Abstract
Tissue ablation of the prostate can be done using prostate cryoablation and has been considered a good minimally invasive salvage treatment option for patients with recurrence after nonexcisional treatment for prostate cancer.
Drawing from the results of such treatment in the salvage setting prostate cryosurgical ablation is now also being made available for the primary treatment of prostate cancer.
The incidences of complications arising out of the prostate cryosurgical ablation are different in the two groups of patients. In the salvage setting the prostate and its surrounding tissues have already been subjected to radiation or other tissue insult, and the resulting endarteritis or fibrosis is responsible for a higher incidence of complications in this group.
Among the complications, pain, lower urinary tract voiding symptoms, urinary retention episodes, impotence, and urinary incontinence are commonly seen. Infections, prostatic abscesses, tissue slough, and prostate-to-rectum fistulas are uncommon, but these are also complications that can be very challenging to manage and thus better avoided. Prevention strategies are discussed in this chapter
Keywords
Prostate tissue ablation, Prostate cryoablation, Complications, Salvage cryoablation
Key Points
- 1.
Cryotherapy causes tissue destruction by freezing, and can cause lower urinary tract symptoms (LUTS) in a fashion similar to that seen after other prostate surgeries like transurethral resection of the prostate (TURP) or laser prostatectomy.
- 2.
In order to optimize results, and minimize the complication rates, careful patient selection is necessary.
- 3.
The incidence of complications is higher in the salvage cryoablation group as compared to the primary cryoablation group.
- 4.
It is challenging to treat large prostate glands. Neo-adjuvant androgen deprivation therapy for size reduction of such glands may help with reduction of gland size but not with oncological outcomes.
- 5.
Erectile dysfunction is one of the commonest complications of prostate tissue ablation, and is multifactorial in etiology.
- 6.
Urethral warming reduces the risks of urethral slough, strictures, pain and incontinence with cryoablation.
- 7.
Saline injection in the layers of the Denonvilliers fascia to cause a separation between the prostate and rectum may reduce the incidence of rectal injuries and fistulas in cryoablation.
Introduction
According to the Surveillance, Epidemiology, and End Results (SEER) Program data, the estimated number of new cases of prostate cancer in 2015 was 220,800, with an estimated death in 27,540 patients. Of the 10,018 patients from a CaPSURE study published in 2004, patients with prostate cancer underwent treatment with either brachytherapy, external beam radiation therapy, or cryoablation in 10.1, 12, and 2.8%, respectively. The number of patients undergoing brachytherapy has since increased, and approximately 30% of patients undergoing radiation therapy will develop a biochemical failure or recurrence. Since salvage radical prostatectomy is a challenging procedure with high morbidity rates, the drive toward minimally invasive treatment of recurrent prostate cancer is increasing. Prostate cryoablation is now a reasonably well-established option for residual or recurrent cancer after primary nonexcisional treatment of prostate cancer. Experience with cryoablation has shown this to be minimally invasive and convenient, requiring short hospital stays, with many centers discharging patients the same day of the procedure. These features make the procedure an attractive choice, and the pool of patients has now been expanded to include even primary cases, in the nonsalvage setting.
Mechanisms of Tissue Injury and Causes of Complications
Prostate tissue ablation causes cell death by causing irreversible injury from nonphysiologic temperatures that are not considered compatible with cell survival. In cryoablation cell damage is caused by intracellular ice formation, altered permeability of the cell membrane, and loss of cellular integrity. Factors that are important are intracellular ice formation, the final temperature achieved, and the rate of cooling. Intracellular ice formation is very important and can be achieved either through multiple (double or even triple) freeze/thaw cycles or by ensuring the right combination of cooling rate and end-point temperature.
In order to achieve optimal results, a good balance needs to occur between adequate freezing of tissues that need to be destroyed and cryoprotection of tissues that should not be frozen. This requires an accurate mapping of the extent of cancer, since a patient could potentially be cured without the risks of complications, if all of his cancer could be completely destroyed without any collateral damage. Focal cryoablations have lower complication rates compared to total cryoablation, and the incidence of incontinence, erectile dysfunction (ED), and fistula rates were higher in patients undergoing total cryoablation as compared to focal ablation (incontinence 13% vs 0%, ED 71% vs 100%, and fistula 4% vs 0%).
Unfortunately focal ablations often undertreat cancers, since prostate cancer is known to be multifocal (79.5% of radical prostatectomy specimens), and various studies have shown that biopsy often does not accurately map out the true extent of the disease. Many cancers are also found to be very close to the urethra, and one study reported that 66% of cases had foci of cancer within 5 mm of the urethra, while another study showed actual urethral involvement in 17% of cases. Also, apical cancers were seen in almost three-fourths of cases (74%) cases, and these tumors were more likely to be closer to the urethra. Technical modifications aimed at reducing the cryo-injury to the urethra could cause undertreatment of these cancers, and many cryoablation failures typically occur in areas that get undertreated, like the prostate apex and the seminal vesical (SV).
Optimal cancer treatment thus requires a balanced approach, and the first step to minimizing complications would be to select patients appropriately.
Patient Selection
Appropriate case selection can go a long way in preventing (or minimizing) complications. In the absence of good diagnostic modalities that allow us to pinpoint the extent and sites of cancer in the prostate, we continue to rely on whole gland (or hemigland) ablation for cure.
The first aim of the treatment is to cure the patient of the cancer, and therefore it is essential to select patients with organ-confined disease. Patients with extraprostatic disease or those with SV involvement will have disappointing outcomes, since they will either have residual cancer or the ablation will have to be so aggressive and extensive that they will have higher risks of more serious complications.
Studies have confirmed this in the setting of primary cryoablation for clinical T3 disease with higher rates of biochemical failure than that after radical prostatectomy (RP) or radiation therapy (RT) in similar groups (biochemical failure seen in 48–52% ) and higher rectourethral fistula rates.
For patients being considered for primary ablation, one should follow accepted parameters that define higher risk disease like prostate-specific antigen (PSA) levels, PSA velocities, biopsy parameters including volume of cancer, and Gleason scores. Patients with Gleason scores 8 or greater, tumor stage ≥T3, or those suspected of having LNI should be offered treatment, but with the knowledge that data on the use of cryoablation in these settings are not robust, although results from published series demonstrate effectiveness for high-grade disease.
For patients undergoing salvage treatment, similar parameters have been studied. The following guidelines used for salvage radiation have often been extrapolated for use in the salvage cryoablation setting: demonstration of localized recurrence with no evidence of distant metastases, time to recurrence after primary therapy of >2 years, PSA levels <10 ng/mL, PSA doubling time of >6–9 months, and a life expectancy >5–10 years.
In an effort to standardize the inclusion criteria for patients undergoing prostate focal therapy as part of clinical trials, a study panel has suggested the following criteria: PSA <15 ng/mL, clinical stage T1c–T2a, Gleason score 3 + 3 or 3 + 4, life expectancy of more than 10 years, and any prostate volume.
Diagnosis of Localized Recurrence for Patients Undergoing Salvage Prostate Ablation
Dynamic magnetic resonance imaging (MRI) using diffusion-weighted imaging (DWI) or dynamic contrast-enhanced (DCE) MRI, and MR spectroscopy (MRS) can be used for assessment of local recurrence of prostate cancer. Combinations of DCE-MRI and DWI have a higher efficacy in detecting recurrence after RT. Multiparametric (mp) MRI also has greater accuracy than T2-weighted imaging alone, for the detection of recurrent prostate cancer after RT. Final confirmation of local recurrence is achieved through a prostate biopsy.
Prostate Biopsy
Doing targeted zonal or hemigland ablations when possible can help to minimize the risks of complications. However, it is important to map out the exact extent of the disease. Prostate biopsies are necessary, but there is a discordance between a conventional transrectal ultrasound (TRUS) guided biopsy and final pathology after radical prostatectomy. True unilateral cancer after radical prostatectomy was noted in only 28–29.3% of patients. , In the lobe classified as benign on prostate biopsy, 5% cases even had T3 tumors noted after RP.
More extensive biopsies and template saturation biopsies may be indicated for patients being considered for focal or hemiablative therapies, although data to support superiority of template biopsy remain limited.
MRI fusion biopsy is another technical advancement and has been included in the list of recommendations for the workup of patients undergoing focal therapy as part of clinical trials. MRI with ultrasound fusion biopsy, identified 30% more high-risk cancers and 17% fewer low-risk cancers. However, even with this advancement in technology, it is still possible for cancer to remain undetected on an mpMRI, as exists the possibility of missing the target lesion on a fusion biopsy possibly from technical errors.
Imaging and Other Tests for Staging
Conventionally, nuclear imaging with bone scans, computed tomography (CT) scans, and MRI have been used to assess the stage of the disease. The chances of these studies being negative even when there is occult metastases is high when the PSA is under 10 ng/mL, and many patients selected for either primary or salvage cryoablation have lower PSAs. The overall staging accuracy using current MRI protocols seems to be around 71–72%. Studies using MRI have also shown that when a patient has either extraprostatic extension or SV involvement that is suspected on MRI, the chances of micro-metastases in lymph nodes as small as 0.8–1 cm in size is higher, especially when used in conjunction with other staging nomograms. Micro-metastases to lymph nodes could be predicted with a sensitivity and specificity of 100% and 65.2% for tumors that were T3a or more and 88.9% and 94.6% for T3b tumors using MRI.
Thus, there may be a role for a pelvic lymph node dissection (PLND) in all patients suspected of having T3a disease or more on MRI. PLND can be done either by the conventional open technique or by laparoscopic or robotic-assisted laparoscopic technique. A conventional PLND may miss 13% of metastases that can occur outside of the drainage area, and extended lymph node dissections may need to be done in selected cases. This may need to include the presacral nodes.
Bone scans have a limited utility because of lower diagnostic yields in asymptomatic patients with PSA <10 ng/mL. The incidence of positive bone scans is higher with higher PSA levels, rising from 8% for PSA levels between 20 and 50 ng/mL to 40% for PSA >50 ng/mL. MRI-DWI and 11C-choline PET/CT have also been shown to be useful for detecting bone metastases. NaF PET/CT using 18F-sodium fluoride has shown some promise in detecting bone metastases from prostate cancer; whole-body DWI showed a higher specificity but lost some sensitivity when compared to 18F-NaF PET/CT. It is possible that DW whole-body imaging may, in the future, be used to aid in the detection and/or follow-up of bone metastatic prostate cancer.
Operative Considerations
Technical Advances in Technology That Help to Reduce Complications
Today’s third-generation cryoablation devices have incorporated many technological advances that make the tissue injury more precise and controlled, thus reducing collateral damage. The first of these modifications is the use of an argon–helium gas combination to produce the freeze–thaw cycle. The use of multiple fine 17G cryoprobes can ensure delivery of well-controlled iceballs of 8–10 mm diameter, and improved glandular destruction has been shown to occur using a 6–8-probe technique compared to a 5-probe technique. The use of transrectal ultrasound (TRUS) to monitor the iceball was developed by Onik et al. and enabled a more accurate assessment of the extent of the “cryolesion.” In order to decrease the effects on the urethra and minimize urethral slough a urethral warming device was later developed. Efforts to minimize injury to the rectum were also described. Onik et al. found that raising the handle of the TRUS probe pushed the tip of the probe against the posterior rectal wall, thereby pulling the rectum off the prostate. Developing further on this, Onik et al. subsequently created a mechanical separation between the rectum and prostate by injecting saline through the layers of the Denonvilliers fascia around the mid and apical regions of the prostate.
Technical Considerations
Based on our experience with cryoablation, we feel that patients with uncontrolled bleeding diathesis or those on anticoagulant therapy can have significant bleeding and must be taken off these medications prior to surgery. These medicines can be resumed within 24–48 hours after the procedure or after the urine clears, whichever is earlier. A complete preoperative assessment includes a fitness for anesthesia. Many centers commonly do these procedures under general anesthesia, because of the ease, and often per patient’s choice, but in patients with anticipated intubation difficulties, the procedure may be done under spinal anesthesia, and this choice is often run by the anesthesiology team. A limited bowel preparation may be used to ensure a rectum free of fecal matter at the time of the procedure, although we have not found this to be necessary or to add value and therefore use bowel preparations selectively. Antibiotics are used at the time of induction of anesthesia. Patients with tight urethral strictures may need an internal urethrotomy prior, since a Foley catheter is required to drain the bladder, and during the procedure a urethral warmer catheter is also used. Tight anal stenosis or a previous abdomino-perineal resection ending up with a closed anal orifice preclude placement of the transrectal probe. Transrectal ultrasound monitoring of the procedure is then not possible, and such patients are better managed by other modalities.
Patients with a very large prostate gland need multiple probes and are at risk for undertreatment. Neoadjuvant androgen deprivation therapy (NADT) may be useful in reducing the size of the gland (a mean reduction of 35% was noted) and a reduction of tumor volume by 50% that can occur within 2 months of therapy, although this rarely downstages the disease. A more recent study with the use of NADT in men undergoing primary cryoablation showed that there were no significant differences in outcomes or complications between the groups except for patients in the intermediate-risk group, who showed better 5-year disease-free status. We usually limit whole-gland treatment to patients with glands of 80 g or smaller and have also had good success with downsizing using luteinizing hormone-releasing hormone (LHRH) agonist therapy for 6 months in patients in whom the treatment delay is not believed to be consequential.
Our practice is to use two freeze–thaw cycles and monitor the ice ball formation with transrectal ultrasound. Temperature sensors are used at the apex, external sphincters, and neurovascular bundle (NVB). We also use the Onik maneuver of injecting saline between the layers of the Denonvilliers fascia in order to cause a zone of separation between the prostate and the rectum ( Fig. 24.1 ). After the procedure patients are discharged home the same day with a catheter, and we remove the catheter in 1 week.
Complications
Complications after prostate tissue ablation occur due to thermal damage to the prostate and surrounding tissues and are similar in patients undergoing cryoablation. They present as troublesome lower urinary tract symptoms or incontinence, sexual dysfunction, and/or as injury or damage to adjacent organs/tissue. The complication rates have been reported in a variable manner in the literature. The maximum variability seen is in the way ED and incontinence are reported. It is not uncommon for ED to be reported only in the group of patients who were previously potent before the initiation of treatment. The International Index of Erectile Function (IIEF-15) and the shortened version the Sexual Health Inventory for Men (SHIM) are two standardized questionnaires that are used, but these have limited utility in men who are not sexually active. A lot of variability is also noted in the way incontinence is reported, and this causes difficulties in comparison of results among studies. With prostate cancer, it is also important to consider the concept of “trifecta,” since the biochemical progression-free survival (BPFS) is also important. It is technically possible to have a lower complication rate, as can be seen with focal ablation, and the tradeoff would be a higher BPFS.
Complications of Cryoablation
We queried the Cryo Online Data Registry (COLD) in addition to a review of literature for complications. As of December 6, 2015, the COLD registry had data from 39 sites, and 10 of these were academic centers. Records of 6771 cases were available, and of these 4102 patients underwent primary whole-gland ablation, and another 1011 patients had primary partial ablation. The remaining cases were either salvage whole/partial ablations or repeat ablations.
Commonly Seen Complications
Erectile Dysfunction
Incidence.
Erectile dysfunction was one of the most commonly seen side effects of cryoablation. The incidence of ED varies from 23.1% to 98.1% of primary series and 50–100% of salvage cryoablation series ( Tables 24.1 and 24.2 ). The incidence is lowest for focal primary ablations but highest for salvage total ablations. In spite of a general lack of standardization for the assessment of ED, many studies currently used standardized questionnaires like the SHIM or IIEF for assessment and follow-up after treatment. The reported incidence depends on the way ED is defined. Most studies report ED only in men who were potent prior to therapy. There are currently no studies that have looked at what constitutes a significant change in the SHIM score in order to be classified as ED. Studies have often used terms like erection sufficient for intercourse, or vaginal penetration, and this is sometimes used in conjunction with the SHIM (IIEF-5) scores; one study also required potency to be classified as a score of 3 or more for Question 2 of the IIEF-5 questionnaire as evidence of potency. However, for erectile function to be meaningful, patients should have the ability to get an erection (assisted or unassisted with phosphodiesterase 5 inhibitors [PDE5I]) and should be able to maintain this through sexual intercourse.
| Author (Year) Reference | Type of Study | # Patients Range | Median FU Range (Months) | 5-Year BPFS (%) |
|---|---|---|---|---|
| PRIMARY CRYOABLATION | ||||
| Alvarez Rodriguez (2015) | Single series | 108 | 100 | 80.4 |
| Guo (2015) | Single series all T3 | 75 | 60 | 48 |
| Lian (2015) | Single series | 40 | 63 | 90 |
| Liu (2015) | Single series | 114 | 24 | 74.6 at 24 mo |
| Tay (2015) | Pooled data COLD | 300 | 18.2 | 59.1 KM est |
| Ward (2014) | Pooled data COLD (T3) | 366 | NA | 51.9 |
| Grossgold (2014) | Single series | 1761 | 320 | 66.9 |
| COLD unpublished | Pooled, unpublished | 4102 | *** | 73.2 |
| SALVAGE CRYOABLATION | ||||
| Li (2015) | Single series | 91 | 15 | 46.5 |
| Chang (2015) | Single series | 12 | 33 | NA |
| Ahmad (2013) | Single series | 283 | 23.9 | 44-55 |
| Abreu (2013) | Single series | 25 Focal | 31 | 54.4 |
| 25 Total | 53 | 86.5 | ||
| Parekh (2013) | Systematic review (16 studies) | 18–279 | 9–113 | 18–83 |
| Nguyen (2007) | Systematic review (9 studies) | 18–131 | 19–57 | 18–77 |
| COLD unpublished | Pooled, unpublished | 925 | *** | 58.4 |
| Author (Year) Reference | # Patients Range | Impotence % | Pelvic/Perineal Pain % | Retention/ Obstruction % | Tissue Slough % (Range) | Incontinence % (Range) | Fistula % (Range) | Stricture and Urethral Complications % (Range) | Others % |
|---|---|---|---|---|---|---|---|---|---|
| PRIMARY CRYOABLATION | |||||||||
| Alvarez Rodriguez (2015) | 108 | 98.1 | 11.1 | 1.9 | 5.6 | 5.6% | 0.9% | NA | 1/9% Hematuria |
| Guo (2015) | 75 | NA | 0 | 0 | 6.7 | 4 | 0 | 0 | |
| Lian (2015) | 40 | 23.1 | NA | 2.5 | 0 | 2.5 | 0 | 0 | |
| Liu (2015) | 114 | 88 | NA | NA | NA | 1.6 | 0 | 3.3 | TURP/OIU 8.8%, scrotal edema 74.7% |
| Tay (2015) | 300 | 83 | NA | 3.3 | NA | 9.5 | 1.3 | NA | |
| Ward (2014) | 366 | 69.6 | NA | 6 | NA | 2.6 | 1.1 | NA | |
| Grossgold (2014) | 1761 | 69.6 | NA | 1.2 | NA | 1.6 | 0.6 | NA | |
| COLD Unpublished | 3843 | ** | NA | 9.7 | NA | 6.4 | 1 | NA | |
| SALVAGE CRYOABLATION | |||||||||
| Li (2015) | 91 | 50 | NA | 6.6 | 1.1 | 5.5 | 3.3 | NA | 1.1% TURP |
| Chang (2015) | 12 | 100 | 0 | 0 | 8.3 | 8.3 | 0 | 0 | Salvage cryo after primary cryo |
| Ahmed (2013) | 283 | 83 | 4 | 7 | NA | 12 | 1.8 | NA | LUTS 14% |
| Abreu (2013) | 25 Focal | 71 | NA | NA | NA | 0 | 0 | NA | |
| 25 Total | 100 | NA | NA | NA | 13 | 4 | NA | ||
| Parekh (2013) | 18–279 | NA | 15.6 (0–39.5) | 9.9 (0–21.4) | 8.2 (0–52.2) | 16.4 (0–91.3) | 1.6 (0–11.1) | 4.2 (0–44.4) | |
| Nguyen (2007) | 18–131 | NA | 36 (5.6–44) | NA | 11 (0–55) | 36 (4.3–83) | 2.6 (0–11) | 17 (0–28) Bladder neck contracture/ retention | |
| COLD Unpublished | 925 | *** | NA | 19.1 | NA | 28.2 | 2.8 | NA | |
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