To evaluate the current status of high-intensity focused ultrasound (HIFU) and cryosurgery as the primary treatment option in patients with prostate cancer.
A MedLine search using specified search terms was done on February 28, 2005. This search rendered 150 papers related to HIFU and 566 papers related to cryosurgery. Very few of these papers presented original outcome data and are included in the present review.
No controlled trial was available for analysis, and no survival data were presented. No validated biochemical, surrogate end point was available for any of the two therapies. HIFU showed progression-free survival (based on prostate-specific antigen ± biopsy data) of 63–87% (projected 3- to 5-yr data), but median follow-up in the studies ranged from 12–24 mo. Negative postoperative biopsies was seen in 82–94% of patients. Complications have been reduced by the combination of transurethral resection of the prostate and HIFU. Cryosurgery showed a progression-free survival of 36–92% (projected 1–7 yr data), depending on risk groups and definition of failure. Negative biopsies were seen in 72–87%, but no biopsy data were available for the currently used third-generation cryotherapy machines. Complications seem to be lower with the third-generation machines.
None of the evaluated therapies has enough data available to support their use as an alternative to established therapies (surgery, radiation) for localised prostate cancer. Until further data become available, the use of both treatments should be restricted to patients unfit for established therapies who still have the need for local therapy.
Keywords: Prostate cancer, Therapy, Review, Cryosurgery, High-intensity focused ultrasound, Outcome.
What therapy should I offer this patient with newly diagnosed prostate cancer? This question is posed by many urologists around the world, every day, every week, every month, every year.
The number of men diagnosed with prostate cancer is increasing in many areas of the world. An increasing life expectancy in the male population  and increasing use of prostate-specific antigen (PSA) for early detection of the disease  are probably the two main factors accounting for the fact that we as urologist see more patients with prostate cancer. Most men diagnosed today are diagnosed with nonmetastatic disease  and  and may thus, from a tumour point of view, be suitable for local, potentially curative therapy.
The two “established” forms of therapy for patients with localized prostate cancer are surgery or radiation therapy. Both therapies have undergone significant technical developments during the last 10 yr and can be delivered in many various ways. Long-term outcome data are available for both therapies. The cutoff/definitions for PSA relapse (biochemical progression) in relation to clinical progression of the disease are relatively well validated. Radical prostatectomy has been compared with conservative therapy in one single randomized controlled trial  and found to have better efficacy. In radiation therapy several prospective, randomized, controlled trials have shown increased efficacy with increased doses of radiation  and  or with combination neoadjuvant or adjuvant hormonal therapy  and . Although it would be good to have more studies that could confirm the efficacy of these therapies, one can conclude that both therapies, delivered with currently used techniques, have enough data to support their use in daily clinical practice (i.e., European Association of Urology guidelines) .
However, both the established therapies, and even more therapies, have been related to significant complications and risks. Also, there are patients who are unsuitable for major surgical procedures or who cannot tolerate radiation therapy because of comorbid medical conditions or because the have had other therapies earlier in life. Thus, there has been a continuous search for alternative procedures with the aim to cure prostate cancer. The general term minimal invasive therapies is used. The goal with such therapies is to offer similar chances for cure but with less side-effects. Of those therapies, high-intensity focused ultrasound (HIFU) and cryosurgery have been clinically available in the last 5–10 yr. The aim of the present report is to try to establish on the basis of current, peer-reviewed literature the place for both these therapies in the management of prostate cancer patients in everyday clinical practice.
2. Material and methods
Both minimal invasive methods have undergone continuos development over time, which makes it difficult when the reader wants to judge the outcome, because follow-up of patients treated with the latest methods always will be short.
2.1. Technical considerations of treatment development over time
For HIFU, the focal length of the probe determines the depth of the treated area. Various methods are used to handle different sizes of prostates with either interchangeable probes or possibly variation in placement of the probe within the rectum  and . Also, the frequency of the ultrasound and length of treatment pulses (energy delivered) have varied over time. In some of the most recent reports, one recommends performing a transurethral resection of the prostate (TURP) first and then going directly to the HIFU procedure  and .
The first generation of cryotherapy was tried in the 1960s with probes chilled with liquid nitrogen placed either transurethrally or directly on the prostate surface via an perineal incision  and . Urethral warming was not used, and freezing was monitored by eyeballing or palpation. Complications were common, to say the least.
The second generation of cryosurgery was developed in the 1990s and included freezing with perineally placed 3-mm probes and cooling with liquid nitrogen . Probe placement and monitoring of the freezing procedure was done mainly with transrectal ultrasound (TRUS) and possibly thermocouples. A urethral warming device was introduced to reduce the complication rates.
Third-generation cryosurgery uses argon and helium gas, which is delivered through thin 1.5-mm probes, using a template similar to the one used with permanent seed implants for brachytherapy. The treatment is under TRUS guidance, and a urethral warming device is used together with thermocouples to better control the freezing process. Third-generation cryosurgery has been in clinical use since 2000.
2.2. Study methodology
The present study is based on a structured literature review. As of February 28, 2006, a MedLine search was performed with the following search terms: “high intensity focused ultrasound and prostate cancer,” “HIFU and prostate cancer,” “cryosurgical ablation of the prostate and prostate cancer,” and “cryosurgery and prostate cancer.”
This search rendered a total of 150 articles related to HIFU and 566 to cryosurgery. The aim was to include all papers that contained relevant information on outcome and complications for the currently used methods of HIFU and CSAP when used as primary therapy for prostate cancer. The following limitations were used to identify relevant papers to meet the aim of the present article:
- Papers written in English language and related to human subjects were preferred.
- Double citations (due to the relatively similar search terms used) were eliminated.
- Review articles were eliminated, and original series were used as sources.
- The majority of papers dealing with outcome and complications came from a few centres.
- Only the most recent publication(s) from each centre were included to avoid the same patients being presented several times.
If only the most recent form of HIFU (no prototype machines, eventually with the combination of TURP and HIFU) or cryosurgery (third-generation, gas-driven cryotherapy) therapy had been included, less than a handful of articles would have been included, all with ultrashort follow-up. This approach would have made it impossible to draw any conclusions at all; therefore, a few papers based on the older forms of therapy were also included in this review.
The aim was to evaluate the outcome after controlled trials first and then for case series, and to evaluate the following endpoints: overall survival, cancer-specific survival, biochemical disease-free survival (BDFS), local control, and complications.
No statistics have been performed, because this form of review does not allow for statistical comparisons.
The search provided a limited number of articles suitable to include in the present review. Neither randomized studies nor studies with any form of matched controls were found. The outcomes presented thus are based on case series, some of which were prospectively collected.
Nearly all series have very limited follow-up, and there are virtually no data, including overall or cancer-specific survival. Thus, the end point available in most series usually is BDFS (i.e., PSA), and, in some instances, biopsy data are the end point. The definition of PSA end points is highly variable among different series.
3.1. Outcome for HIFU
The outcomes from HIFU series are presented in Table 1. Often results presented as failures are either a positive biopsy or a pure PSA failure according to the chosen criteria for BDFS.
Biochemical and biopsy disease-free survival after HIFU therapy
|Series||No. of patients||Median or mean follow-up (mo)||Outcome (PSA and/or biopsy)|
|Uchida et al. ||63||22||75% PSA-free (ASTRO criteria) for the full series, depending on risk factors such as PSA, Gleason score, and T-stage; 13% positive biopsy rate|
|Vallencien et al.a||30||20||Mean PSA 0.9 ng/ml; no progression-free data provided; 27% positive biopsies|
|Blana et al. ||146||22||87% had PSA < 1 ng/ml, 71.5% <0.4 ng/ml, and 54% <0.2 ng/ml; 7% positive biopsies|
|Thüroff et al. ||402||11b||Median PSA: 0.6 ng/ml; mean: 1.8 ng/ml; no progression-free data provided; 13% positive biopsies|
|Gelet et al. ||102||19||3 consecutive increases in PSA and a velocity of >0.75 ng/ml/yr or a positive biopsy of 66%; 25% positive biopsy rate|
|Chaussy and Thüroffa||271||19||ASTRO criteria: 80–84%; positive biopsies in 29–34%, 12–18% after <1 HIFU treatment|
a Studies aiming at evaluation of the combination of TURP and HIFU.
b In mean 1.4 HIFU sessions/patient.
ASTRO: American Society for Therapeutic Radiology and Oncology; HIFU: high-intensity focused ultrasound; PSA: prostate-specific antigen; TURP: transurethral resection of the prostate.
3.2. Outcome for cryosurgery
The outcomes for patients treated with cryosurgery are presented in Table 2. A selected series of data from second-generation cryotherapy were included to show any follow-up data with some length of follow-up. Readers should be aware that this therapy is no longer available.
Biochemical and biopsy disease-free survival after cryotherapy
|Series||Type of machine||No. of patients||Median follow-up (mo)||Outcome (PSA and/or biopsy)|
|Cohen et al. ||Second generation||239||Minimum 21||PSA < 1 ng/ml: 69–77% and <0.4 ng/ml: 40–60%; positive biopsies: 31% (one treatment), 18% (after retreatment)|
|Long et al. ||Second generation||975||24||PSA < 1 ng/ml: 63% and <0.5 ng/ml: 52%; positive biopsies: 18%|
|Aus et al. ||Second generation||54||58||Projected 5-yr data: PSA < 1 ng/ml and negative biopsy: 39%|
|Prepelica et al. ||Third generationa||65 (high-risk patientsb)||35||Projected 6-yr data: ASTRO: 81.7% PSA < 4 ng/ml: 50% and <1 ng/ml: 35%|
|Bahn et al. ||Second and third generationa||590||68||Projected 7-yr data: ASTRO: 89.5%, PSA < 1 ng/ml: 76% and <0.5 ng/ml: 62%; positive biopsies: 13%|
|Han et al. ||Third generation||122||12||PSA < 0.4 ng/ml: 75%|
|Cytron et al. ||Third generation||31||13||PSA < 1 ng/ml: 68% and <0.5 ng/ml: 81%|
a Gas-driven system but with thicker probes than used today.
b PSA >10 ng/ml or Gleason >7.
ASTRO: American Society for Therapeutic Radiology and Oncology; PSA: prostate-specific antigen.
In the early reports for both therapies (not included in the present survey as more mature data have emerged from the same centres), rectal fistulas, obstruction of the urinary flow, and incontinence were relatively common. In general, the number and severity of complications have decreased with the evolution of the techniques used.
3.4. HIFU complications
For HIFU this “evolution” means the combination of TURP and HIFU  and  and specific treatment criteria (i.e., less energy) for patients with radiation failure . Complications of modern series with HIFU may be summarised as stress incontinence: 5–10%; fistula: 0–0.7%; stricture: 9–12 (24)%; UTI: 5–13%; impotence: 55–70%. Table 3 presents the complication rates presented after the combination of TURP and HIFU as compared with HIFU alone  and .
Complications after the combination of TURP and HIFU
|Series||HIFU||TURP and HIFU||Comments|
|Chaussy and Thüroff  (n = 274)||Catheter time: 45 d||Catheter time: 13.7 d||Significant differences in all parameters. Sexual function was not assessed; 60% and 68.2% indicated no change in sexual function when asked.|
|Incontinence grade 1–2: 15.4%||Incontinence grade 1–2: 6.9%|
|UTI: 47.9%||UTI: 11.4%|
|IPSS after therapy: 8.9 (increasing, compared with preop)||IPSS after therapy: 3.4 (decreasing, compared with preop)|
|27.1% needed TURP after HIFU||8% needed TURP after the combination|
|Vallencien et al.  (n = 30)||Urinary retention: 6%||Mild hematuria for 2–3 wk in 66%; 32% had decreased sexual function after treatment.|
HIFU: high-intensity focused ultrasound; IPSS: International Prostatic Symptom Score; preop: preoperative; TURP: transurethral resection of the prostate; UTI: urinary tract infection.
3.5. Cryosurgery complications
For cryosurgery the development of the third-generation technique was associated with less morbidity  and also with the use of specific rectal heating needles . Table 4 presents complications for second and third generation of cryosurgery in prostate cancer.
Complications after second- and third-generation of cryotherapy for prostate cancer
|Complication||Second generation cryotherapy||Third generation cryotherapy|
UTI: urinary tract infection.
Both HIFU  and cryotherapy  have been used as salvage therapy after radiation failures, but it is outside the scope of this article to describe the detailed outcomes from second-line therapies. Also, both HIFU and cryosurgery are repeatable in the case of local failure.
4.1. Study design
Despite a relatively large number of matches on the MedLine search, only a few articles were found to contain relevant outcome data. The applied limitations aimed at avoiding “double counting” of patients from the same centres with multiple publications but may have missed a small number of patients. Also the limitation to the English language may have limited the information, although most articles presented in French or German language are from centres included in the present study. Data with longer follow-up may sometimes be available from abstracts or user groups, but only peer-reviewed literature has been used in the present review. Even with the mentioned limitations, the chance that including more data from other sources would have changed the main findings in any significant way is small.
4.2. Study outcomes and follow-up
There are no randomised controlled studies available to compare the outcome of these therapies with each other, other therapies, or watchful waiting. In practice, no studies provided data on overall, cancer-specific, or metastasis-free survival for any of the two treatment methods. The median follow-up was short (HIFU: maximum 22 mo (Table 1); cryotherapy: 68 mo (Table 2)), but that data were mainly for second-generation machines, which are no longer available. For third-generation cryotherapy machines, the maximum median follow-up was limited to 13 mo (Table 2).
Biochemical (i.e., PSA) disease-free survival was presented by most studies. The cutoff points used were highly variable for different studies, and no validation of any of the surrogate end points used could be found. The use of different end points has a profound effect on how the outcome is judged when the follow-up is short. For example, Blana and coworkers  presented the outcome after HIFU in 137 patients with a median follow-up of 22 mo and projected 5-yr data. They found that 87% of the patients had a PSA of <1 ng/ml and 93% had negative posttreatment biopsies. However, when a fixed PSA cutoff of 0.4 ng/ml was used, the projected 5-yr BDFS was 71.5%; if 0.2 ng/ml was used, the rate dropped to 54%. The treatment, patients, follow-up, and end point (BDFS) were all the same, but the actual definition of the end point made up for these differences. The same was true for cryosurgery for which Bahn and coworkers  presented the outcome for 590 patients with a median follow-up of 63 mo and projected 7-yr data from mainly second-generation cryotherapy. Using the ASTRO: American Society for Therapeutic Radiology and Oncology (ASTRO) criteria with three consecutive raises in PSA, 88–92% were disease-free at 7 yr (depending on risk groups), but this rate dropped to 61–68% if a fixed cutoff of >0.5 ng/ml was used. Again, the definition of BDFS had a large impact on how the outcome was judged.
4.3. Outcome from HIFU
The development of the HIFU equipment means that the currently used machines were more or less ready around the year 2000 , which means that series including patients treated before this day also have used various forms of prototypes of the equipment. From all the studies presented, there is clear evidence that the treatment could affect prostate cancer, as shown by both a substantial decrease in serum PSA and negative biopsies after therapy , , , , , and . The effect has also been demonstrated on radical prostatectomy specimens examined 2 wk after HIFU . The treatment may be repeated, and in fact many patients do need more than one HIFU session before they convert to negative biopsies . The key question of whether the therapy will kill all tumour cells present and thus provide long-term cure for a substantial part of treated patients cannot be answered with the follow-up data available today.
The combination of a TURP performed just before an HIFU seems to reduce the complications (Table 3) but without affecting the oncologic outcome negatively  and . It seems that most patients will tolerate the operative procedure well. Intermediate-term complications include some risk of urinary incontinence, obstruction, and impotence , , , and . Uchida et al.  had a stricture rate of 24% requiring intermittent dilatations in their series using the Sonoblate system without concomitant bladder neck incision or TURP. Reported rectal injuries were rare/absent in recently presented series (Table 3).
As of today, it is not possible to compare the outcome of HIFU with other treatment modalities for localised prostate cancer.
4.4. Outcome from Cryotherapy
Intermediate-term (around 5–7 yr) follow-up data were available for some series of cryotherapy. These series present the outcome after therapy with second-generation cryomachines (mainly utilising liquid nitrogen as the cooling medium). Also available were machines that used argon gas but with somewhat thicker probes than those used by the so-called third-generation machines. The third-generation machines use 17G cryoneedles and a template for implantation that was similar to the one used with permanent seed implants . It is essential to understand that there is a difference in methods used and that the oncologic outcome from second-generation machines cannot be automatically interpolated to the third-generation machines.
With these limitations in mind, it seems also very clear that cryotherapy has the potential to affect prostate cancer as is evident from the decrease in PSA and the negative biopsies , , , , and . One study on radical prostatectomy specimens (salvage prostatectomy) revealed viable cancer cells within the area covered by the ice-ball . However, these were patients selected as having positive biopsies after cryotherapy and they were also treated with a comparatively short duration of the freezing, which is not currently recommended.
Second-generation cryomachines have shown that it is possible to maintain a PSA level of <0.5 ng/ml  or <1.0 ng/ml  for at least a 5- to 7-yr period in a substantial number of patients. For third-generation cryomachines available today, the follow-up is limited to 12–13 mo, and no intermediate-term follow-up data are available (Table 2)  and . Cryotherapy can be repeated; however, the general impression from the literature is that repeat therapies are less common than after HIFU.
Complications from second-generation cryomachines were mainly related to difficulties with having a functioning urethral warming system , , and  and temperature monitoring at critical areas (as towards the rectum). If the urethra is not adequately protected by a warming system, tissue sloughing may occur with risk for urinary tract infection, bladder neck sclerosis, and even stone formation in the prostatic urethra . Third-generation cryotherapy seems to be associated with lower complication rates except for impotence rates, which remain high (Table 4).
4.5. HIFU and cryotherapy for treatment of radiation failures
Although outside the main scope of this review, it is worth mentioning that both HIFU  and cryotherapy  have been used for the treatment of prostate cancer patients who failed radiation therapy (radiation failures). Treating these patients was associated with significantly higher complication rates in comparison with de novo cases. Nevertheless both therapies have been approved by some health care authorities in the situation with failed radiotherapy.
It is worth pointing out that second-line therapy after radiotherapy seems to be given to far more advanced cases than when second-line radiotherapy is give to patients with failure after radical prostatectomy. The ASTRO recommends giving salvage radiotherapy before PSA has risen above 1.5 ng/ml after radical prostatectomy , whereas pretreatment PSA was as high as 7.7 ng/ml in salvage HIFU series  and 7.5 ng/ml in salvage cryotherapy series . This may explain the relatively poor results also after a comparatively short follow-up.
Outcome data from randomised controlled trials are not available for HIFU or cryosurgery, and practically no data are presented on cancer-specific or overall mortality. In general, the median follow-up time in the available case series is short, and the definition of the available biochemical progression-free (i.e., PSA) survival varies highly among studies. All these facts make it very difficult to assess the potential role of HIFU and cryotherapy in the management of patients with prostate cancer. Both methods are in clinical use, and, until further data become available, it seems prudent to restrict their use as primary therapy for prostate cancer to patients unsuitable for established therapies (as surgery or radiation). Information should be given that the available follow-up is short, and a careful, individual judgement about whether treatment with curative intent is necessary is strongly recommended in this subset of mostly elderly patients with localised prostate cancer.
Transrectal high-intensity focused ultrasound (HIFU) and cryotherapy are among the most promising medical technologies in local therapy of prostatic cancer, the most common oncologic disease in men.
Local cancer therapy can have a curative or a palliative approach. Curative therapy is only possible in localised disease. Palliative therapy, by local tumour debulking, can be indicated in all nonlocalised, systemic or recurrent tumour stages. By tumour debulking local tumour progression with rectal, sphincter, bladder, and ureter infiltration can be avoided and therefore reduce local pain, obstruction, bleeding, and speed of progression.
Surgical tissue-ablating therapies such as radical prostatectomy, cryotherapy, and HIFU have additional advantages. In cases of tumour recurrence, tumour aggressiveness (Gleason score) does not increase (a phenomenon that mostly occurs after radiation or hormonal ablation therapy).
As the author correctly states, there are no results from prospective, comparative studies available yet because they have just started. Neither cryotherapy nor HIFU can substitute for radical surgery; both will leave the treated capsule and seminal vesicles in situ, so they are not as “radical” as surgery.
Only about 50% of patients with localised prostate cancer are “well indicated” for surgery (localised tumour, moderate tumour volume, Gleason, prostate-specific antigen, comorbidity, and body mass index). For all other patients with localised prostate cancer the local ablative therapy with HIFU or, in advanced cases, combined with hormonal ablation is a choice that is increasingly accepted  and .
To date, results in these “new” (cryoablation since 1960, HIFU since 1995) technologies are based on cohort studies and single-centre experiences. Within the technologies different stages of development are mixed (cryoablation of the 1960s has very little in common with a third-generation cryoablation device; HIFU with Ablatherm® is very different from HIFU with Sonablate®). Papers that mix these results make it difficult to understand which ones are based on “current” technology.
Evidence suggests that the numbers of prostate cancer cases are increasing. Because medical systems have fewer and fewer resources, it is imperative to integrate and accept less invasive technologies that provide alternative therapeutic options for the benefit of the patient.
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