Download Focal Cryotherapy in the Treatment of Localized Prostate Cancer

Focal cryotherapy may be an
alternative to active surveillance
in men with early prostate cancer.
Michele R. Sassi. Baldwin Hill, The Berkshires, Massachusetts. Photograph.
Focal Cryotherapy in the Treatment of Localized Prostate Cancer
Huy D. Nguyen, BS, Bryan J. Allen, MD, and Julio M. Pow-Sang, MD
Background: The management choice for newly diagnosed localized prostate cancer presents a challenge to
both the physician and the patient. Traditionally, surgery and radiation therapy have been the most commonly
recommended options. More recently, active surveillance is recommended as the preferred management choice
for a subset of men with localized, low-risk cancer. Recent reports also suggest that focal cryotherapy may be
considered as a management option for selected cases of clinically localized prostate cancer.
Methods: A review of the literature on focal cryotherapy from 2002 to 2012 was performed. Outcomes on
cancer control, complications, and quality of life were extracted and assessed.
Results: The biochemical disease-free survival at 5 years is comparable to whole gland treatment modalities.
Complications are minimal and comparable with other local treatment modalities.
Conclusions: Focal cryotherapy is safe and effective, and it may improve failure rates in men who initially
pursue active surveillance protocols. Early outcomes with cancer control are encouraging.
Introduction
PSA screening has led to a dramatic increase in the
incidence of prostate cancer, with the majority of
cases currently diagnosed at earlier, clinically favorable stages.1 Since prostate cancer grows slowly, men
diagnosed with this disease might die of causes unrelated to their cancer. Thus, active surveillance is a
valid option for men who fit the recommended criteria
and do not want to consider any type of invasive or
From the Department of Urology at the University of South Florida
Morsani College of Medicine, Tampa, Florida (HDN, BJA), and
the Department of Genitourinary Oncology at the H. Lee Moffitt
Cancer Center & Research Institute, Tampa, Florida (JMP-S).
Submitted August 15, 2012; accepted February 11, 2013.
Address correspondence to Julio M. Pow-Sang, MD, Department of
Genitourinary Oncology, Moffitt Cancer Center, 12902 Magnolia
Drive, WCB-GU PROG, Tampa, FL 33612. E-mail: Julio.Powsang@
Moffitt.org
No significant relationship exists between the authors and the
companies/organizations whose products or services may be referenced in this article.
July 2013, Vol. 20, No. 3
radical treatments. While studies on active surveillance have shown a 10-year overall survival rate of
approximately 80%, there is still a lingering concern
of allowing a potentially curable cancer to progress to
incurable disease before establishing definitive treatment.2,3 However, a recent prostate intervention vs
observation trial (PIVOT trial) by Wilt et al4 indicated
that for men with low-risk tumors, no distinct differences were seen in overall or cancer-specific survival
benefits when comparing radical prostatectomy with
active surveillance. The PIVOT trial reported that 171
of 364 men (47%) in the radical prostatectomy group
died, while 183 of 367 men (49%) in the observation
group died. A strategy of incorporating focal therapy
as definitive treatment for selected men with focal disease and clinically significant cancer may reduce the
number of men who will require treatment while on
active surveillance. Considered a minimally invasive
treatment, questions related to focal therapy include
patient selection, evaluation of treatment success, and
Cancer Control 177
the best technology to use. The technology most
commonly available for focal therapy is cryosurgery.
This technology allows for treatment of selected areas
within the prostate in which cancer is present while
sparing noncancerous areas through a transperineal,
percutaneous approach using ultrasound imaging.
Procedure
Cryotherapy is performed under anesthesia, with
the patient in the lithotomy position through a transperineal percutaneous approach. A 7.5-MHz ultrasound probe is utilized for real-time visualization
of the prostate and attached to an ultrasound probe
stand secured to the surgical table. A mapping grid
is placed close to the perineum attached to the ultrasound stand, and 17-gauge cryoprobes are introduced
percutaneously into the area to be treated within the
prostate gland under ultrasound imaging guidance.
Temperature probes are placed in Denonvilliers’ fascia, apex of the prostate, and external urinary sphincter to monitor temperature in these areas during the
procedure. A flexible cystoscopy is performed, and
a 0.038 semi-rigid guide wire is inserted, the cystoscope is removed, and a urethral warming catheter
is placed over the guide wire. The procedure begins
by delivering argon gas, and freezing of the area is
monitored with ultrasound imaging. After adequate
freezing is achieved, the thawing part of the procedure
is then conducted using hydrogen gas. The process
is repeated one more time. Once the procedure is
completed, the cryoprobes, temperature probes, ultrasound probes, and urethral warmer are removed, and
an 18 Foley catheter is inserted and left indwelling.
The patient is discharged home on the day of the
procedure, and the catheter is removed 1 week later.
index lesion (largest tumor volume within the prostate)
and occasionally a secondary index lesion will determine the biological potential of the cancer. Bott et al7
reported that the index lesion comprised 73% of tumor
volume in a total of 374 tumor foci examined. This
has led to considering a more preservative approach
to treating prostate cancer, including hemi-ablation
(half-gland treatment) and focal ablation.8 Several
diagnostic modalities are being investigated to improve
the selection of candidates for focal therapy.
Three-dimensional pathological mapping (3DPM)
of the prostate gland has been proposed as a method
to stage patients prior to focal therapy. In a study of
140 patients, 3DPM of the prostate gland was superior in detecting clinically significant prostate cancer
compared to standard transrectal ultrasound (TRUS)guided biopsy.9 The use of 3DPM of the prostate
gland allowed precise location of the cancer for focal
ablation. Sensitivity of the repeated TRUS biopsy
in this study was 34%, with a false-negative rate of
52%. All cancers detected by the standard TRUS biopsy were also detected on 3DPM biopsies. Another
study by Falzarno et al10 showed a 10% correlation
between the unilaterality of cancer detected by TRUS
with unilateral cancer in the final pathological finding.
Another modality assisting with risk estimation is
multiparametric prostate magnetic resonance imaging
(MRI). Turkbey et al11 reported that multiparametric
MRI has a positive predictive value of 98% to 100% and
68% sensitivity for detecting prostate cancer tumors > 5
mm in diameter. A study by Rastinehad et al12 reported
94% sensitivity for lesions in the peripheral zone of the
prostate, with 99% specificity using multiparametric
MRI. MRI/ultrasound fusion-guided biopsy is a more
recent imaging modality that is under investigation.
Pinto et al13 reported a detection rate of 89.5% using
MRI/ultrasound fusion-guided biopsy.
Two newer promising modalities are histoscanning and real-time elastography. Prostate histoscanning incorporates spectral analysis and pattern recognition to detect cancer lesions. Simmons et al14
reported 90% sensitivity for cancer volume ≥ 0.20 mL
and 72% specificity using histoscanning. Real-time
elastography utilizes ultrasound and the compression
nature of soft tissue to detect the index lesion. Walz
et al15 reported 58.8% sensitivity and 43.3% specificity
in locating the index lesion when using elastography
alone. However, combining elastography and data
from 12-core biopsies increased the sensitivity and
specificity of locating the index lesion to 84.9% and
48.4%, respectively.
Evaluation of Patients for Focal Therapy
Prostate cancer presents more often as multifocal disease. However, most of the areas are considered to
harbor insignificant tumors. It is hypothesized that the
Reported Series on Focal Cryotherapy
Onik et al16 first reported on the use of cryotherapy
as focal therapy. They reported on 9 patients with an
average follow-up of 3 years. All of the patients had
Cryobiology
The mechanism of cell death in tissue treated with
cryotherapy includes direct cellular injury that occurs
secondary to cellular dehydration and the formation
of ice crystals within the cell. As the tissue begins to
freeze, solute concentration increases outside of the
cell, resulting in osmotic dehydration. The dehydration causes disruption of intracellular proteins and
destabilization of the cell membrane. Additionally,
freezing results in stasis within the blood vessels of
the prostate gland, leading to tissue necrosis secondary to ischemia.5 The treatment may be selectively
applied to part of the prostate-bearing cancer and
could potentially reduce the morbidity associated with
whole gland treatment.6
178 Cancer Control
July 2013, Vol. 20, No. 3
a stable PSA at the time of reporting, and 7 of the 9
previously potent men maintained erectile function
satisfactory for penetration. Three patients underwent
bilateral gland ablation with an attempt to spare one
of the neurovascular bundles, 1 patient had the area
of the tumor ablated with a margin around the tumor,
and the remaining patients underwent hemi-ablation.
A follow-up report included 48 patients with a minimum follow-up of 2 years and an average follow-up
of 4.5 years.17 Forty-five of 48 men had a stable
PSA according to the ASTRO definition. Potency was
maintained in 36 of 40 men (90%) who were initially
potent. All patients remained continent (Table).
The Cryosurgery On-Line Database (COLD) registry provides one of the largest data sets for patients
treated with cryotherapy.18 A total of 1,160 patients
were treated with focal therapy. The authors noted
that in 1999, focal cryosurgery represented 2.1% of
the treatments used for patients entered into the database. By 2007, the percentage had increased to
38.2%. Of the patients treated with focal cryotherapy,
47%, 41%, and 12% were stratified into low-, intermediate-, and high-risk groups, respectively. The 3-year
biochemical-free survival was 74.7%. This is compa-
rable to patients in the COLD database treated with
whole gland cryotherapy.18 Maintenance of spontaneous erections and urinary continence was 58.1% and
98.4%, respectively.
Bahn et al19 reported on 73 patients treated with
focal cryotherapy. The mean follow-up was 3.7 years.
Using the ASTRO definition for PSA failure, 75% of
patients were free of biochemical recurrence. Potency
was preserved in 86% of patients, and 100% of the
patients maintained continence.
Lambert et al20 reported on a cohort of 25 patients
treated with focal cryotherapy. PSA failure was defined
as nadir + 2 (Phoenix definition) or a decrease in the
PSA of less than 50% of the pretreatment PSA value.
At a mean follow-up of 2.3 years, the biochemical-free
survival rate was 85%. Erectile function was preserved
in 71% of the patients in this study, and no patients
experienced worsening of their urinary symptoms.
Ellis et al21 reported on 60 men treated with focal cryotherapy, with a mean follow-up of 1.3 years.
The biochemical-free survival rate was 80.4%, and the
potency rate was 70.6% at 12-month follow-up. The
incontinence rate was 3.6%; however, no patients
required the use of absorbent pads for protection.
Table. — Clinical Characteristics and Oncologic/Functional Outcomes of Focal Cryotherapy
Onik17
Ward18***
Bahn19
Lambert20
Ellis21
No. of Patients
48
1,160
73
25
60
Average Age
(yrs)
N/A
68
64
68
69
Average Follow-up
(yrs)
4.5
1.8
3.7
2.3
1.3
Gleason Score,
No. of Patients
(%)
N/A
≤ 6: 844 (74)
7: 240 (21)
≥ 8: 64 (6)
6: 30 (41)
7: 43 (59)
6: 13 (52)
7: 12 (48)
≤ 6: 47 (78.3)
7: 12 (20)
≥ 8: 1 (1.7)
Clinical Stage,
No. of Patients
(%)
N/A
≤ T2a: 1,013 (87)
≥ T2b: 147 (13)
T1c: 41 (56)
T2a: 31 (43)
T2b: 1 (1)
T1c: 25 (100)
≤ T2a: 55 (91.7)
≥ T2b: 5 (8.3)
Risk Category,
No. of Patients
(%)*
N/A
Low: 541 (47)
Int: 473 (41)
High: 143 (12)
Low: 24 (33)
Int: 49 (67)
N/A
Low: 40 (66.7)
Int: 14 (23.3)
High: 6 (10)
Pre 7.8
Post 2.2
Pre 7.2
Post 2.15
Pre 5.9
Post 1.6
Pre 6.0
Post 2.4
Pre 7.2
Post 2.15
Biochemical
Disease-free Survival
(%)
94
74.7
75
85
80.4
Incontinence
(%)
0
1.6
0
0
3.6
Potency Maintained
(%)
90
58.1
86
71
70.6
Average PSA
(ng/mL)**
* Risk categories were based on D’Amico risk stratifications.
** PSA nadir > 50% was indicative of biochemical disease-free survival.
*** Certain data are not available for some patients in this study.
NA = not available, Int = Intermediate.
July 2013, Vol. 20, No. 3
Cancer Control 179
Discussion
The optimal management for localized prostate cancer
is controversial. While men with low-risk and selected
intermediate-risk prostate cancer can be managed by
active surveillance, the majority of men with early
prostate cancer are radically treated with either surgery or radiation therapy. With better patient selection
by defining the biological potential of the cancer and
with improvements in technology to follow these men,
active surveillance will become more widely used. For
low-risk and some intermediate-risk patients, active
surveillance is usually recommended since the cancer
is noninvasive and has an overall survival rate comparable to other radical treatments.2,3 Nevertheless,
there is a subset of men with early cancer who will
benefit from active treatment; however, they also may
benefit from focal treatment of their localized cancer
without subjecting them to the potential risks and
complications of radical local treatment.22
Outcomes of the cryosurgery series show a biochemical disease-free survival rate of approximately
80% at 3 to 5 years with minimal incontinence and
high potency rates. However, weaknesses from these
series include the small number of patients in each
series, inconsistent patient follow-up, and the use of
the ASTRO definition for biochemical recurrence that
was intended for use in patients treated with radiation
therapy. The COLD registry, while large in numbers,
represents nonstandardized treatment and a compilation of cases from multiple surgeons with variable
levels of experience. Additionally, some of the cases
are doubly reported as single-institution series.17-22
While the literature on focal cryotherapy for clinically localized prostate cancer is still limited, the number of procedures is increasing when compared to
whole gland cryosurgery. In 2008, the American Urological Association published a “Best Practice Statement on Cryosurgery,”23 which recommended that
patients treated with focal cryotherapy should be included in a registry for future analysis. The report also
notes the challenges in determining which patients
may be offered focal cryotherapy safely. Prospective
trials with adequate follow-up are needed. These
trials should also include more precise criteria for
selecting patients for focal cryotherapy. Finally, there
is also a need to better define cancer progression.
Conclusions
The use of prostate-specific antigen to screen for prostate cancer has led to a downward stage migration.
Treatment options for newly diagnosed prostate cancer
are numerous. A review of the recent literature demonstrates increasing use of minimally invasive treatments, including the use of focal therapy in the treatment of localized prostate cancer. Focal cryotherapy
yields short-term biochemical disease-free survival
180 Cancer Control
comparable to whole gland treatment modalities in
men with low-risk prostate cancer while providing
better functional outcomes.
References
1. Neppl-Huber C, Zappa M, Coebergh JW, et al. Changes in incidence, survival and mortality of prostate cancer in Europe and the United
States in the PSA era: additional diagnoses and avoided deaths. Ann Oncol.
2012;23(5):1325-1334.
2. Klotz L, Zhang L, Lam A, et al. Clinical results of long-term follow-up
of a large, active surveillance cohort with localized prostate cancer. J Clin
Oncol. 2010;28(1):126-131.
3. Abern M, Tsivian M, Polascik T. Focal therapy of prostate cancer:
evidence-based analysis for modern selection criteria. Curr Urol Rep. 2012;
13(2):160-169.
4. Wilt T, Brawer M, Jones K, et al. Radical prostatectomy versus observation for localized prostate cancer. N Engl J Med. 2012;367(3):203-213.
5. Hoffmann NE, Bischof JC. The cryobiology of cryosurgical injury.
Urology. 2002;60(2 suppl 1):40-49.
6. Tsivian M, Polascik TJ. Focal cryotherapy for prostate cancer. Curr
Urol Rep. 2010;11(3):147-151.
7. Bott SR, Ahmed HU, Hindley RG, et al. The index lesion and focal
therapy: an analysis of the pathological characteristics of prostate cancer.
BJU Int. 2010;106(11):1607-1611.
8. Karavitakis M, Winkler M, Abel P, et al. Histological characteristics of
the index lesion in whole-mount radical prostatectomy specimens: implications for focal therapy. Prostate Cancer Prostatic Dis. 2011;14(1):46-52.
9. Barzell W, Melamed M. Appropriate patient selection for focal therapy
of prostate cancer: the role of transperineal 3-dimensional mapping of the
prostate - an 8-year experience. Urology. 2010;183(4 suppl):e56.
10. Falzarano SM, Zhou M, Hernandez AV, et al. Can saturation biopsy
predict prostate cancer localization in radical prostatectomy specimens:
a correlative study and implications for focal therapy. Urology. 2010;76(3):
682-687.
11. Turkbey B, Mani H, Shah V, et al. Multiparametric 3T prostate magnetic resonance imaging to detect cancer: histopathological correlation using prostatectomy specimens processed in customized magnetic resonance
imaging based molds. J Urol. 2011;186(5):1818-1824.
12. Rastinehad AR, Baccala AA Jr, Chung PH, et al. D’Amico risk stratification correlates with degree of suspicion of prostate cancer on multiparametric magnetic resonance imaging. J Urol. 2011;185(3):815-820.
13. Pinto PA, Chung PH, Rastinehad AR, et al. Magnetic resonance imaging/ultrasound fusion guided prostate biopsy improves cancer detection
following transrectal ultrasound biopsy and correlates with multiparametric
magnetic resonance imaging. J Urol. 2011;186(4):1281-1285.
14. Simmons LA, Autier P, Zát’ura F, et al. Detection, localisation and
characterisation of prostate cancer by prostate HistoScanning™. BJU Int.
2012;110(1):28-35.
15. Walz J, Marcy M, Pianna JT, et al. Identification of the prostate cancer
index lesion by real-time elastography: considerations for focal therapy of
prostate cancer. World J Urol. 2011;29(5):589-594.
16. Onik G, Narayan P, Vaughan D, et al. Focal “nerve-sparing” cryosurgery for treatment of primary prostate cancer: a new approach to preserving
potency. Urology. 2002;60(1):109-114.
17. Onik G, Vaughan D, Lotenfoe R, et al. The “male lumpectomy”: focal
therapy for prostate cancer using cryoablation results in 48 patients with at
least 2-year follow-up. Urol Oncol. 2008;26(5):500-505
18. Ward JF, Jones JS. Focal cryotherapy for localized prostate cancer:
a report from the national Cryo On-Line Database (COLD) Registry. BJU Int.
2012;109(11):1648-1654.
19. Bahn D, de Castro Abreu AL, Gill IS, et al. Focal cryotherapy for clinically unilateral, low-intermediate risk prostate cancer in 73 men with a median follow-up of 3.7 years. Eur Urol. 2012;62(1):55-63.
20. Lambert EH, Bolte K, Masson P, et al. Focal cryosurgery: encouraging health outcomes for unifocal prostate cancer. Urology. 2007;69(6):11171120.
21. Ellis DS, Manny TB Jr, Rewcastle JC. Focal cryosurgery followed by
penile rehabilitation as primary treatment for localized prostate cancer: initial
results. Urology. 2007;70(6 suppl):9-15.
22. Abern MR, Tsivian M, Polascik TJ. Focal therapy of prostate cancer: evidence-based analysis for modern selection criteria. Curr Urol Rep.
2012;13:160-169.
23. Babaian RJ, Donnelly B, Bahn D, et al. Best practice statement
on cryosurgery for the treatment of localized prostate cancer. J Urol.
2008;180(5):1993-2004.
July 2013, Vol. 20, No. 3