Achieving the ‘bifecta’ using salvage cryotherapy for locally recurrent prostate cancer: analysis of the Cryo On-Line Data (COLD) Registry data
The COLD Registry is sponsored by an unrestricted research grant from Health Tronics©. Data are held and analysed by Watermark, an independent research company under the direction of an independent physician board.
Philippe E. Spiess, Department of Genitourinary Oncology, H. Lee Moffitt Cancer Center, 12902 Magnolia Drive, Office 12538, Tampa, FL 33612, USA. e-mail: firstname.lastname@example.org
Study Type – Outcomes (cohort)
Level of Evidence 2b
What's known on the subject? and What does the study add?
The cancer-specific outcomes of salvage cryotherapy for locally recurrent prostate cancer have been well established within contemporary scientific literature. However, very little is known about the outcomes of salvage cryotherapy encompassing health-related quality of life considerations such as continence after treatment.
We think the present study is quite novel, as it proposes a new therapeutic endpoint to evaluate the efficacy and outcomes of salvage therapies for locally recurrent prostate cancer, which we have termed the ‘bifecta’. In addition, we report that in a large multicentre data registry, such as the COLD Registry, the therapeutic ‘bifecta’ can be achieved in most patients.
- • To evaluate the contemporary outcomes of salvage cryotherapy for locally recurrent prostate cancer using the Cryo On-Line Data (COLD) Registry.
- • We also evaluate the outcomes of salvage cryotherapy in achieving the therapeutic ‘bifecta’ consisting of: (i) achieving a post-cryotherapy nadir serum PSA level of <0.6 ng/mL and (ii) no urinary incontinence.
PATIENTS AND METHODS
- • A prospectively, centrally collected secure online database has been developed of patients undergoing salvage cryoablation for locally recurrent prostate cancer. Of the patients undergoing salvage cryotherapy (in the absence of neoadjuvant hormonal ablative therapy) included within the COLD Registry, complete medical records pertaining to continence status and serial PSA measurements after treatment were available in 183 patients.
- • The therapeutic ‘bifecta’ was achieved in 133 of these patients (72.7%).
- • Of the patients achieving the ‘bifecta’, the mean (sd) age at presentation was 71.5 (6.6) years.
- • Most patients (91%) had a baseline pre-salvage total serum PSA level of <10 ng/mL and a pre-treatment biopsy Gleason score of <8 (85%).
- • The mean duration of follow-up of patients achieving the ‘bifecta’ was 36.5 months.
- • The therapeutic ‘bifecta’, a new surrogate benchmark for salvage therapies, can be achieved in most patients undergoing salvage cryotherapy.
- • Therefore, salvage cryotherapy is a reasonable treatment choice for locally recurrent prostate cancer in appropriately selected patients.
Cryo On-Line Data
Institutional Review Board
Despite the significant advances in radiation delivery and toxicity, locally recurrent prostate cancer after primary radiotherapy remains a clinically challenging therapeutic dilemma affecting 30–40% of treated patients . Salvage treatment methods available to such patients include salvage prostatectomy, cryotherapy, high-intensity focused ultrasound, and hormonal ablative therapy . Each of these salvage methods have their respective merits and problems, and all but hormonal ablation have curative intent. The Cryo On-Line Data (COLD) Registry has provided a unique opportunity to gather cumulative academic and community experiences, with both primary and salvage prostate cryotherapy . In a recent paper by Pisters et al. , the authors reported the COLD Registry salvage cryotherapy results in 279 patients, with a 5-year biochemical disease-free rate of 54.5% (using the Phoenix definition). Among that patient cohort, the urinary incontinence (UI) rate (pad use) was 4.4% and rectal fistula rate 1.2%. One of the major sequelae of salvage therapy for locally recurrent prostate cancer has been the significant risk of impaired postoperative erectile function (85–90%), so preservation of potency is not a goal of this treatment approach [5,6].
The therapeutic ‘trifecta’ of immediate cancer control (as characterized by negative surgical margins for radical prostatectomy patients) and recovery of sexual and urinary function has been recently defined as a clinical benchmark for clinicians to determine and compare the therapeutic outcomes of the primary treatment methods for prostate cancer [7,8]. In the salvage cryoablation setting, a PSA nadir of <0.6 ng/mL has been shown to be an immediate predictor of cancer control associated with a high likelihood of long-term biochemical disease-free survival, whereby serving as a potential surrogate marker for disease control similar to negative surgical margins for radical prostatectomy . Urinary continence is an important goal for prostate cancer treatment methods. In this regard, we propose the therapeutic ‘bifecta’ of cancer control and urinary control preservation constitutes a useful endpoint to evaluate salvage treatment methods in which the potency aspect of the ‘trifecta’ is not an expected outcome.
The aim of the present study was to evaluate the therapeutic outcomes of salvage cryotherapy in patients treated within the COLD Registry and determine its ability to achieve the therapeutic ‘bifecta’ defined as: (1) achieving a nadir post-cryotherapy serum PSA level of <0.6 ng/mL and (2) no post-treatment UI (physician reported).
PATIENTS AND METHODS
The COLD Registry was developed in an effort to gather cumulative experience with primary and salvage prostate cryotherapy across numerous academic and community centres. This registry is industry sponsored (Health Tronics©; Austin, TX, USA); however, all data collection, analysis, and reporting is conducted by an independent research company (Watermark Research Partners©; Indianapolis, IN, USA) and supervised by an independent physician board of 11 urologists. An independent audit of the data is conducted at sites yearly to ensure the accuracy of data entry. Currently, there are >6000 patient records across 44 active international sites. The goal of the COLD Registry is to provide a platform for physicians to pool collective data in an attempt to improve the scientific data and report the evidence-based outcomes of prostate cryotherapy. The COLD Registry is a web-based data gathering tool capturing the important clinical parameters and endpoints associated with prostate cryotherapy. Data entry was completed by either participating physicians or by a data-entry person who had successfully completed a training course on COLD Registry data entry. Participating physicians within the COLD Registry have all agreed to provide only de-identified data that are fully de-identified in accordance with the Health Insurance Portability and Accountability Act of 1996. Similarly, participating physicians agree (to the extent deemed feasible and appropriate) to obtain any authorisation, informed consents, Institutional Review Board (IRB), and/or other required approval before submission of the data to the COLD Registry. A global IRB approval has been in place since 2006 by Liberty©; an independent IRB, and all academic sites have approval from their IRBs.
Patient characteristics collected within the COLD Registry baseline case-entry form include serum PSA level, pre-treatment biopsy Gleason score, and clinical stage at time of diagnosis. Information pertaining to the primary radiotherapy as well as post-radiotherapy (before salvage cryotherapy) continence status (physician reported) was collected. After salvage cryotherapy, clinical data pertaining to the salvage treatment outcomes including serum PSA level and post-cryotherapy prostatic biopsies (obtained at the treating physician's discretion) were obtained. Data were also gathered on the morbidity of salvage cryotherapy (urinary continence/retention and urethrocutaneous fistulas). The use of adjuvant hormonal therapy after salvage cryotherapy was noted.
All patients undergoing salvage cryotherapy within the COLD Registry underwent whole gland ablation, with none of the patients receiving concomitant or adjuvant hormonal ablative therapy. Recent data has shown that a post-cryotherapy serum PSA nadir <0.6 ng/mL is strongly correlated with biochemical disease-free survival hence serving as one of our important study endpoints [3,9]. Within the COLD Registry, UI was physician reported and defined as not requiring any absorbent pad(s) within the first 12 months after salvage cryoablation.
In all, 608 patients have undergone salvage cryotherapy within the COLD Registry. Patients receiving neoadjuvant hormonal ablative therapy (270 patients) were excluded from the present study. Of the remaining 338 patients, ‘bifecta’ data was available in 183 patients constituting our study population. Rates of achieving the therapeutic ‘bifecta’ were compared amongst patients stratified by pre-salvage PSA subgroups using the chi-squared test.
The primary objective of the present study was to evaluate the therapeutic outcomes of salvage cryotherapy in patients treated within the COLD Registry and determine its ability to achieve the therapeutic ‘bifecta’ defined as: (i) achieving a nadir post-cryotherapy serum PSA level of <0.6 ng/mL and (ii) no post-treatment UI (physician reported).
The clinical characteristics of the patient population (183 patients) who underwent salvage cryotherapy within the COLD Registry and had ‘bifecta’ data available are summarised in Table 1.
Table 1. Patient characteristics of entire salvage cryotherapy study population
|Study population, n||183|
|Mean (median; sd) age, years||70.6 (70.0, 6.6)|
|Biopsy Gleason score*, n (%)|| |
| <6||35 (18)|
| 6||63 (34)|
| 7||59 (32)|
| 8||16 (9)|
| 9–10||8 (4)|
|Clinical stage, n (%)|| |
| <T2b||166 (91)|
| ≥T2b||17 (9)|
|Pre-salvage PSA (ng/mL), n (%)|
| <4||74 (40)|
| ≥4 to <10||89 (49)|
| ≥10 to <20||17 (9)|
| >20||3 (2)|
The therapeutic ‘bifecta’ was achieved in 133 of 183 patients (72.7%). The mean time to achieving a nadir PSA of <0.6 ng/mL (from date of salvage cryotherapy) in patients achieving the ‘bifecta’ was 26.3 days. The mean duration of follow-up of patients achieving the ‘bifecta’ was 36.5 months and their characteristics are shown in Table 2. The median (sd) age of these patients at time of diagnosis (with recurrence) was 71.5 (6.6) years. The pre-cryotherapy biopsy Gleason score of patients was most frequently Gleason 6 or 7 (35% and 32%, respectively). The clinical stage of patients was ≤T2b in 120 patients (90%). Patients had a baseline pre-salvage total serum PSA level of <10 ng/mL in most cases (<4 ng/mL in 57 patients [43%] and 4–10 ng/mL inclusive in 64 patients [48%]). The rates of achieving the ‘bifecta’ stratified by pre-salvage PSA level of <5 ng/mL, 5–10 ng/mL, and >10 ng/mL were 77.6%, 68.3%, and 60.0%, respectively. There was no statistical differences in the rates of achieving the ‘bifecta’ among these three subgroups although there was a trend toward statistical significance among those with a pre-salvage PSA level of <5 ng/mL and >10 ng/mL (P= 0.09). Patients were continent and free of biochemical failure using the Phoenix and American Society for Therapeutic Radiology and Oncology definitions at 1 year in 95.7% and 87.4%, respectively.
Table 2. Patient characteristics of patients achieving and not achieving the ‘bifecta’
|Mean (median; sd) age, years||71.5 (71.0; 6.6)||68.1 (67.5; 5.8)|
|Biopsy Gleason score*, n (%)|| || |
| <6||23 (18)||10 (20)|
| 6||47 (35)||16 (32)|
| 7||43 (32)||16 (32)|
| 8||11 (8)||5 (10)|
| 9||6 (5)||2 (4)|
|Clinical stage, n (%)|| || |
| <T2b||120 (90)||46 (92)|
| ≥T2b||13 (10)||4 (8)|
|Pre-salvage PSA (ng/mL), n (%)|| || |
| <4||57 (43)||17 (34)|
| ≥4 to <10||64 (48)||25 (50)|
| ≥10 to <20||11 (8)||6 (12)|
| >20||1 (1)||2 (4)|
Salvage cryotherapy is one of the most frequently used treatment methods for locally recurrent prostate cancer after primary radiotherapy . One of the major concerns limiting the widespread application of salvage cryotherapy is the clinical difficulty in discerning a local vs a systemic failure in patients with a rising PSA after primary radiotherapy, as well as concerns of the morbidity attributable to salvage cryotherapy . In the present study, we have defined what we think is a new treatment benchmark for ideal outcomes after local salvage therapy termed the therapeutic ‘bifecta’. Similar to the therapeutic ‘trifecta’, which has been developed as an important benchmark for ‘ideal outcomes’ after primary treatment of localized prostate cancer, the ‘bifecta’ encompasses two important parameters consisting of: 1) freedom from biochemical recurrence and 2) recovery of continence, strongly impacting perioperative morbidity [7,8]. For the purpose of the present study, achieving a post-cryotherapy nadir serum PSA of <0.6 ng/mL served as our definition of freedom from biochemical recurrence as this has been shown in prior studies to constitute an important predictor of biochemical disease-free survival in patients treated with prostate cryotherapy [3,9]. However, we do acknowledge the paucity of data validating a nadir PSA of <0.6 ng/mL as the optimal definition of freedom of biochemical recurrence particularly in the salvage setting. The reason why we think erectile function should not be considered in the proposed salvage ‘bifecta’ endpoint is that loss of erectile function is practically guaranteed with all local salvage therapies [5,6]. In this regard, patients considering salvage cryotherapy or other salvage methods should be told of this likely loss of erectile function, and its occurrence should not be regarded as a failure to achieve a favourable therapeutic outcome. These patients are as well candidates for penile prostheses or other forms of penile rehabilitation or treatment.
Using the prospectively collected COLD Registry, the therapeutic ‘bifecta’ was achieved in >70% of patients providing encouraging results to patients that in over two-thirds of these most challenging patients, favourable outcomes can be achieved. None of the present study population had received neoadjuvant or adjuvant hormonal therapy whereby avoiding the confounding impact this could have had on our PSA endpoint (i.e. post-cryotherapy nadir serum PSA of <0.6 ng/mL). Thus, salvage cryotherapy is an effective treatment with acceptable morbidity in appropriately selected patients. Importantly, the therapeutic ‘bifecta’ can serve as an important benchmark to compare currently available salvage therapies, not only from a cancer-specific standpoint but also for their impact on a patient's health-related quality of life.
Among the present study population, most had an initial total serum PSA of <10 ng/mL and pre-treatment biopsy Gleason score of <8, which prior studies would suggest represent important predictors of cancer-specific outcomes with salvage cryotherapy . To date, the findings of previous studies would suggest that among patients with pre-salvage PSA levels of >8–10 ng/mL that treatment failure is more likely and thus should discourage salvage therapy in most patients with such adverse clinical parameters. In an attempt to investigate this further, we determined the likelihood of achieving the therapeutic ‘bifecta’ stratified by pre-salvage PSA values. Among patients with pre-salvage PSA levels of <5 ng/mL, the therapeutic ‘bifecta’ was achieved in 77.7% of cases whereas in patients with pre-salvage PSA levels of 5–10 ng/mL and among those with PSA levels of >10 ng/mL, the therapeutic ‘bifecta’ was achieved in 68.3% and 60.0% of cases, respectively. There were no statistical differences in the rates of achieving the ‘bifecta’ among the three pre-salvage PSA subgroups, although there was a trend toward statistical significance (P= 0.096) for patients with pre-salvage PSA levels of <5 ng/mL having a higher rate of achieving the ‘bifecta’ than those with pre-salvage PSA levels of >10 ng/mL.
We would like to emphasise the importance of careful patient selection when assessing patients best suited for salvage cryotherapy. Failure to do so can result in a significant proportion of treated patients undergoing salvage therapy with a low likelihood of a favourable oncological outcome as they are likely to harbour occult metastases or are bound for systemic failure. Similarly, the treatment-related morbidity is significantly higher than that of primary therapies for prostate cancer. The treatment-related outcomes of salvage cryotherapy must be stringently assessed for the likelihood of local cancer control and potential cure.
We do acknowledge that there are several limitations to the present study including that the COLD Registry is a large prospectively collected data registry across multiple academic and community centres. In this regard, data entry was completed by multiple healthcare professionals imparting some degree of heterogeneity, although all participating physicians or data entry personnel must have successfully completed a training course on COLD Registry data entry. Similarly, random data audits were performed across participating sites to ensure that all data was conducted as accurately and completely as possible. At each participating site, a percentage of entered cases were reviewed and compared with the information entered in the database. Any errors detected were corrected and additional training was provided to the site if needed. A very high degree of accuracy was identified during the audits. It nevertheless remains that not all data entry points were entered for many of the patients accrued across all sites. In addition, data pertaining to pre-treatment Gleason biopsy scores as reported with the COLD Registry did not specifically state whether this was based on prostatic biopsies obtained before radiotherapy vs before cryotherapy; hence we acknowledge there could have been some discrepancy on how this data was entered, interpreted, and/or reported, and it is possible that the Gleason score before radiotherapy was entered in this field. Another important limitation to the present study was that UI after treatment was physician reported, imparting a degree of subjectivity in how accurately this study endpoint was measured across all sites. Because the registry was created without the use of validated instruments to assess continence status, this limitation cannot be overcome in this dataset.
In conclusion, the therapeutic ‘bifecta’ constitutes a new and important endpoint for salvage therapies to be gauged and contrasted taking into account cancer-specific outcome and risk of UI after treatment. Within the COLD Registry, the therapeutic ‘bifecta’ was achieved in 72.7% of patients, thus validating the merit of salvage cryotherapy as a local salvage therapy in appropriately selected patients.
CONFLICT OF INTEREST
Philippe E. Spiess, Robert W. Given, and J. Stephen Jones are all paid consultants and advisory board members of the COLD Registry.