, has led to an escalation from the previously mentioned “partial gland therapy” to the currently preferred term of true focal therapy.
The development and progression of prostatic neoplastic transformation seem to depend on a variety of different, yet androgen-dependent, possibly mutagenic events. It is not yet clear whether all these pre-malignant high-grade prostatic intraepithelial neoplasia (HGPIN) lesions are the precursors of an unfavorable clinical progression (most likely only a subset of the identified HGPINs).
However, it is somehow more clear that the risk of prostate cancer increases according to the number of contiguous HGPIN foci found in prostate biopsies. Consequently, urologists and oncologists have to take therapeutic decisions in cases with a high PSA, benign findings at the digital rectal examination, and several negative biopsies. No doubt, these patients would be likely to accept a multimodal treatment aimed to prevent the development of malignancy in those prostates which kept their anatomical-neoplastic peculiarities revealing a high PSA and undergoing the negative biopsies.
The list of modalities which can be used as focal treatment is growing rapidly. This review summarizes both experimental and clinical data. An English-language MEDLINE database was used to search for relevant literature. A combination of keywords (prostate; prostate tumor; prostate cancer; combination of treatment; multimodal treatment; combination of chemotherapy; finasteride; androgen deprivation; selective adrenoceptor blockers; glycine transporter inhibitors) was used.
Several authors have studied performing multimodal treatment to prevent the development of prostatic adenocarcinomas or the high-grade prostatic intraepithelial neoplasia. Urologists and oncologists should be involved in the discussion of the development and the current availability of multimodal treatments which could be offered to prevent the development of malignancy in prostates which have exhibited a high PSA and have undergone several negative biopsies.
Notice that the American Academy of Urology has recently published a good guideline about the clinical utility of PSA in the management of prostatic cancer.
Prostate cancer (PCa) is a round-shaped, grey, solid, indurated nodule; its consistency is similar to cartilage. Across the margins of the nodular tumor mass, multifocal orange-yellow fragile nodules are also seen compressing the prostatic urethra. HIFU produces tissue damage by whole cell nucleation at high temperature levels in the focal necrosis area. It also causes protein coagulation with rapid denaturation in the perifocal area.
Computer-driven focusing of HIFU heats a target to high necrotic-level temperatures instantaneously while sparing the surrounding tissue. The main advantage of HIFU is treatment accuracy with the possibility of retreatment. A recurrence of prostate cancer with HIFU is a good indication for retreatment. Frequent side effects of HIFU in the treatment of localized prostate cancer include erectile dysfunction, frequency, and urgency. Increased experience and improvements in the HIFU technology have led to substantial improvements in function preservation.
TUR and/or androgen deprivation are advisable in the days before the procedure to reduce prostate volume. In the management of TRUS, neurovascular bundles and seminal vesicles should not be treated. After HIFU treatment, PSA levels decrease immediately to undetectable values, but then a PSA level is typically most probably found at 1 month (3% persistently undetectable). Radiation proctitis has been a rare occurrence even during long-term follow-up. HIFU applied to elderly prostate cancer patients is very well indicated with multiple comorbidities.
Clinically confined intervention for prostate cancer management by focal therapy aims to cause cancer cell death by a minimally invasive technique limited to the prostate and especially to the cancer site. The development and updating of imaging techniques for accurately mapping the tumor and the treatment effect are crucial for this progress.
Among these imaging tools, multiparametric MRI has a prominent place. There is increasing interest in focal ablation to treat organ-confined prostate cancer when patients are affected by aggressive cancers with low-volume tumors, long life expectancies, and few medical comorbidities or when patients are affected by intermediate-risk prostate cancer. Several techniques with a different mechanism of action are currently suggested as focal therapies for prostate cancer, but data on functional prostate imaging improvements influenced by the treatment performed are still scarce.
The probes used to freeze tissue are large and intra-urethral sought that are used routinely could become stuck. Many patients are offered varying degrees of urethral protection to minimize the risks of intra-urethral freezing and urinary retention. Those wanting to maximize urethral preservation also have ice slush inserted after the placement of catheters put in place to refuse, cool, and monitor urine output. Such proponents feel this increases the rate of post-operative urinary retention.
Some series have observed high rates of salvage cryotherapy post-radiotherapy. Results were no different in the immediate reports than in historical data. However, long-term, a clear signal that previous treatment resulted in poorer outcomes was observed. It is felt that secondary cryotherapy decreases the likelihood of regaining continence and potency following surgery and thus it is performed sparingly. Indeed, it should not be offered to this group as a standard of care but rather an option.
Multiplanar needle access allows for the simultaneous destruction of large regions of the prostate using 12 triple-freeze cryoprobes in an area 2 cm apart resulting in a rapid reduction in size to 0.7 cm2. However, the ability of the cryoprobe to reach the anterior prostate is limited and rates of positive biopsies post-therapy in the anterior region are high.
Whole-gland salvage has a significant risk of side effects. Argon gas is used to freeze tissue to -180°C. During the thaw cycles, tissues warm up to 20-40°C causing cell lysis and apoptosis. Faraday’s Law shows that the amount of energy involved in this process dramatically increases with decreasing tissue diameter as does the time involved.
Whole-gland therapies have limitations. These treatments are best offered to those men with very localized or unifocal disease. Cryotherapy has the added advantage over other focal therapies of retreatment. In the instance of a positive biopsy post-treatment, these patients may get further appropriate therapy within the initial therapy window.
After preparation of transrectal ultrasound (TRUS) map of the dimension of the prostate, the base and length of the bladder, geometric focal therapy treatment planning software was used to measure distance from the urethra, and factors based on the thickness and depth of the prostate to determine the placement and direction of converging multiple laser fibers selecting the appropriate energy density between 50-100 J/cm to cover the heat sensitive chromophores of the target areas. The fibers were inserted using the brachytherapy template for the presence before the laser energy was applied.
Using magnetic resonance thermography, the volume of coagulation necrosis and the actual prostatic area covered by the laser fibers was determined. Ten-year results indicated that all patients achieved an initial PSA nadir of 0.2 ng/ml, and 50% maintained biochemical disease-free survival. Recurrent disease was treated with salvage radiation therapy, and the remaining patients chose androgen ablation.
Major adverse events included urinary and/or rectal burning, and prostatorectitis. A focal laser technique was applied in the early 1980s using available software from laser manufacturers. Ideal candidate patients should have an exophytic peripheral lesion and be suitable for a brachytherapy template placement under general anesthesia.
The procedure can be repeated when necessary, and urinary incontinence rates are low. The next phase will involve dose escalation with pre-focal laser ablation of the urethra using thermal resistive balloons and exploration of synergy with specific oncolytic gene delivery or platinum cisplatinum-based combination therapy.
Laser ablation involves the focal application of energy through necrosis of the target tissue when endorectal sonography or MRI images are used to guide and monitor the thermally-induced necrosis simultaneous with direct temperature readings using catheter-based thermistors or optical fiber-based temperature sensors.
A laser diffuser is used to fan the energy along the tumor, especially with larger tumors. For multicentric tumors, multiple fibers can be inserted. Scremeyer and associates used a neodymium yttrium aluminum perovskite (Nd:YAP) laser with an output of 2.0 W, 1 cm diffusing tip, wavelength of 1.318 um operated in continuous mode delivering energy at 6.0 to 7.0 J/cm to treat five patients with prostate cancer.
The FocaliS Bronze and Silver studies should demonstrate whether current selection criteria for medium- and index-targeted therapy are safe or ought to be adapted. Registry data and Phase II and Phase III intervention studies will need to ultimately demonstrate the oncological safety and functional outcome of focal therapy for localized prostate cancer.
The severe concerns with patient selection have led some to believe that focal therapy for localized prostate cancer will become a comprehensive test of clinical judgment. The chapter provides a substantive discussion of why focal therapy criteria differ appreciably from previous patient selection criteria for prostate cancer and a justification for medially targeted therapy under the uro-oncological equivalent criteria.
As with any new treatment modality, patient selection is paramount. Similar to the development of established prostate cancer treatments, a change in focus from prostate- to patient-oriented treatment selection criteria is required. Instead of targeting anatomical tumors visible on multiparametric magnetic resonance imaging, patient selection criteria should include different aspects such as index tumor importance, tumor topographical aspect, use of neurosafe surgical techniques, and realization of targeted biopsies. This change in treatment paradigm is sure to affect patient outcomes. The aim of this review is to give a critical overview of the available noninvasive and invasive staging methods.
Currently, patients with confined intermediate-risk and high-risk, low-volume disease can be candidates for focal therapy and have been introduced into clinical trials. More prospective comparative studies are needed to detect if the new volume measurements will improve the quality of management of oncological organ-confined prostate cancer, especially for those undergoing focal therapy with a real possibility of direct final pathology cross-reference.
In many prostate cancer patients, the discovery of low-grade tumors has led to changes in the treatment strategy employed and has opened the door to the use of focal therapy. This important difference between focal therapy and other oncologic disciplines allows treatment of all patient groups regardless of their volume or stage. In focal therapy, location plays a more one-second role than in other therapies.
Focal therapies appear to offer important advantages regarding side effects (which are less frequent than conventional therapies) and also a reduction in patient anxiety due to the lower degree of risk undergone. Despite it is difficult to assess intermediate- and long-term oncological outcomes after undergoing focal therapy, data from some of its modalities is currently being reported. Low-risk groups are usually recommended therapies and the different technologies are seemingly less efficient in intermediate-risk tumors. The process of tumor focal treatment is monitored using imaging studies performed during the first postoperative semester.
With time, everyone will agree that he was already my patient, from the beginning; he did not understand the concept and was not psychologically fit or has sought a second “normal” invasive treatment that could at best give the same consequences as my first decision.
At the same time, we await the result of tumor foci studied and ablated in any patient to adjust the treatment to the actual reality and anatomy of the cancer in the prostate and in other organ systems. We need more robust evidence; therefore, our applaud the ongoing trials. It just turned off a hot TV emotional post with important men treated with my criteria that have failed after more than 10 years of follow-up a focal therapy. We need continuous and centered evidence. We need to scrupulously respect the patient’s rights and autonomy to obtain the foundations of a clinical empire proven over time.
The true mainstay for consolidating focal therapies will come not only from a prospective global surveillance of the patients but also from combinations in a multitasking approach. We know that a significant number of patients may have an anterior prostate cancer, a cancer in close proximity to the prostatic urethra, with an elevation of the overexpression of PSMA in prostate cancer and disease in lymph nodes. Therefore, the use of transperineal, transurethral approach for therapy is under investigation. The trend of short-term stereotypes and its combination in individualized cancer models and artificial intelligence skills in predicting cancer behavior as well as multimodal fusion imaging of MRI-ultrasound is dictating the future of focal therapies. Companies are already investigating.