Cryoablation of the Prostate

PCRI Insights February 2005 vol. 8, no. 1
Duke K. Bahn, MD and Paul Silverman, MD Prostate Institute of America at Community Memorial Hospital,Ventura, CA
John C. Rewcastle, PhD Department of Radiology, University of Calgary, Canada and Endocare, Inc., Irvine, CA

CRYOABLATION, OR FREEZING, OF THE PROSTATE WAS FIRST INTRODUCED IN THE 1960s FOLLOWING THE DEVELOPMENT OF THE FIRST LIQUID NITROGEN CRYOPROBE.1 Gonder and colleagues first attempted prostate cryoablation using a transurethral approach monitored with digital rectal palpation.2,3 Because the procedure was associated with significant side effects, it was abandoned until the early 1990s, when the characterization of frozen prostate tissue as visualized with ultrasound was achieved.4

Since the reintroduction of cryoablation, several significant technical and procedural advances have occurred, including the development of vacuum-insulated cryoprobes, the evolution of intraoperative treatment planning systems, the introduction of systematic temperature monitoring, and, most recently, the development of a temperature feedback automated freezing system. These technical advances can be used piecemeal, in concert, or not at all, depending on the experience and skill of the physician performing the procedure and the individual patient anatomy. Each of them has been designed to assist the physician in learning and performing the three fundamental steps involved with prostate cryoablation:

1. Planning the procedure based upon individual patient anatomy,
   
2. Placing the cryoprobes and thermocouples within the prostate, and
   
3. Freezing the prostate such that the cancer is destroyed without compromising such sensitive adjacent structures as the external sphincter, urethra and rectum.

Smaller,Vacuum-Insulated Cryoprobes

Most published reports establishing prostate cryoablation as a therapy with durable safety and efficacy have been based on patients treated with blunt-tipped 3.4-mm diameter cryoprobes.5,6 Insertion of cryoprobes of this size necessitates the use of a dilation system that results in the consumption of a significant amount of operating room time for all but the most experienced physician. Fortunately, 2.4-mm diameter cryoprobes with vacuum-insulated shafts are now available with thermal profiles nearly identical to those produced by 3.4-mm cryoprobes (< 1-mm changes in isotherm locations).

Treatment Planning

Placement logic
In-vivo human studies have shown that reaching a temperature of -40° C on two successive freeze thaw cycles ensures ablation of prostate carcinoma tissue.8 Therefore, prostate cryoablation is performed with the goal of exposing the entire gland to a temperature of -40° C or lower while minimizing cold exposure to the rectum and external sphincter and thereby avoiding collateral damages that can result in rectal problems and urinary symptoms. Determination of an optimal probe placement is a mathematical problem. The available planning algorithm utilizes the four accepted ‘rules’ of cryoprobe placement as reported by Ellis in 20028:

1. Cryoprobes should not be placed more than 2.0 cm apart,
   
2. Cryoprobes should not be placed more than 1.0 cm from the margin of the prostate,
   
3. The distance between the urethra and any cryoprobe should not be less than 0.8 cm, and
   
4. The posterior cryoprobes should be placed such that their separation is less than twice the distance to the posterior capsule of the prostate.

Mapping patient anatomy and determining probe placement
An ultrasound transducer mounted to a stepper that is fixed in space relative to the patient is used to serially image the longitudinal plane of the prostate. Collected images are transferred to a treatment planning system. Image recognition software is used with the aid of anatomic reference points defined by the user to determine the geometric anatomy of the prostate, urethra and rectum. Utilizing this information, the system specifies an optimal probe placement. A brachytherapy-like grid that allows for angled cryoprobe placement can be attached to the ultrasound stepper and used to assist with cryoprobe placement (see Figure 1). Cryoprobes are inserted though the perineum and advanced to the base of the bladder. The grid can be removed from the platform and the stepper, and then the ultrasound probe can be used freehand, unobstructed by a stepper or grid. Because the grid is lightweight plastic, it will not pull the probes out of the body when released from the platform. Experienced physicians may bypass this time-consuming procedure and can place the cryoprobes by free hand, yet still satisfy the basic “rules”.

Systematic temperature monitoring
The fundamental advancement that sparked renewed interest in prostate cryoablation was the use of real-time ultrasound to visualize cryoprobe placement and iceball growth. Ultrasound, however, is not without limitation. Ice has an acoustic impedance much different that that of soft tissue. Consequently, nearly all the incident acoustic signal is reflected when the wave reaches the frozen/unfrozen interface. This allows for excellent visualization of the hyperechoic line representing the proximal iceball edge, but the user is rendered blind to all other structures since no signal is returned from structures within or beyond the iceball.

Temperature monitoring is used to overcome this acoustic shadowing effect. Temperature monitoring is accomplished in the following manner. Prior to the commencement of the freezing process, thermocouples are placed at strategic locations within and around the prostate. They are used to both ensure that adequately cold temperatures are reached within the prostate and that sensitive adjacent structures, namely the rectum and external sphincter, are maintained at temperatures warm enough to ensure maintenance of their structural and functional integrity.

Automatic freezing
Keeping track of the power settings of six to eight cryoprobes, thermocouple temperature readings, and the progression of the iceball as visualized on ultrasound can be a daunting task for inexperienced physicians. Fortunately, automatic freezing software has been developed that allows the physician to input targeted temperatures. The physician selects the target temperature for each thermocouple.Typically, this is -40° C for the thermocouples placed in zones to ensure ablation and > 0° C for those placed in sensitive structures to ensure their preservation.

All cryoprobes are controlled by a computer that determines the optimal cryoprobe power settings based upon real-time temperature feedback from the thermocouple tips. Freezing commences in a front-to-back manner to maximize transrectal ultrasound visualization. If at any point during the procedure, the temperature reading of any thermocouple placed in a sensitive structure drops below the safety margin set by the physician, all probes stop freezing and begin to actively thaw to ensure that no damage occurs.

The freezing process must still be monitored carefully by the physician who can override the process at any point and either stop the freeze or continue the freeze by manually controlling the cryoprobe power settings. Many experienced physicians do not utilize this automatic freezing technique. They can actually sculpture the ice to make an exact fit for the prostate, resulting in a complete ablation. It is indeed an art form.

Efficacy and Morbidity

In deciding what treatment is best for him, the individual patient balances the perceived risks and benefits associated with each treatment option in concert with his physician. No therapy can guarantee a cure, and, unfortunately, no therapy can promise complete maintenance of quality of life or avoidance of all morbidities (complications). Many factors are taken into account when choosing a treatment treatment including the stage and aggressiveness of the cancer, age, life expectancy, physical and sexual activity level, and co-morbidities. The treatment decided upon is a balance of the patient’s acceptance of cure probability (efficacy), tolerance of potential side effects, and long-term quality of life impact.

Primary cryoablation
Randomized prospective clinical trials comparing the efficacies and side effects of primary prostate cancer therapies are lacking. As such, even the most accurate comparisons of different treatment modalities are complicated by the use of often retrospective, single-institution case studies with a history of non-uniform patient selection. Further, definitions of biochemical failure (PSA-based failure) vary from study to study. That being said, comparisons looking at trends in efficacy and morbidity are certainly possible and are merited.

Fortunately, many institutions have reported outcomes following prostate cancer therapy with patients categorized according to risk group. This is done by reviewing three fundamental measurements of prostate cancer: clinical stage, Gleason sum (score), and PSA. Each of these can be considered to be favorable or unfavorable. A favorable stage is T2a or less. Favorable Gleason sum and PSAs are < 7 and < 10 ng/ml, respectively. Low risk disease has no unfavorable characteristics, moderate risk disease has one, and high-risk disease has two or three.

In 2003, Katz and Rewcastle presented an analysis of the literature based upon all studies that were published as full manuscripts in the peer-reviewed literature over a 10-year period. They reported five-year Biochemical Disease-Free Survival (BDFS) rates following definitive prostate cancer intervention.9 Although there wasn’t consistency in the definition of BDFS, the analysis was intended to look for trends and was not designed to conclusively compare the different therapies.

Figures 2 through 4 show the published range of BDFS rates for five therapies observed five years following treatment for low, moderate and high-risk prostate cancer, respectively. As shown in Figure 2, for low-risk disease, all five therapies achieved excellent local and systemic control. Given the relative equivalence in efficacy, the treatment decision for this risk group should be based heavily on quality of life factors.

Figures 3 and 4 compare the range of reported 5-year BDFS rates for patients with moderate and high-risk disease. Comparing these rates with those of Figure 2 shows a drop in efficacy trend for all therapies with increasing disease risk. However, the drop in trend is not as substantial for cryoablation as it is for both surgical and radiation series. Based on this comparison, the trend in efficacy of cryosurgery appears to be at least equivalent to that of surgery and both external and 3-D conformal forms of radiation therapy for moderate and high-risk patients.

Figure 2 Comparison of Biochemical Disease Free rates for low-risk disease

Figure 3 Comparison of Biochemical Disease Free rates for moderate-risk disease

Figure 4 Comparison of Biochemical Disease Free rates for high-risk disease

Another measure of efficacy is the positive biopsy rate, which was also reviewed by Katz and Rewcastle.9 The positive biopsy rates recently reported following cryoablation have been reported to be between 2 and 18%. The mean follow up of these studies was 5.1 and 2 years, respectively. The positive biopsy rates reported in the literature for brachytherapy, conformal beam radiation, and external beam radiation tend to be higher. Studies of brachytherapy found positive biopsies to range from 5-26%, with mean follow-up periods of 18 months to 10 years. One study reporting positive biopsy rates following conformal beam radiation found the average positive biopsy rate to be 48% at a mean follow-up of > 30 months. Following external beam radiation therapy, the rates ranged from 20%-71%,with a mean follow-up of 2-6.8 years.(It should be noted,however, that the positive biopsy rates following radiation therapy can be misleading because radiation protocols are continuously changing, and these rates may reflect outmoded dosing strategies.)

Not only is the efficacy of cryoablation at least equivalent to that of the local treatments of radical prostatectomy and the two reported forms of radiation therapy, it also appears to be superior in the treatment of higher risk disease. Katz and Rewcastle9 provided a hypothesis as to why this may be so.There are two fundamental shortcomings to the standard therapies that can limit their ability to effectively treat locally extensive or biologically aggressive prostate cancer: (1) positive margins observed after radical prostatectomy and (2) the preferential killing of lower Gleason grade cancer by radiation therapy.

The ability of radical prostatectomy to cure prostate cancer is defined by its ability to remove all tumor cells. Following prostatectomy, cancer is observed at the edge of the removed prostate in up to 52% of patients.10 (This, of course, can have a great deal to do with patient selection and individual risk factors.) Detection of such a positive margin indicates that the tumor removal was incomplete and that cancer cells remain in the body. Conversely, during cryoablation, lateral freeze beyond the capsule of the prostate is possible and is usually done if microscopic capsular penetration by the tumor is suspected. Seminal vesicle freezing is also possible if tumor involvement is confirmed. This decreases the probability of cancer remaining in the patient. The known and probable extent of the disease defines how aggressively the physician freezes laterally.

Radiation therapy ablates tissue by damaging the nucleus of individual cells. The more aggressive the cancer, the harder the cells are to kill. Certainly any cell will be irreversibly damaged if exposed to enough radiation, but the sensitivity of nearby anatomic structures limits the lifetime dose of radiation that can be delivered to the prostate gland. Clinical results indicate that the efficacy of radiation therapy declines significantly if a patient’s Gleason score is greater than 7 or if he has an aneuploid tumor. In fact,if cancer recurs following a trial of radiation therapy, it is often a more aggressive form.11 This indicates that there was a preferential killing of less aggressive cells only to leave those that are more radio-resistant. Recently, Bahn and his colleagues reported that the efficacy of cryoablation is independent of the ploidy.12 Cryoablation offers mechanical destruction of treated tissue as a whole rather than just the destruction of individual cells, which occurs during radiation therapy. This is a result of freeze damage to the blood supply of the frozen tissue.

Procedural and technical advances, along with increasing experience of individual physicians have resulted in a steady decline of cryoablation side effects. Urethro-rectal fistula (urine leakage) was a great concern during cryoablation. Of the three latest cryoablation studies,5,6,13 only one reported rectal complications (Bahn et al with fistula < 0.1%). This improvement is directly related to an increased use of temperature monitoring of the Denonvillier’s fascia and improved ultrasound technology. Incontinence in the three studies ranged from 1.3% to 5.4%, and rates of post-operative impotence ranged from 82.4% to 100%. Table 1 summarizes the comparative incidence of different forms of rectal injury as well as incontinence and impotence reported in the literature.

A prospective quality of life impact analysis covering three years following cryoablation is available.27 The authors administered two scales, the FACT-P and the SNQ. A return to pre-surgical functioning in all areas except for sexual functioning was observed one year after cryoablation. At three years, 47% of impotent men who had been potent prior to the surgery were again able to have intercourse with or without assistance. All other areas of functioning remained high. There was no delayed-onset morbidity associated with cryoablation. These results, compared with those of other therapies, imply that overall quality of life after cryoablation is comparable, if not superior, to that of other treatments. (Personal lifestyles and viewpoints of the patient should be considered and discussed in the context of these differences in potential side effects among the different therapies.)

Salvage Cryoablation

The results of radiation therapy used to treat localized prostate cancer unfortunately are inconsistent. (Of course, the wide variation of radiation methods used makes the comparisons somewhat ambiguous.) Nevertheless, published biochemical recurrence rates five years after therapy range anywhere from 7 % to 80%.28,29 and positive biopsy rates range from 5 % to 93 %.21,30 In the great majority of cases, if radiation therapy fails, it cannot be repeated.31 The unique characteristics of radio-resistant prostate cancer leave patients with limited options if and when the disease does recur.

Primary radiation therapy causes micro and macroscopic tissues changes that often result in the unfortunate situation of aggressive disease being located in a challenging surgical environment. Radical prostatectomy following failed radiation therapy can be performed with curative intent, but it risks significant side effects. Hormonal therapy (androgen deprivation) may reduce tumor size and slow the growth, but it is ultimately not curative and is too associated with a significant impact on quality of life.

Considering the limitations of these treatments, an alternative approach to cure recurrent prostate cancer with minimal morbidity is desired. Significant interest in the potential ability of cryoablation to fill this therapeutic void has resulted in much work in the past decade that has established cryoablation as the preferred therapy for localized radio-resistant prostate cancer.

Comparing the outcomes of salvage cryoablation and salvage radical prostatectomy is limited to comparing similar reports. Again, no comparative trials exist. Table 2 lists the ranges of 5-year BDFS, rectal injury, and incontinence rates as published in the literature. For both therapies, the survival rates are lower and the morbidity rates are higher than they are when prostates that have not been irradiated are treated. Survival rates at five years appear to be similar,and a conclusion other than equivalence would be inappropriate. The difference arises when one looks at the side effects. Although statistical comparison would be ineffectual, the differences are compelling: compared to salvage radical prostatectomy, salvage cryoablation results in essentially five and ten-fold reductions in rectal injury and incontinence rates, respectively.

Although patients are carefully assessed prior to salvage therapy, be it cryoablation or radical prostatectomy, undetected metastatic disease remains a concern. Treatment failure is often thought to be due to micrometastatic disease overlooked in salvage therapy workup. These micrometastatic cells, found most often in bone marrow or lymph nodes, spread concurrently with radiation treatment, and since they are outside of the prostatic capsule, they remain beyond the realm of any salvage prostate cancer treatment.

There is a correlation between elevated Gleason score in the primary tumor and increased prevalence of micrometastatic cells,38 and a newer marker, reverse-transcription polymerase chain reaction amplification of PSA ,mRNA, has been proven to characterize metastatic cell proliferation.39 An association between androgen ablation and a reduced prevalence of metastatic cells that Cher et al. have found could be useful in adjuvant primary therapies.40 A phenotypic characterization assay performed in addition to standard bone scans would detect distant metastases earlier and improve treatment plans in patients likely to have micrometastatic bone marrow or lymphatic cancers. It is plausible that patients who fail definitive salvage therapy may have an etiology based on preexisting extra-capsular or systemic cancers. With more careful screening and patient work-up, the success of cryosurgery to fully ablate localized radio-resistant cancer may be even greater than reported.

Focal Cryotherapy

With earlier use and popularity of PSA testing, many young men in particular are diagnosed with early-stage prostate cancer. If the Gleason stage is 6 or under, if the tumor volume is small and is seen in only one out of many cores, and if the PSA level is still under the predicted range, we have a dilemma. In view of the fact that existing treatment options threaten side effects and complications that may jeopardize the quality of life at such an early age, the question arises: “Do these tumors need any treatment or not?”

Watchful waiting is certainly an option, but many men are not quite comfortable with this approach. Alternatively, focal cryotherapy is an investigational procedure that represents a compromise between the radical treatment and doing nothing. It is postulated that if we cryoblated the cancer tumor focus only, we could save most of the nerve bundles as well as the external sphincter, thereby maintaining the potency and urinary continency.

Our follow-up data (Table 3) shows that half of the men (55%) maintained potency up to 70 months after the focal cryotherapy. Another 32% currently are partially potent and need medication to get full erections. No one was incontinent, and no other complications were noted. Recovery and the time needed to keep a Foley catheter in place after the procedure is a matter of just a few days. The procedure has certain requirements. Patients need to undergo a through color-Doppler ultrasound and a re-biopsy (1) to clearly identify the cancer location in the prostate and (2) to confirm that there is no evidence of extracapsular penetration by the tumor into the seminal vesicle or nearby neurovascular bundle.

The major drawback to the use of focal cryotherapy is that it is likely to be a temporary solution. At least half of the prostate is untreated and may harbor small microscopic tumor foci. Hence, this patient will face an intense follow-up program and must anticipate that if a tumor is found in the future, he will have to undergo additional appropriate therapy at that time. Balanced against this drawback is the fact that he may enjoy an uninterrupted quality of life in the interim. The choice is his; if he thinks the risk is worth taking, he will be a candidate for focal cryotherapy.

Personal Experience

We have published 7-year outcomes of 590 patients who underwent cryoablation as a primary prostate cancer therapy5 and 59 patients who had the procedure following biopsy-proven post-radiation-therapy recurrence.32 A summary of these results is contained in Table 4. As a primary therapy, the results are comparable or superior to the rates of efficacy of all conventional radiation therapy modalities for prostate cancer.

There are also other advantages to cryoablation in comparison to conventional prostate cancer therapies. The procedure is extremely well tolerated. Only a short hospital stay is required with most patients being discharged within 24 hours. Cryoablation provides hope for those patients with locally advanced prostate cancer due to its ability to ablate laterally outside the glandular margin. It is also possible to ablate the seminal vesicles allowing the treatment of stage T3 disease.

An interesting psychology is at play after the procedure. In terms of quality of life in general and continence in particular, patients tend to improve over time. This yields a patient who tends to be happier than one whose quality of life decreases following the procedure (as can occur after radiation therapy regardless of the delivery modality).

Post-procedure impotence was high in our series. This was not surprising as the average age was 71 years, and many patients had aggressive and/or bulky disease. Recent reports indicate that when baseline and post-procedure sexual functions are objectively quantified, impotence post-procedure may not be as high as once thought.27 There are no known latent complications following cryoablation. We believe that the results we and others have published will lead to a greater acceptance and utilization of cryoablation as a primary treatment option for localized prostate cancer.

Recurrent prostate cancer following definitive radiation therapy tends to be extremely aggressive and dangerous. We have found that salvage cryosurgery is a promising form of treatment, and we routinely offer it to patients who have failed radiation therapy. Our 7-year data confirms the consensus data presented in Table 2. It shows that biochemical control rates are comparable with salvage radical prostatectomy series, and that incontinence and rectal injury rates are significantly lower than those following salvage radical prostatectomy. (Although there have been some early cryoablation series that have been published with high incontinence and fistula rates, these should be considered historic as they are not reflective of outcomes achieved with the modern procedure performed with advanced technology.)

Conclusion

Technical and procedural modifications of cryoablation have led to a procedure today that is very different than what it was ten years ago. It is a minimally invasive procedure, requiring a short hospital stay, with most patients discharged within 24 hours. Modern cryoablation, as a definitive therapy for both primary and radio-recurrent prostate cancer, is associated with no known latent complications. In fact, quality of life seems to continually improve following the procedure.

Thus, cryoablation is now a curative therapy with acceptable side effects for a patient population that is very hard to manage. It should be considered as a viable option for any patient who has been diagnosed with localized prostate cancer. Like all other options, it may not be the best choice for everyone, but certainly there is sufficient evidence that indicates that it should at least be considered by everyone. In addition, we encourage physicians to follow patients treated with radiation therapy closely as there is a window of opportunity in which the disease is still localized and a cure is possible.

Thank you to Current Oncology Reports for granting permission to reproduce figures 2-4 of this article.

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