The wide range of treatment options for clinically localized prostate cancer includes radical prostatectomy, radiation therapy (external beam radiation therapy (EBRT) and/or brachytherapy), or even more conservative approaches as active surveillance and watchful waiting [
Currently new technologies are being implemented with guaranteed limits of oncological efficacy and a clear benefit to the patient and the healthcare system. Since 1996, cryotherapy has been established by the American Urological Association (AUA) as a therapeutic option for the treatment of localized prostate cancer and in 1999 Medicare and Medicaid approved the cryosurgery as primary treatment of prostate cancer moving in the United States from the category of research to a clinical practice application recognizing cryotherapy as a therapeutic option. With short-term results, effective, safe and an acceptable adverse-effect profile has been proved; however, studies with longer followup [
We present a prospective study of a case series with a maximum followup of 132 months, and 50% of the cases exceeding 5 years of followup. 20 patients were followed longer than 10 years. Median protocolized followup were 61 months (range 10–132), with criteria of biochemical recurrence unified according to the American Society for Therapeutic Radiology and Oncology (ASTRO), was conducted in our institution.
Cryotherapy induces cellular damage by direct and indirect mechanisms immediately at the time of treatment and also deferred in time [
It is possible that some cells can escape to the lethal action of the cold (because of microvascular disturbance or directly) but it is also possible that sublethal damage drives the cell into a process of programmed death. Apoptosis occurs between 6° and 10°C and activation time needs minutes. In the periphery of the ice ball the maintained temperatures of 0°C many minutes can induce the setting up of this mechanism and increase the number of dead cells.
Prospective study of series of cases (108 patients) treated by primary cryoablation for prostate cancer at our center were stratified according to the Gleason Score and D’Amico risk group. The low-risk group was defined as patients with clinical stage ≤T2a, PSA level <10.0 ng/mL, and Gleason score ≤6. The moderate-risk group was defined as patients with stage T2b, PSA level between 10.0 and 20 ng/mL, or Gleason score 7. The high-risk group included men with stage ≥T2c, Gleason 8–10, or PSA ≥ 20 ng/mL. A total of 114 treatments were performed including cases where a second procedure was repeated.
Inclusion criteria comprised patients diagnosed with localized prostate cancer at clinical stage T1c-T2c and negative extension studies were carried out whether value of PSA at diagnosis was above 20 ng/mL, with the exception of two patients treated in clinical stage T3aN0 M0 as described later.
All cases were carried out following the same surgical protocol, performed by the same surgeon in more than 80% of cases. The technique is usually performed under regional anaesthesia. The patient is prepared with a broad-spectrum antibiotic prophylaxis and cleaning enema. The patient is positioned in dorsal lithotomy, facilitating a good exposure of the perineum and the handling of transrectal transducer (longitudinal biplane probe to 7.5 Hz).
In all cases we used the Stryker Cryo/44 coaxial system with cryoprobes of 2.4 mm of diameter, in number of six to eight depending on the prostatic volume. Equipment used argon (300 bars of pressure and temperature of −180°C) for the freeze cycle and helium for the heating cycle (200 bar pressure with exchange of temperature of −180°C to 40°C in 30 seconds). Temperature is monitored inside and outside the prostate. The thermal sensors are placed in apex, external sphincter, and left and right neurovascular bundles. Hydrodistention of the prostatorectal area is done by injecting saline solution with broad-spectrum antibiotic at Denonvilliers’ space such as protection of the rectal wall (Onik Manoeuvre) [
Biochemical recurrence was defined according to the Phoenix criteria defined by the ASTRO as a rise in prostate-specific antigen (PSA) of nadir plus 2 ng/mL.
The followup has been carried out with labs analytics with PSA every 3 months during the first two years of followup; every 6 months to five years; and subsequently annually. Prostate biopsy is performed at 6, 12, and 24 months and at the fifth year of treatment. Biopsy confirming local recurrence is mandatory in the case of PSA elevation above the established as cut-off point of biochemical recurrence.
The analysis of histological samples was made by specialized and limited uropathologist.
Descriptive variables are analysed by mean, median, standard deviation, and 95% confidence interval (95% CI). Survival analysis was carried out with the Kaplan-Meier method (K-M) and Log-Rank test to compare two or more K-M curves (statistical dependence) and association between different risk groups, clinical stage, and Gleason at the biopsy.
We discuss the results of 108 patients who underwent cryotherapy as a primary treatment for prostate cancer with a maximum followup of 132 months, with 50% of the cases exceeding 5 years of followup. Median was 61 months (range 10–132). The middle age at time of treatment was 72,05 years. Only a single case was lost during followup.
A descriptive analysis of patients and tumours characteristics and associated comorbidities, as well as the descriptive analysis of the treated tumours, is shown in Tables
Descriptive values.
Patients | |
---|---|
Age (years) | |
Median | 72.05 (±5,409) |
Range | 53–81 |
Associated comorbidity | |
Other neoplasms | 15 (13.9%) |
Cardiovascular pathology | 20 (18.5%) |
High blood pressure | 49 (45.4%) |
Diabetes mellitus | 21 (19.4%) |
Anticoagulant drugs | 30 (27.8%) |
Prior erectile dysfunction | 67 (62%) |
Characteristics and Risk stratification.
Tumor characteristics | ||
---|---|---|
Ng/mL PSA | Median 8.25 (1,818–56,171) | Mean 10.517 95% CI (9,013–12,021) |
Prostate volume (cc) at diagnosis | Median 33 (range 11–91) | Mean 37.13 95% CI (34,13–40,13) |
Gleason | ||
5 ( |
1 (0.9%) | |
6 ( |
54 (50%) | |
7 ( |
19 (17.6%) | |
7 ( |
18 (16.7%) | |
8 ( |
14 (13%) | |
9 ( |
2 (1.9%) | |
Stage (adapted according to |
||
cT1c | 57 (52.8%) | |
cT2a | 20 (18.5%) | |
cT2b | 16 (14.8%) | |
cT2c | 13 (12%) | |
cT3a | 2 (1.9%) | |
Pathological report | ||
Right side | 33 (30.6%) | |
Left side | 31 (28.7%) | |
Bilateral | 44 (40.7%) | |
RISK (according to D’Amico criteria) | ||
Low | 28 (25.9%) | |
Intermediate | 34 (31.5%) | |
High | 46 (42.6) | |
Hormone treatment | 44 (40.7%) | |
Prostate volume at treatment (cc) | Median 31 (range 14–80) | Mean 32,66 95% CI (30.15–35,17) |
Two cycles were made in 91 cases (84.2%) and a third cycle was required in 17 patients (15.8%) because of high volume or length of the gland.
The median pretreatment PSA was 8.25 ng/mL with a confidence interval of 95% for the average of 9,013 to 12,021 ng/mL (Figure
PSA distribution.
Biochemical relapse occurred in 21 cases and the definition of biochemical failure was accepted as an increase of PSA of Nadir plus 2 ng/mL according to previously established criteria. Applying the Kaplan-Meier curves, biochemical progression-free survival (BPFS) was 80.4% with an average of 100.2 months (90.9–109,6 months with 95% CI) as reflected in Figure
Global BPFS.
Overall survival stratified by risk groups is reflected in Figure
Log Rank test comparative risk.
Risk | Average | |||||||
---|---|---|---|---|---|---|---|---|
Censored | 95% CI | |||||||
Total number | Events |
|
Percentage | Estimate | Typical error | Lower limit | Upper limit | |
Low | 28 | 1 | 27 | 96.4% | 120,926 | 3,988 | 113,090 | 128,762 |
Intermediate | 34 | 3 | 31 | 91.2% | 112,643 | 6,742 | 99,429 | 125,857 |
High | 45 | 17 | 28 | 62.2% | 79,554 | 8,413 | 6,065 | 96,044 |
|
||||||||
Gleason | ||||||||
5 ( |
1 | 0 | 1 | 100.0% | — | — | — | — |
6 ( |
54 | 4 | 50 | 92.6% | 119,321 | 5,418 | 108,702 | 129,939 |
7 ( |
19 | 3 | 16 | 84.2% | 112,217 | 10,434 | 91,767 | 132,666 |
7 ( |
17 | 5 | 12 | 70.6% | 90,500 | 14,373 | 62,329 | 118,671 |
8 ( |
14 | 7 | 7 | 50.0% | 45,093 | 9,799 | 25,886 | 64,299 |
9 ( |
2 | 2 | 0 | 0% | — | — | — | — |
|
||||||||
Global | 107 | 21 | 86 | 86.4% | 100,254 | 4,769 | 90,908 | 109,600 |
Pairs comparison | |||||||
---|---|---|---|---|---|---|---|
Risk | 1 | 2 | 3 | ||||
Chi-square | Sig. | Chi-square | Sig. | Chi-square | Sig. | ||
Log Rank |
Low | .927 | .336 | 10,337 | .001 | ||
Intermediate | .927 | .336 | 6,730 | .009 | |||
High | 10,337 | .001 | 6,730 | .009 |
BPFS according to risk.
BPFS according to Gleason score.
Comparing survival curves with the Log-Rank test, statistically significant differences are only found in high-risk patients, maintaining a rate of freedom from biochemical relapse of 62% (
Followup protocolized biopsy at 6, 12, and 24 months and 5 years was only performed in the first 50 cases of the series. Results were repeatedly negative when PSA levels remained below the established level for biochemical recurrence. No cases presented positive biopsy findings in the absence of biochemical recurrence. However, due to the prospective nature of the study, 85 cases (78.7% of the sample) underwent protocolized biopsy as mentioned before with exactly the same results.
Among the 21 cases presenting biochemical relapse, a positive biopsy was detected in 7 (33%), including one patient with distal metastasis confirmed at bone scan. Conversely, in 5 patients (24%) biopsies were reported as posttreatment changes without signs of metastasic disease (bone scan and CT). Nine cases (43%) presented with imaging studies confirming the presence of metastasis or PSA doubling time making them suppose the existence of distant disease.
After recurrence diagnosis ten cases (47.8%) initiated treatment with androgen deprivation therapy (ADT) with a combination of bicalutamide and LHRH agonist, 5 (23.8%) remained under active surveillance, and 6 cases (28.4%) underwent a second round of cryotherapy. The recurrence and followup after salvage treatment is resumed in Table
Salvage cryotherapy.
Case | Risk | Time to relapse |
Time tracking |
Recurrence | |
---|---|---|---|---|---|
1 | Intermediate | 6 | 126 | Not | Exitus non cancer related |
2 | Low | 6 | 126 | Not | |
12 | Low | 15 | 6 | Not | |
23 | High | 6 | 90 | Not | |
55 | Intermediate | 60 | 48 | Not | |
78 | High | 12 | 15 | Not |
Considering all treatments, the global BPFS was estimated in 88.1%, with a mean estimate of 106,862 months (typical error 4,298) and values for a 95% CI between 98,439 and 115,285 months. K-M survival curve is shown in Figure
Global BPFS including salvage treatment.
Rate of complications included incontinence in 5.6%. In our study we consider urinary incontinence according to the definition of the International Continence Society (ICS) (any involuntary loss of urine that is a social or hygienic problem) or requirement of ≥1 pad/day [
Complication rate.
Complications | |
---|---|
Incontinence | 6 (5.6%) |
Erectile dysfunction | 106 (98.1%) |
Obstruction | 2 (1.9%) |
Urethral sloughing | 6 (5.6%) |
Haematuria | 2 (1.9%) |
Pain | 12 (11.1%) |
Prostato-rectal fistula | 1 (0.9%) |
Exitus occurred in 6 occasions (5.6%). In 2 cases (1.9%) dead was related to prostate cancer (cancer specific) after biochemical recurrence. In four patients death resulted from causes unrelated to the disease. Cancer-specific survival was 98.1%. Overall survival reached 94.4%.
Many studies have been published reporting the results of cryotherapy depending on patient and tumour characteristics, classified according to the extraprostatic progression risk and clinical stage. However, there is a lack of randomized studies and most of the publications are based on case series that include patients with any clinical stage, even locally advanced T3-T4. Studies also refer to treatments carried out with first generation devices that only managed five cryoprobes of bigger diameter and procedures that did not include the Onik maneuver for rectal protection, so the incidence of fistula incidence seems to be much higher than at present. Another fact is the definition of which PSA level should be used as cut-off point to determine biochemical failure, with no universally established consensus leading to a bias when studies are compared. Followup biopsies and a standard surveillance protocol are not standardized. Only Donnelly et al. in 2010 [
Our series is the continuance of a work begun in 2001 and carried out in collaboration with the Office of Evaluation of New Sanitary Technologies by Lain Entralgo Agency and sponsored by Carlos III Institute.
Nowadays, one of the problems in assessing the results of cryotherapy lies in the lack of consensus on the value of PSA used as cut-off point to define the biochemical relapse criteria. Levels of PSA of 0.1, 0.3, 0.4, and 0.5 ng/mL have been established as criteria of biochemical recurrence compared to radical prostatectomy. Given that cryotherapy is an interstitial procedure, it makes more sense a comparison with radiotherapy. This is the reason why the definition of biochemical recurrence of the American Society of Therapeutic Radiology and Oncology (ASTRO) seems more appropriate, using the Phoenix criteria (nadir of PSA +2 ng/mL) as a threshold to define the biochemical relapse.
Immediately after treatment serum PSA levels can arise because of intracellular PSA release by necrosis. The nadir value is generally reached after three months. Levels may not drop to undetectable levels by the persistence of viable periurethral prostate tissue [
In our series, routine determination of PSA was assessed every three months for 2 years; every 6 months up to 5 years and subsequently on a yearly basis indefinitely.
It has been shown that the low the PSA values achieved, the low the likelihood of positive biopsy results and elevation of PSA at followup. Control biopsies must be performed at least 6 months after the procedure to reduce the effect of inflammation on the gland. The indication of followup biopsy is not well established. Positive biopsy rates in the group biopsied based on suspicion of treatment failure due to increase in PSA were higher than in those in absence of biochemical recurrence (38.4% versus 15.4%) [
In our series protocolized biopsies are scheduled at 6, 12, and 24 months and 5 years, and eventually in case of sudden elevation of PSA levels. This scheme has been applied exclusively in the first 50 cases. Subsequently, and given the prospective nature of the study, biopsy has been done at 6, 12, and 24 months until the case number 85 (78.7%). Data obtained in our series were repeatedly negative when PSA values were kept below the established level for biochemical failure. Scientific evidence, the absence of positive findings for adenocarcinoma at biopsies in the absence of biochemical recurrence, and the risk derived from the realization of transrectal biopsy forced us to modify biopsy criteria. In fact, the only case of rectourethral fistula in our series, happened subsequent to the transrectal biopsy of 24 months, without signs of biochemical relapse and absence of malignancy in the samples sent to the pathologist. Up to this point the negative biopsy rate was 94.1% even in the presence of patients with biochemical recurrence. As described previously, 5 patients are kept under surveillance for presenting criteria of biochemical recurrence, negativity in prostate biopsy, and absence of distant disease, corroborated by a slow PSA kinetics and long PSA doubling time (>24 months). Currently, biopsies are only performed in case of PSA increase [
We believe that transrectal biopsy should only be done to confirm the existence of local recurrence once biochemical recurrence has been established.
According to the recommendations of the European Urological Association Guidelines (EAU 2012), potential candidates for cryosurgery would be patients at low risk of progression (PSA < 10 ng/mL, <T2a, or Gleason <6) or intermediate risk (PSA > 10 ng/mL or Gleason 7, or stage >T2b). Cryoablation of the prostate is recognized as minimally invasive, nonexperimental procedure, and a feasible option for treatment.
For the American Urological Association (AUA updated 2010) it is figured as an option in organ-confined disease, at any grade, showing absence of metastatic disease, and preferably at intermediate risk. It is also recommended prior lymphadenectomy or multimodal treatment if the risk of lymphatic involvement is greater than 25% according to established nomograms (i.e., Partin tables) by PSA > 20 ng/mL or Gleason 8–10.
Primary cryotherapy is a possible alternative treatment for prostate cancer. It is a recognized “option” accepted by AUA and EAU Guidelines (2013 Guidelines: Grade of Recommendation: C) for the treatment of localized prostate cancer. It could be indicated in patients at low risk of extracapsular disease but with high surgical risk, unfit for surgery or life expectancy less than ten years. Patients with a life expectancy longer than 10 years should be informed that minimal data are available on the long-term outcome for cancer control at 10 and 15 years. It should also be considered in patients who desire minimally invasive therapy for intermediate risk prostate cancer. However, patients who are bad candidates for surgery by associated comorbidity, obesity, previous pelvic surgery, or negative for signing of the informed consent, contraindications for radiotherapy (prior radiotherapy for rectal cancer, narrow pelvis, or inflammatory bowel disease) by their backgrounds may be candidates for treatment with cryosurgery, regardless of the risk, even assuming the possibility of a second treatment or combination therapies needed.
Comparison of treatment modalities from prostate cancer is complicated by the absence of uniform criteria to define results in terms of biochemical recurrence, the lack of randomized studies, being all available data retrospective, single centre reports, and also because of an inherent bias in patient selection. Another factor to bear in mind is that techniques and dose, especially in radiotherapy, have changed throughout periods of time and comparison between historical cohorts is difficult in this respect.
Compared to invasive treatments, note that patients who are candidates for ablative proceedings as cryotherapy are older than patients suitable for radical prostatectomy (RP). In our series median age was 72 years, being cohorts of surgery quite younger, around 63 years [
Active surveillance is an option in low-risk patients, with followup available data of less than two years. The largest cohort by Klotz et al. [
Most recent series of RP for low- and intermediate-risk prostate cancer (EUA guidelines) show 10-year PSA-free survival rates between 60 and 65% and 10-year cancer-specific survival of 94 to 97% with 53 to 153 months-followup. For high risk prostate cancer reported PSA failure rate remains in 44% and 53% at 5 and 10 years, respectively [
Radiotherapy and IMRT results are difficult to compare because of the different biochemical relapse criteria. Estimated 10-year biochemical disease-free survival reported in each risk group was 84–70% for low-risk patients, 76%–57% for intermediate-risk Patients, and 55%–41% for high-risk patients. Intermediate- and high-risk results also vary depending on the adjuvant and neoadjuvant treatment with a short- or long-term androgen deprivation [
Recent data suggest an equivalent outcome in terms of the BPFS in comparison with high-dose EBRT (HD-EBRT). In a retrospective analysis of modern series, BPFS rates of 85.8%, 80.3%, and 67.8% in men with low-risk, intermediate-risk, and high-risk prostate cancer, respectively, were reported after a mean followup of 9.43 years [
Donnelly et al. published in 2010 a randomized trial comparing men with localised prostate cancer treated with EBRT versus cryosurgery [
There have been no randomised trials comparing brachytherapy with other curative treatment modalities, and outcomes are based on nonrandomised case series. The BPFS after 5 and 10 years has been reported to range from 71% to 93% and from 65% to 85%, respectively, with a median followup ranging from 36 to 120 months [
Donnelly et al.’s group [
Radiotherapy seems to affect erectile function to a lesser degree than surgery [
In terms of quality of life, there are several studies comparing surgery with cryotherapy for localized prostate cancer. Men treated with cryotherapy and brachytherapy reported higher urinary symptoms compared to RP [
In our series, followup exceeds 10 years in twenty patients and more than a half have up to five years monitoring; still, biochemical recurrence-free survival remains high. The BPFS for low-risk patients is 96.4% and for patients at intermediate risk reaches 91.2% without statistically significant differences between them. For high-risk patients data are favourable (62.2%) and differences are significant. Globally the BPFS is 86.4% without statistically significant differences seen when calculating the BPFS including salvage treatments for biochemical relapse (BPFS 88.1%).
These data are comparable to those published in the literature and using similar criteria for recurrence and outcomes longer than 5 years. Cohen et al. in 2008 [
Our series only included cases of organ-confined disease, except two cases classified as T3a. Indication in the extracapsular cases has been made by the existence of a previous abdominal neoplasm treated with radiotherapy and chemotherapy and life expectancy of less than 5 years. In the literature there are references to series including T3a and T3b cases with freezing of seminal vesicles [
Prostate volume is another factor to take into account. Volumes higher than 45–50 cc. contraindicate cryotherapy as Onik [
Clinical guidelines of the EAU and AUA refer to the recommended maximum prostate volume, 40 mL and 45 cc respectively, advising the use of hormone therapy to decrease gland volume [
In 17 cases, three complete freeze-thaw cycles were performed, 8 (7.4%) because of a prostate volume higher than 45 cc, and on 9 occasions for prostates of longitudinal diameter larger than 35 mm, associated also with “pull back” maneuver. No differences were observed in terms of BPFS between two-cycles-treated patients and those treated with a third cycle, mobilization of the cryoprobes independently.
Actually there are no absolute contraindications for the realization of cryosurgery, except the haemorrhagic diathesis and rectal fistulas (inflammatory bowel disease, etc.). Transurethral resection of prostate (TURP) is a relative contraindication; it is associated with a significant higher risk of urethral sloughing because of the difficulty for the coaptation of the urethral warming device. Patients with previous obstructive lower urinary tract symptoms have higher risk of urinary obstruction after treatment. The existence of a significant prostate mid lobe requires a previous treatment before cryosurgery because it will always be out of reach of the ice ball by anatomic location. In our study patients with a mid lobe detected by ultrasound were rejected for treatment. Previous pelvic and urethral surgery that can disturb the anatomy also contraindicated the technique, although according to the literature, not in an absolute way. In these cases, it has been suggested the realization of an urethrocystoscopy in order to assess the integrity of the urethra ensuring the correct placement of the urethral warming catheter. In our series, any patient had prior urethral surgery.
Pathological findings at prostate biopsies after cryoablation include necrosis, fibrosis, hyalinization, microcalcifications, inflammation, stromal haemorrhage, basal cells hyperplasia and transitional and squamous metaplasia, depending on the time relapsed between cryoablation and control biopsy as well as an increase in stroma vascularization. Even some degree of glandular regeneration have been found, which sometimes can reach up to 60% of the total of the material sent to study [
All these described lesions and a cold-induced effect do not limit the repeat use of cryotherapy. The failures, by tumour recurrence, can be treated with new sessions. No interferences are seen with other therapeutic modalities: hormone treatment or radiation. Moreover, the freezing-induced necrotic areas are surrounded by hyperaemic areas that probably boost the effect of these treatments.
In our series we have treated six cases with a second salvage treatment. It is worth noting that 4 of them are included in the first cases treated. Cases 1, 2, and 12 were made before the rectal Onik manoeuvre was well established. As described in the literature, the highest incidence of complications and the worst results occur in the series published prior to the development of this maneuver. An increase in complications rates has not been appreciated after salvage treatments and all cases are free of biochemical relapse with a maximum followup (132 months) in the first and second cases of the study.
The Cochrane Library in its prostate cryoablation review (Cochrane reviews: Cryotherapy for Localized Prostate Cancer
Data of our series reflect a rate of 5.6% incontinence, erectile dysfunction of 98.1% regardless of its presence before treatment, urinary obstruction in 1.9%, and fistulae in 0.9%, with a cancer-specific survival of 98.1%. These findings are consistent with those published in the literature.
Cryotherapy is an effective treatment and minimally invasive, with low surgical risk, low morbidity, with good results in the long followup in terms of survival, biochemical recurrence, cancer-specific survival and overall survival. It is a valid technique for organ-confined tumours and preferably in low- and intermediate-risk groups. It is a safe alternative for patients with high surgical risk or contraindication for radiotherapy, with a low rate of complications. It can be repeated in case of biochemical relapse after histological confirmation of local recurrence.
When evaluating cryosurgery as a treatment option the main problem is the quality of the data presented to date. The lack of randomized clinical trials and the inexistence of a validated standard definition of failure are the most problematic.
The low rate of complications, with the exception of erectile dysfunction, is a good basis for the future for the election of cryosurgery as the technique of choice for the development of prostatic focal therapy. In fact, although on an experimental basis, it is considered in clinical guidelines.
All authors declare that they received no support from any organisation for the submitted work. There are no financial relationships with any organisation that might have an interest in the submitted work in the previous three years. There are no other relationships or activities that could appear to have influenced the submitted work.