Abstract
Prostate cancer treatment has undergone vast development over the last few decades, but the most notable changes have included nerve-sparing open radical prostatectomy, laparoscopic radical prostatectomy, including robot-assisted and, more recently, cryotherapy and high-intensity focused ultrasound (HIFU). While radical surgery is the current gold standard, the less invasive therapeutic options of cryotherapy and HIFU are regarded as largely experimental by governing bodies. In the case of cryotherapy, a wealth of experience has been accumulated demonstrating its efficacy. Initially used as a salvage treatment for radiation-failed prostate cancer, cryotherapy has been widely used as a primary treatment for localized and locally advanced prostate cancer. More recently, there has been interest expressed in the concept of focal therapy in prostate cancer. This has been evaluated as a primary treatment for prostate cancer, but little information is available regarding the potential use as a salvage treatment. In this article, we evaluate the potential for focal treatment in the salvage setting.
Introduction
Cryotherapy as a concept or a treatment option has been around for more than a century, 2 but it was not until the 1980s, when transrectal ultrasonographic (TRUS) scanning was introduced, that it became a real therapeutic option. 3,4 As a procedure, it has undergone numerous changes apart from the introduction of TRUS, including the use of ultrathin cryoneedles, the use of temperature monitoring probes to accurately monitor the temperatures reached in various parts of the prostate and surrounding tissue, and the use of a urethral warming catheter, all of which have allowed the procedure to become standardised, reproducible, and relatively easy to learn. 5 –8
Cryotherapy was initially used as a salvage treatment for patients in whom radiation had failed with variable success. This was partly because of the evolving technique and partly because of patient selection. Nonetheless, the results were, on the whole, encouraging, with biochemical disease-free survival rates of more than 70% for good- and intermediate-risk patients and 46% for high-risk patients with a 7-year follow-up. 9
Soon after its introduction as a salvage treatment, cryotherapy use was extended to that of a primary treatment. 10 Data from experienced centers have demonstrated disease-specific survival at 5 years of more than 90% and post-treatment positive biopsy rates of 7.7% to 25% at 3 to 24 months after treatment. 4,11 –13 Cohen and associates 14 recently published their series with a median follow-up of 12.55 years. Using a nadir plus 2 ng/dL definition, Kaplan-Meier analysis demonstrated a biochemical disease-free survival rate at 10 years of 80.56%, 74.16%, and 45.54% for low-, moderate-, and high-risk groups, respectively. The 10-year negative biopsy rate was 76.96%. These results based on cryotherapy as a primary treatment demonstrate a variation in the results using risk-based criteria, highlighting the importance of appropriate patient selection and accurate diagnostic and staging tools.
In the salvage setting, most patients have experienced radiation failure. In this group of patients, adequate staging is difficult because of the previous radical treatment, and adequate risk categorization before treatment may be limited by the lack of histology that is gained from radical prostatectomy specimens.
Multifocal Nature of Prostate Cancer
Our understanding of prostate cancer has improved over the last few decades, including the natural history of the disease, its multifocal nature, and predictors of outcome. Prostate cancer is known to exist in a unifocal or multifocal form, the latter being more common, although geographic variations exist. In a multifocal form, the index tumor is considered to be the main site of cancer, with smaller satellite tumors considered less significant. 15,16 This point has been debated and forms one of the bases used to justify the use of focal therapy or hemiablation of the prostate gland. Adequate treatment of the index tumor is thought to be an adequate treatment, although no long-term data are available.
Multifocal tumor sites also can be bilateral in their distribution even with small-volume disease <0.5 mL, in which about 20% of cases have a bilateral presentation. 15 The diagnostic dilemma with this is the difficulty in accurately identifying the location of the index tumor and the presence of satellite tumors unilaterally or bilaterally. The current literature on the multifocal nature of prostate cancer comes from articles related to radical prostatectomy specimens. In patients who are receiving primary radiation treatment, detailed histologic cancer information is not available, because conventional sextant or limited extended core biopsies would have been used in conjunction with MRI and bone scan.
Staging
The standard staging tools for prostate cancer in current use are MRI of the pelvis and bone scan. MRI is good at identifying larger foci of tumors within the prostate and can, to an extent, be used in the diagnosis of extracapsular extension (ECE), which is a prognostic indicator for biochemical failure. Bone scan is useful in identifying bony metastases, but a negative scan does not confidently rule it out.
Newer techniques that can give further information regarding the disease layout within the prostate are clearly needed. Emerging techniques, such as dynamic contrast-enhanced (DCE) MRI, high field (3T) MRI coupled with diffusion-weighted and dynamic contrast-weighted imaging, spectroscopic biomarkers, and more sensitive spectroscopic imaging techniques, such as hyperpolarized 13C magnetic resonance spectroscopy, have been described in the literature with sensitivities and specificities more than 80%. 17 –21 They can detect tumors more accurately when compared with the final histopathology results but are unable to identify the index tumor.
Insufficient information exists for the conventional use of these techniques at present, but they are promising alternatives to the existing tools. Nonetheless, these investigative tools are being used in trials in treatment-naïve prostates in which previous treatment-related artefact is not present. In patients in whom brachytherapy has failed, such investigations are likely to be of limited value. The routine use of pelvic lymph node dissection will undoubtedly provide additional information, which we have noted in our clinical practice, but perhaps not enough to categorize the patients based on risk.
Prostate Biopsies
TRUS-guided prostate biopsy in its originally described sextant format had a high false-negative rate. 22 Extending the number of biopsies to 8 to 12 has yielded a higher pickup rate of cancer. 23 –25 Although this will provide enough information for whole-gland treatment options, such as radical prostatectomy (open or laparoscopic), EBRT, brachytherapy, and cryotherapy, it does not provide adequate information, such as location of the index tumor, number of tumors, and laterality, which are crucial if focal therapy or hemiablation is to be considered.
Extending the number of biopsies further has resulted in a yet higher pickup rate as well as, in some cases, a Gleason grade increase, which is likely to influence the treatment options. A number of approaches exist for extended biopsies, but the most accepted one is using a template for TRUS-guided transperineal biopsies. 17,18 The acceptable rule for this is to take up to two biopsies for every cc of prostate gland with yields up to 80 biopsy specimens. Further information about the location of the tumor/s can be ascertained if a quadrant approach is used and accurately labeled. This approach is perhaps the most relevant for radiation failures, because more accurate information about the grade of cancer and location of the cancer can be ascertained.
Focal Cryotherapy
Much information has been published regarding the relevance of index tumor in prostate cancer. It has been thought that adequate treatment of this tumor will result in acceptable oncologic control. The satellite tumors are smaller and often of a lower Gleason grade and can be regarded as insignificant tumors. 26,27 Focal therapy that targets either only the index tumor or extended to the entire lateral lobe would achieve this. The expected result would be good oncologic control with minimal morbidity. For this to be successful, accurate diagnosis of the focality and laterality of the tumors is essential.
Template transperineal quadrant biopsies in addition to imaging techniques such as dynamic contrast-enhanced (DCE) MRI potentially can provide this information, which can allow for appropriate patient selection. The two techniques that have been assessed as suitable to provide focal therapy are cryotherapy and HIFU. 28,29 Onik and coworkers 30 recently published their series of focal cryotherapy with a follow-up of at least 2 years (range 2–10 yrs) and found a 94% biochemical disease-free survival rate and a 90% potency rate. In this group of 48 patients, there were only four failures, who subsequently received whole-gland treatment. These results are for primary cryotherapy. 30
To translate these results to the potential for salvage focal therapy is difficult, because it is likely that the radiation failures belonged to patients in a high-risk group to begin with who, as a result, are likely to fare badly with focal therapy. Accurate assessment and restaging of these failures would be imperative before considering focal salvage cryotherapy.
In our view, the current staging tools that will provide reasonable information would be template transperineal mapping biopsies of the prostate and seminal vesicles (SV) in conjunction with a pelvic lymph node dissection. In addition, repeated MRI of the pelvis to rule out gross ECE or SV involvement would add to this information. Focal cryotherapy in this setting potentially could provide good oncologic control.
The benefit of focal cryotherapy on potency and continence is a second issue. With dual insults to the prostate gland and perhaps surrounding tissues, the complication rate is higher compared with cryotherapy as a primary treatment. 9,10 A proportion of the salvage group patients may have been rendered impotent or with a degree of erectile dysfunction from their primary procedure; similarly, continence may have been affected as well. This needs to be considered while assessing patients for focal salvage cryotherapy and in justifying its use. It is also likely that the primary concern of a patient in whom primary radiation treatment failed is oncologic control rather than functional outcome. This, in our opinion, is a relevant and important point, because the concept of focal cryotherapy for prostate cancer is attractive not primarily from an oncologic control point of view, but because of lower morbidity, which may not be important for a patient with failed primary radiation therapy.
Conclusion
Focal cryotherapy of the prostate is a real prospect, but clear guidance on adequate grading and staging of the cancer is needed that will enable appropriate patient selection. Reliable imaging modalities need to be evaluated to facilitate accurate staging. Primary focal cryotherapy has been used to date with encouraging results, but no studies have described salvage focal cryotherapy. As a concept, it is feasible, but accurate restaging is difficult and may be inadequate. The use of template transperineal prostate and SV biopsies along with pelvic lymph node sampling may provide some information along with MRI, but this information may still prove to be insufficient in this potentially high-risk group of patients who may benefit more from whole-gland cryotherapy rather than focal cryotherapy.
Disclosure Statement
No competing financial interests exist.