From Whole-Gland to Targeted Cryoablation for the Treatment of Unilateral or Focal Prostate Cancer

ABSTRACT: ABSTRACT: The intermediate and long-term results of primary full-gland cryoablation for localized prostate cancer with moderate- and high-risk patients suggests a cancer control rate similar to what can be achieved with radiotherapy and surgery, with an acceptable rate of complications. A recent shift in the treatment paradigm toward unilateral cryoablation (hemiablation) or ablation of unifocal lesion(s) in select patients suggests the ability of this approach to maintain a quality of life closer to the pretreatment level. However, trials with longer oncologic follow-up are needed. The development of more accurate imaging-based techniques-ie, image-guided prostate biopsy sampling and image-guided prostate cryoablation-is of paramount importance to selecting appropriate candidates for an organ-sparing procedure. To make this approach scientifically sound, further investigation to establish patient selection criteria, the development of molecular and imaging parameters of cryoablative efficacy, and regular careful follow-up of these patients is needed.

Recently, third-generation cryosurgery has been widely introduced into clinical practice using argon-driven, ultrathin 17-gauge cryoprobes in accordance with the Joule-Thompson principle.[1-3] Contemporary cryosurgery includes these technologic advances along with the routine utilization of ultrathin needles incorporating a thermal monitoring system (TMS) for temperature surveillance, transrectal ultrasound (TRUS) imaging, and a urethral warming catheter to minimize morbidity associated with the procedure.[4-7] These developments allow for accurate targeting of even small solitary lesions that can aid in focal cryoablation of prostate cancer.

This review highlights trends in cryotechnique development, basic cryobiology, and primary whole-gland cryoablation including a recent trend toward organ-sparing procedures such as hemiablation and focal targeted cryoablation.

Advances in Cryotechnology and Cryobiology

Refining Cryoneedles and Temperature Monitoring

Gowardhan et al[8] recently presented experimental testing in an in vitro phantom prostate model and subsequent clinical study of 20 prostate cancer patients. These patients were treated with cryoablation using new developments in third-generation cryotechnology such as the IceRod^TM (Oncura, Amersham, UK) 17-gauge cryoneedles with an advanced heat exchanger and the Multitemp^TM 1601 TMS (InvivoSense, Trondheim, Norway).

The IceRod^TM probes demonstrated a better ability to freeze tissue reaching lower temperatures and forming iceballs with a maximum diameter > 6 cm after freezing at full power for 10 minutes. In other words, these probes can be used in prostates measuring > 3.5 cm in sagittal length, obviating the need for a “pull-back” technique sometimes required when using probes that generate smaller volumes of ice. TMS monitoring depicted real-time temperature gradients over either 4 or 8 temperature points arranged in linear gradients, suggesting that single-point temperature monitoring might not accurately depict the lowest critical temperatures reached during treatment when completely ablating tumor cells. These innovations may potentially improve cryosurgical technique and facilitate the procedure in a potentially safer, targeted, reproducible form, allowing beginners to learn the procedure more quickly and efficiently.

Baust et al[6] presented an update of critical experimental and clinical issues regarding the successful clinical application of cryosurgical ablation for prostate cancer. These authors presented information on the molecular basis of tissue response to freezing, identifying apoptosis as a significant part of tumor destruction after cryoablation. This paper provides an excellent basic science foundation for translational research highlighting suggested improvements in the clinical implementation of this technique, such as optimization of the freeze cycle duration, optimization of target tissue temperature, and adjunctive combination of chemotherapy with cryotherapy.

Cryochemotherapy

Adjunctive measures to enhance cell death in patients with intermediate- and high-risk prostate cancer have focused, in part, on methods to minimize locally recurrent disease in the treated site. Whether the cause of potential local failure is disease-based (eg, extracapsular extension beyond the therapeutic ice field) or technique-related (eg, inability to subject areas of cancer to a –40°C isotherm), cryosurgery for aggressive prostate cancer may benefit from adjunctive therapy. The addition of anticancer drugs or radiotherapy may increase the rate of cell death in the peripheral zone of the therapeutic cryolesion, an area where cell survival may be tenuous for several days posttreatment.[9,10]

Klossner et al[11] investigated tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) as a cytotoxic agent that preferentially induces apoptosis when combined with cryoablation in human prostate cancer (PC-3) compared to normal prostate (RWPE-1) cells. The synergistic use of cryoablation and TRAIL significantly reduced the temperature threshold required for a lethal effect from –40°C toward normally sublethal temperatures (–5°C to
–10°C) in cancer cells, and this synergistic phenomenon was not observed in normal cells.

One principle of cryosurgery is to overlap adjacent iceballs so that sublethal "warm pockets" between iceballs are avoided. Given that the outer edge of an iceball does not subject cells to sufficiently cold temperatures for destruction, the ability to enhance apoptosis at less cold temperatures is a significant finding, providing support for the clinical application of combined treatment.

Table 1

Cancer Control After Primary Cryosurgery Using
Third-Generation Technology

bDFS

Reference

N

Median Follow-up

Cryounita

Low Riskb

Intermediate Riskb

High Riskb

PSA
Cutoff

Prepelica
et al[5]
(6-yr data)

65

30 mo

SeedNet

-

-

82%

ASTRO criteriac

Cryocare

-

-

50%

< 4.0
ng/mL

-

-

35%

< 1.0
ng/mL

Han et al[2]
(1-yr data)d

175

12 mo

SeedNet

76%

73%e

< 0.4
ng/mL

Polascik
et al[7]
(4-yr data)

50

18 mo

SeedNet

90% (all groups)

< 0.5
ng/mL

Cresswell
et al[24]
(1.5-yr data)

31

9 mo

SeedNet

80%

-

71%

< 0.5
ng/mL

a SeedNet™ (Galil Medical, Plymouth Meeting, Pa); Cryocare™(Endocare, Irvine, Calif).

b D´Amico[49] risk stratification: low risk = PSA < 10 ng/mL and Gleason biopsy ‰¤ 6 and clinical stage T1c,T2a (1992 AJCC); intermediate risk = PSA 10–20 ng/mL or Gleason biopsy 7 or clinical stage T2b (1992 AJCC); high risk = PSA > 20 ng/mL or Gleason biopsy ≥ 8 or clinical stage ≥; T2c (1992 AJCC).

c ASTRO criteria = three consecutive PSA rises.[42]

d Results of a multicenter clinical trial.

e Intermediate and high risk.

AJCC = American Joint Committee on Cancer; ASTRO = American Society for Therapeutic Radiology and Oncology; bDFS = biochemical disease-free survival; PSA = prostate-specific antigen.

Cryoimmunotherapy

The possible mechanism of the specific immunostimulatory effect in response to deep freezing has been the subject of debate. While some experimental and clinical data support this synergism,[12-14] other reports demonstrate suppressed immunity, enhanced tumor growth, and metastases following cryoablation.[15,16] With the introduction of dendritic cells in clinical immunotherapy as an ideal antigen-presenting cell, some investigators have combined this modality with cryoablation.

Udagawa et al[17] tested antitumor immune responses against shared and unique tumor antigens expressed after cryoablation with intratumoral administration of dendritic cells stimulated with bacillus Calmette-Gurin cell wall skeleton (BCG-CWS) in a murine CT26 colon cancer model. These results showed augmented antitumor effects when immunotherapy is initiated before cryoablation. Cryodestruction ultimately enhanced the uptake of tumor antigens introduced by the dendritic cells, which subsequently resulted in the induction of tumor-specific CD8-positive T cells responsible for in vivo tumor regression of both treated and remote untreated tumors.

In another study using the 3LL murine Lewis lung carcinoma and the B16 melanoma models, cryoimmunotherapy caused robust tumor-specific cytotoxic T lymphocyte responses, increased Th1 responses, significantly prolonged survival, and dramatically reduced lung metastasis.[18] These results support the concept of cryoimmunotherapy for the systemic treatment of cancer and may translate into a clinical application.

Table 2

Complication Rates After Primary Cryoablation of the Prostate Using Third-Generation Technology

Reference

N

Cryounita

Impotence

Incontinenceb

Fistula

Urethral Stricture

Urethral Sloughing

Obstruction/Retention

Cohen[50]

98

SeedNet

NA

0%

0%

NA

2%

NA

Han and Beldegrun[2]

175

SeedNet

84%

3%

0%

0%

3%

3%

Polascik et al[7]

50

SeedNet

50%c

3.7%

0%

0%

0%

0%

Cresswell et al[24]

31

SeedNet

70%d

6.5%

0%

0%

0%

6.5%

a SeedNet™ (Galil Medical, Plymouth Meeting, Pa).

b In most of the studies incontinence is defined as use of more than 2 pads per day.

c Of 6 preoperatively potent patients, 3 could achieve medication-assisted erection.

d Of 13 patients, 4 reported normal erections prior to cryosurgery regained partial erectile function (2 were using medications).

NA = not available.

Primary Cryoablation of Prostate Cancer

Shelley et al[19] searched eight large databases maintained over the past decade to evaluate the clinical and economic benefits of cryotherapy compared to standard therapies for the primary treatment of localized prostate cancer. Cancer control at a follow-up of 5 years was impressive in four recent studies using temperature monitoring, with progression-free survival ranging from 71% to 87%.[5,20-22] The complications observed in all studies included impotence (47%–79%), incontinence (1.3%–4%), and urethral sloughing (3.9%–5.5%), with rectourethral fistula (< 0.1%), bladder neck obstruction (0%–4%), and pain (0%–3.1%) less often observed. The authors concluded that cryotherapy offers a potential alternative to standard therapies for the primary treatment of localized prostate cancer.

A limitation of the paper is insufficient stratification of the different cryotechnologies used. Ideally the study would have separately presented outcome data based on first- (eg, liquid nitrogen–based), second- (argon-based), and third-generation technology (17-gauge needles, brachytherapy template). By categorizing outcome stratified by technology, the reader would more easily appreciate the diminution of complications such as urethral sloughing, rectal fistula, and bladder neck obstruction following the recent introduction of more targeted third-generation devices.[19]

Jones et al[23] presented an analysis of a contemporary multicenter database (the Cold registry) with up to 5 years follow-up on 1,198 patients with primary prostate cancer who were treated with cryosurgery using the CryocareTM device (Endocare, Irvine, Calif). Nearly 1 in 4 men who had a follow-up biopsy for rising prostate-specific-antigen (PSA)-comprising 7% of the total population-were cancer-positive. The incontinence rate was 2.9%, and the fistula rate was 0.4%. Impotence remains the most problematic complication (83%). These results strongly reflect what is in the literature, suggesting that whole-gland cryoablation using modern technologies is competitive with radiation and surgery, except in the domain of erectile function. However, uniform criteria for biochemical and treatment failure need to be established and validated.

Tables 1 and 2 summarize the results of reported cancer control and complication rates, respectively, from recent series of men with prostate cancer treated by primary cryosurgical ablation since the introduction of third-generation cryotechnology. The higher morbidity presented in earlier reports could be attributed to the use of first- or earlier second-generation systems, less refined ultrasound technology, banning of the urethral warming device by the US Food and Drug Administration at that time, among other factors.

Using third-generation technology and 17-gauge cryoneedles, Polascik et al[7] reported on 50 patients with clinically localized prostate cancer treated with primary cryosurgery. With a median follow-up of 18 months, the distribution of serum PSA at the most recent visit was as follows: < 0.5 ng/mL in 45 patients (90%) and ≥ 0.5 ng/mL in 5 patients (10%). Two patients had persistent prostate cancer confirmed by biopsy and were treated with salvage cryotherapy or external-beam radiotherapy. The overall survival rate was 100%. Han et al[2] described the results of a multicenter trial that included 175 patients with a median follow-up of 12 months and a biochemical disease-free survival (bDFS) of 76% in low-risk patients and 73% in intermediate- and high-risk men, respectively.

Cancer control in other contemporary series was also quite remarkable, with bDFS rates ranging from 71% to 82% and a median follow-up from 9 to 30 months.[5,24] Long-term data with at least 7 to 10 years of follow-up are needed to confirm these short- and intermediate-term results. However, the data presented above using third-generation technology for localized prostate cancer demonstrate the feasibility and safety of this procedure.

Table 3

Cancer Control and Complication Rates After Unilateral Cryoablation

Reference

N

Number of Biopsy Cores

Median Follow-up

Cryounita

bDFS

PSA Cutoff

Biopsy-Proven Recurrence

Potency Preserved

Lambert et al[40] (3.5-yr data)

25

12

28 mo

SeedNet

84%
88%

< 50% nadir
Nadir +
2 ng/mLb

Total: 12%
Untreated lobe: 8%
Treated lobe: 4%

71%

Bahn et al[41] (5-yr data)c

31

6–12

70 mo

Cryocare

93%
96%

ASTROd
Negative
biopsy

Untreated lobe: 4%

Total: 88.9%
Fully recovered: 48.1%
Medically assisted: 40.8%

a SeedNet (Galil Medical, Plymouth Meeting, Pa); Cryocare (Endocare, Irvine, Calif).

b Phoenix definition.[51]

c Results of two-center clinical trial.

dASTRO definition: three subsequent rises of PSA.[42]

ASTRO = American Society for Therapeutic Radiology and Oncology; bDFS = biochemical disease-free survival; PSA = prostate-specific antigen.

Economic Aspects and Quality of Life After Cryosurgery

A number of improvements in technology and clinical algorithms may be expected to facilitate ongoing improvements in cancer efficacy, cost-benefit considerations, and quality-of-life (QoL) issues. Mouraviev et al[25] performed a financial analysis comparing four surgical treatment arms (open retropubic and perineal prostatectomy, laparoscopic robotic prostatectomy, and cryoablation) with respect to total direct and indirect hospital costs for 462 patients. The cost advantages associated with cryoablation include its outpatient nature, which minimizes hospital-associated costs, the absence of pathologic costs, and avoidance of the need for blood transfusion.

Robinson et al[26] analyzed the QoL of men initially enrolled in a phase II clinical trial for the treatment of localized prostate cancer based on the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 and the UCLA Prostate Cancer Index, two multidimensional instruments, during a 3-year follow-up. Compared to men receiving standard treatments such as radical prostatectomy (RP) and radiation therapy, men treated with cryosurgery appeared to have a similar QoL, with the exception of decreased sexual function.

Ball et al[27] reported results in 719 patients from a single institution in a prospective longitudinal study of early health-related QoL outcomes comparing five surgical treatment approaches for localized prostate cancer. The surgical procedures performed include open radical prostatectomy, laparoscopic radical prostatectomy, da Vinci robotic prostatectomy, 103Pd brachytherapy, and prostate cryoablation. Early urinary function (at 1 month) was better after brachytherapy than cryoablation, but this difference was lost at 6 months. Furthermore, the irritative and obstructive symptoms were significantly worse at 3 months after brachytherapy than cryoablation. In an older population, the tissue destruction resulting from cryoablation appears to better relieve obstructive and irritative urinary symptoms (as compared with brachytherapy), but at the sacrifice of sexual function.[27]

Ultimately, varying the extent of cryoablation (eg, whole-gland vs focal therapy) in carefully selected patients should allow patients and physicians to contemplate tradeoffs between QoL and cancer control for the appropriate clinical situation.

Focal Targeted Cryoablation

Pathologic Background

The current prostate cancer stage shift toward low-risk disease has renewed the enthusiasm of interdisciplinary groups to better understand the tumor biology of small-volume cancers.[28] Current basic and clinical research is exploring earlier phases of oncogenesis, leading to further improvements in genetic markers, pathology parameters, and diagnostic imaging. The search for biochemical recurrence predictors of small-size tumors is of utmost importance in identifying which tumors may potentially be ablated with novel, minimally invasive techniques.

To date, many studies have assessed prostate cancer progression in association with clinical and pathologic variables. Several studies have suggested that maximal tumor diameter was a significant predictor of biochemical recurrence.[29-33] Stamey et al measured tumors in RP specimens demonstrating tumor progression in only 14% of cases with tumor volumes ranging from 0.5 to 2.0 cm3.[30,31] Noguchi et al demonstrated that secondary cancers seen in multifocal prostate cancer did not adversely influence the results of preoperative parameters, including PSA and needle-biopsy findings.[32] The percentage of Gleason score 4 or 5 cancer in biopsies and RP specimens was the most powerful predictor of biochemical failure in men with clinical stage T1c disease after RP.

In a 57-patient study, Renshaw et al[29] found no recurrences among those with a tumor less than 1 cm in maximal diameter. However, all patients with tumors greater than 2 cm experienced recurrence. In a later study of 434 patients, these authors demonstrated that 15% of patients with a maximal tumor diameter less than 1 cm have had biochemical failure, compared to 73% of patients with a tumor size greater than 2 cm. Rukstalis et al[34] presented a retrospective analysis of 112 RP specimens. These investigators hypothesized that if the largest tumor were the one detected by biopsy, by limiting treatment to 9 of 12 prostate zones-and thereby sparing the contralateral neurovascular bundle-cancer control could be achieved with a 21% risk of significant (ie, > 0.5 mL) residual disease.

In contrast, Epstein et al[35] showed only a weak correlation between tumor volume and Gleason grade when examining 720 individual tumor foci. Cheng et al[29] demonstrated tumor multifocality and bilaterality of small tumors (> 0.5 mL) in whole-mount RP specimens from 371 consecutive men with localized prostate cancer in 69% and 37% of all cases, respectively. Based on careful analysis of spatial distribution and various pathologic parameters of small-volume tumors, the authors assumed that many patients would most likely show disease progression over time. Therefore, eradication of the most aggressive prostate cancer focus (or foci) in an early stage may offer a better chance for reducing cancer morbidity and mortality.

Mouraviev et al[36] analyzed 1,184 paraffin-embedded RP specimens from patients with clinically localized prostate cancer. Pathologic assessment was performed with particular attention to laterality and percentage of tumor involvement along with pathologic Gleason score. Completely unilateral cancers were identified in 227 (19.2%) of patients. These data demonstrated an even higher rate (39.4%) of clinically significant (Gleason score ≥ 7) tumors among low-volume (≤ 5% tumor involvement), unilateral prostate cancer foci than previously appreciated by other groups.[29,37] This study suggests that almost 1 in 5 men treated with RP may be amenable to focal ablation therapy targeting one lobe in clinically appropriate situations.

A recent study by the same group[38] correlating surgical pathology data and clinical outcomes demonstrated that tumor laterality does not affect PSA recurrence after RP. One possible explanation of this finding is that aggressive prostate cancer that is likely to recur does so independent of laterality. From a tumor biology viewpoint, unilateral cancer represents a similar risk to that of bilateral cancer regarding the development of PSA progression after surgery. For men in whom it would be possible to identify early prostate cancer confined to a single lobe, this study suggests that unilateral (hemi)ablation of the prostate may not lead to an increased risk of PSA recurrence.

Ohori et al[39] presented an analysis of 1,000 RP specimens from early-stage prostate cancer patients demonstrating a frequency of unilateral lesions (18%) similar to that seen in the aforementioned study. The mean percentage of tumor involvement for the largest focus of cancer was 80% of the volume of all cancer present. Extracapsular extension, if present, emanated from the largest index lesion in over 90% of these patients. These data suggest that it may be reasonable to target therapy to the largest focus of cancer, if known, as identified by systematic biopsy or imaging. If the largest focus of cancer could be eradicated, the tumor burden would be reduced by approximately 80% and the focus giving rise to extracapsular extension would be controlled in > 90% of patients, which may be sufficient for cancer control depending on the clinical situation.

Hemiablation as a Feasible Option

Table 3 summarizes the first clinical trials of focal hemiablation for unilateral lesions and targeted cryoablation of unifocal lesions. Lambert et al[40] reported data on 25 patients treated with hemiablation. The authors developed criteria for suspicion of biochemical failure as a PSA nadir less than 50% of the pretreatment PSA level. According to this definition, of the 25 patients, 21 (84%) demonstrated PSA disease-free survival over a median follow-up of 28 months. Repeat prostate biopsy revealed prostate cancer in the untreated contralateral lobe in 2 patients and in the treated lobe in 1 patient. Of 24 patients who were potent preoperatively, 17 (71%) maintained potency following treatment. Baseline urinary function was preserved in all patients, with complete continence maintained.

Bahn et al[41] reported the results in 31 patients from two institutions with clinically organ-confined, unilateral prostate cancer confirmed by targeted and systematic biopsy with color Doppler TRUS guidance. Tumor control data at a mean follow-up of 70 months were impressive, eg, bDFS using the ASTRO definition (three consecutive PSA increases)[42]was maintained in 92.8% of patients, with a 96% negative-biopsy rate. The one patient with a positive biopsy in the apex of the contralateral untreated lobe was subsequently retreated with full-gland destruction and remains disease-free. The total potency-preservation rate was 88.9%. There were no cases of incontinence or other complications.

While these initial results of hemiablation are promising in terms of the ideal balance between cancer control and QoL outcome, long-term oncologic efficacy needs to be investigated further in phase II and III multi-institutional randomized trials before these approaches become standard.[43-47]

Focal Targeted Cryoablation: Future Directions

Onik[48] recently published his updated series of 21 patients treated with focal targeted ablation of a unifocal tumor with at least 2 years of follow-up. The author also used color Doppler TRUS examination and biopsy of any suspicious areas of abnormally increased flow or hypoechogenicity. Although prostates that were biopsied after treatment remained negative for malignancy, a cancerous lesion in the untreated side was identified in one patient by magnetic resonance imaging spectroscopy. Potency was maintained in 17 of 21 patients (80%) without any other complications reported, including incontinence or rectal fistula formation.

Although targeted cryoablation of a single cancer focus may be an attractive concept, we currently do not have sufficient basic science data regarding the biology of prostate cancer heterogeneity nor accurate genetic or molecular markers of early tumorigenesis. Furthermore, the lack of accurate imaging modalities and limitations of image-guided prostate biopsy technology prevent one from defining all small prostate cancer lesions within the prostate or predicting behavior and aggressiveness so that a clinically significant index lesion amenable to cryoablation can be distinguished. Inadvertently excluding a lesion from treatment that may potentially become clinically aggressive over time might compromise the concept of focal therapy if proper surveillance mechanisms are not in place.

By extrapolating innovations from the treatment armamentarium of breast cancer (lumpectomy with radiation, hormone or chemotherapy combinations), additional treatment options in the setting of localized prostate cancer may be developed. Similar combined modalities may be effective when cryoablating an index prostate cancer lesion and preventing the progression of other lesions.

Conclusions

The further development of cryotechnology, advances in the basic science of experimental cryobiology, and wide introduction of cryoablation into clinical practice may serve as a solid foundation to foster improvements in cryoablation outcomes in both cancer control and QoL. The recently reported short- and intermediate-term experiences with third-generation cryotechnology demonstrate that cancer control for primary, whole-gland cryoablation can compete with other established modalities such as surgical prostatectomy and radiation treatment.

Experimental cryobiology studies at the molecular level elucidate potential avenues for more effective treatment of high-risk prostate cancer patients or those with locally advanced disease, potentially combining cryochemotherapy or cryoimmunotherapy. The recent shift toward early-stage disease suggests that in treating localized prostate cancer, cryoablation may potentially fit all requirements for minimally invasive organ-sparing thermoablation.

References:

References

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