The morbidities associated with prostate cancer treatments have improved over the years. However, potential overtreatment and the risks of adverse events associated with radical treatment still pose a considerable challenge. Targeted focal therapy (TFT) of prostate cancer appears to be part of a logical continuum in the quest to improve upon the management of early organ-confined disease. TFT is a procedure in which only the cancer in the gland is ablated. The normal gland, sphincter, and in most cases the neurovascular bundles are preserved. Therefore, this approach averts some of the common complications of more radical therapy. Initial experience has been encouraging; however, long-term data and full implementation of emerging advances in imaging are urgently needed before the widespread adoption of this approach. In this review, we present the current status of our knowledge about this procedure and the most important challenges that need to be addressed. We also present the initial results with this approach at our center.
Prostate cancer is the most commonly diagnosed noncutaneous cancer in men, and the third most frequent cause of cancer mortality. Treatment choice is largely dependent on clinical stage, grade, and patient preference. The treatment spectrum includes watchful waiting, active surveillance (treatment delayed until signs of progression based on serum prostate-specific antigen [PSA] and follow-up biopsies), and major therapies such as radical prostatectomy, complete cryotherapy, and various forms of radiation therapy. Radical treatment has the potential to lead to urinary incontinence, impotence, and other complications. All the aforementioned treatment modalities lack the fundamental balance of achieving adequate control of the disease without compromising patient quality of life.
The increasing popularity of prostate cancer screening using PSA and digital rectal exam (DRE) has raised valid concerns for overdiagnosis of clinically insignificant disease and overtreatment of many patients. A recent review of 24,405 men with low-risk prostate cancer showed that 2,564 men (10%) were overtreated with radical surgery and 10,973 men (45%) with radiation therapy. The observed stage-shifting of the disease to early organ-confined, low-grade disease, underscores the concern about overtreatment of some men.
A rational alternative treatment is targeted focal therapy (TFT) of prostate cancer. This refers to the complete ablation of all clinically significant cancer foci within the prostate using a minimally invasive technique. A comparative analogy can be drawn with the evolved management of breast cancer in women, where radical mastectomy and total axillary clearance was the main treatment option until a decade ago. This was associated with significant morbidity and a prolonged postoperative recovery period. Currently, simple lumpectomy and wide excision with axillary sampling became the treatment of choice for the majority of women diagnosed with early-stage disease. This landmark shift in management has proven to be associated with a substantial improvement in morbidity incidence without compromise of a survival benefit.
Nonetheless, apparent anatomic and natural history distinctions between breast and prostate cancer must be taken into account when addressing the adoption of TFT in prostate cancer. Aside from obvious topographic differences between the two organs for utilization of imaging techniques, the challenge in the application of TFT in prostate cancer is mainly related to the fact that it is a slow-growing cancer, more often a multi-focal disease, and with bilateral involvement in more than two-thirds of newly diagnosed cases. In addition, controversy surrounds the accurate depiction of clinically relevant disease as opposed to insignificant tumor burden.
Radical Treatment of the Prostate vs Active Surveillance
Appropriate management options for men with clinically localized prostate cancer remain uncertain despite increasing efforts in the past decade to introduce new techniques such as laparoscopic and robotic surgery, and conformal and hypofractionated radiotherapy. This is partly due to the lack of accurate clinical staging at the time of diagnosis and to the inability to avoid adequately damage to vital structures in the vicinity of the prostate.
The definition of clinically significant disease includes a combination of the aggregate and index (largest) tumor volume (> 5 mm3), tumor grade sum (≥ 7), individual life expectancy, and cancer doubling time. However, many of these parameters are difficult to define preoperatively and constitute a challenge for patient selection toward expectant management and immediate radical treatment. Accurate staging of the disease at the time of diagnosis may spare many men the adverse events experienced after any of the radical treatment modalities, when it has no survival benefit.
Large published series have revealed a significant rate of undergrading in men who underwent radical prostatectomy, as compared to the diagnostic transrectal ultrasound (TRUS)-guided biopsy Gleason score. Undergrading would have, at least hypothetically, caused a missed opportunity for a more aggressive neoadjuvant combined treatment, including participation in multiple ongoing experimental clinical trials. In a recently published large study depicting outcome after radical surgery for unilateral disease, clinical overstaging (pT2) occurred in about one in four patients. Clearly, many patients would have missed the opportunity for a more informed decision before embarking on one of the available management options aimed at maximizing survival benefit while preserving a good quality of life.
Imaging of the Prostate
A crucial element for the future success of TFT involves advances in imaging of the prostate. Current imaging technology does not allow accurate demarcation of cancer foci within the prostate. Indeed, existing imaging modalities lack the specificity and sensitivity to aid in the early clinical staging of the disease.
Independently, computed tomography (CT) scan and even magnetic resonance imaging (MRI) with endorectal coils provide inadequate information about prostate cancer stage. However, promising advances in positron-emission tomography (PET) combined with CT provide functional and morphologic data simultaneously, improving the precise localization of the regions of uptake within the prostate. Nevertheless, limitations of the existing radioisotope fluorine-18 deoxyglucose (18F-FDG) have dampened the initial optimism for this imaging modality in identifying prostate cancer.
Another emerging MRI combined imaging technique is magnetic resonance spectroscopic imaging (MRSI), a noninvasive method of evaluating metabolic markers of prostate cancer such as choline and citrate. However, initial application in early-stage prostate cancer did not show a significant advantage over the use of MRI alone in this setting.
Ideal imaging modalities, or a combination thereof, should be:
(1) Highly disease-specific with acceptable sensitivity for identifying prostate cancer foci
(2) Able to localize prostate cancer foci in a reproducible fashion—ie, having a real-time component for regeneration of the coordinates of tumor foci by generating a four-dimensional (4D) image
(3) Easy to use, with minimal risk to the patient
(4) Cost-effective when implemented on a large scale.
TRUS is currently the most commonly utilized imaging modality to guide prostatic biopsy and minimally invasive therapeutic options. Several modifications to the ultrasonic image, such as the use of elastography and color Doppler, have not as yet produced a significant rise in accuracy for detecting and localizing prostate cancer foci. The foremost advances in ultrasound over the past decade have been focused on the rendering and segmentation of the ultrasonic image into a three-dimensional (3D) representation of the prostate.
Dr. Barqawi is sponsored by Oncura, Inc.
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