REVIEW
PROSTATE CRYOTHERAPY: MORE QUESTIONS
THAN ANSWERS
GREGORY S. MERRICK, KENT E. WALLNER, AND WAYNE M. BUTLER
ecause of the absence of prospective random- prostate cancer in 1968 with the advent of probes
B ized trials comparing the relative efficacy of
various local treatments, the management of clini-
cooled by liquid nitrogen in a closed circulation
system.11 First-generation cryosurgery was per-
cally localized prostate cancer remains one of the formed without transrectal ultrasound guidance or
most controversial topics in oncology. Radical urethral warmers and was plagued by significant
prostatectomy (RP), external beam radiotherapy complications, including urinary incontinence,
(EBRT), and brachytherapy (BT) represent univer- urethral sloughing, and rectourethral fistulas.5,6
sally accepted local approaches. Recently, cryo- These complications were attributed to a lack of
therapy has been resurrected as an additional po- accurate monitoring of the freezing process. Sec-
tential treatment option.1 This resurgence of ond-generation cryosurgery witnessed the devel-
interest in cryotherapy reflects increased interest opment and implementation of transrectal ultra-
in less-invasive forms of therapy and has been fa- sound guidance and urethral warmers.5,8
cilitated by a better understanding of cryobiology, Ultrasound guidance allowed for accurate probe
improved cryotechnology, and a perception placement and real-time monitoring, and urethral
among some that the currently accepted treatment warmers decreased the risk of urethral sloughing.
options are of suboptimal efficacy and/or signifi- Most recently, the implementation of gas-driven
cant morbidity.1– 4
probes in which pressurized gas is used to both
Cryotherapy induces cell death by two main
freeze (argon gas) and actively thaw (helium gas)
mechanisms: direct cellular toxicity from disrup-
using the Joule-Thompson effect heralded the de-
tion of the cellular membrane by iceball crystals
and vascular compromise from thrombosis and velopment of third-generation cryosurgery.5,6 The
ischemia.5 The degree of cell destruction is depen- transition from liquid to gas permitted the use
dent on rapid freezing, the lowest temperature of smaller diameter probes (ie, 17-gauge cryo-
achieved, and slow thawing and is maximized by needles) and facilitated a more conformal cryosur-
two or more freeze-thaw cycles.5–9 During the ini- gical approach secondary to the placement of a
tial freeze cycle, the complete eradication of malig- greater number of probes.5,6
nant cells requires a minimal freezing temperature The goals for all minimally invasive prostate can-
of ⫺40°C for at least 3 minutes.5,8 Tatsutani et al.10 cer therapies include eradication of local disease, a
demonstrated that complete cell death was un- shorter recuperative period, minimal postopera-
likely at temperatures greater than ⫺20°C; temper- tive morbidity, and a reduction in overall cost.1
atures less than ⫺40°C were required to destroy Although cryotherapy has the proven ability to ab-
cells.10 However, cells not destroyed by initial late malignant and benign cells, it has not yet been
freezing to ⫺20°C were eradicated with a second established whether the prostate gland represents
freeze cycle.10 an ideal organ for cryoablative therapy. Although
Cryosurgery was first used in the treatment of long-term results (ie, longer than 10 years) are
available for RP, EBRT, and BT, minimal detailed
G. S. Merrick is a study investigator funded in part by Theragen- information exists regarding optimization of the
ics Corporation. cryoablative technique. Long-term biochemical
From the Schiffler Cancer Center, Wheeling Hospital; Wheel-
ing Jesuit University, Wheeling, West Virginia; Puget Sound control and quality-of-life outcome data for a sig-
Healthcare Corporation; Group Health Cooperative; and Univer- nificant number of patients will not be available for
sity of Washington, Seattle, Washington at least another 5 years. Before the routine use of
Reprint requests: Gregory S. Merrick, M.D., Schiffler Cancer cryosurgery as a mainstream treatment of prostate
Center, Wheeling Hospital, 1 Medical Park, Wheeling, WV
26003-6300. E-mail:
cancer, questions regarding technique, patient se-
Submitted: September 29, 2004, accepted (with revisions): De- lection, thermal dosimetry, local control rates, and
cember 15, 2004 morbidity should be addressed.
© 2005 ELSEVIER INC. UROLOGY 66: 9 –15, 2005 • 0090-4295/05/$30.00
ALL RIGHTS RESERVED doi:10.1016/j.urology.2004.12.039 9
, IS CANCERICIDAL DOSIMETRY ACHIEVED the procedure, the optimal warming regimen re-
WITH PROSTATE CRYOTHERAPY? mains unknown.18 To date, no studies have deter-
mined the volume of periurethral tissue that must
Urethral preservation is critical to prevent mor-
be spared from freezing, and no data exist regard-
bidity in patients treated with cryosurgery. The use
ing the depth of penetration of the urethral
of prostate parenchyma-sparing urethral warming
warmer. During transurethral microwave hyper-
devices has reduced the incidence of incontinence, thermia, Larson et al.19 demonstrated that urethral
urethral sloughing, and irritative voiding symp- cooling resulted in sparing tissue from necrosis for
toms.12 In addition, the implementation of thermo- a distance of 5 mm from the urethral mucosa. In
couples to monitor temperatures at specific sites conjunction with the Mayo Clinic RP data, this
has improved tolerance and intraoperative moni- suggests that periurethral prostate cancer may be
toring during prostate cryotherapy. “spared” in as many as 84% of patients treated with
To ensure preservation of urethral function, a a urethral warming device.17,19 Because the inci-
urethral warmer at a temperature of approximately dence of periurethral and apical malignancy is
38°C should be used before, during, and after cryo- high, it is likely that the currently accepted ther-
surgery.13 In addition, four to six thermocouples mographic dose distributions at the periurethral
are routinely placed in the region of the neurovas- and apical locations may result in a “cancer-spar-
cular bundles, apex, and Denonvilliers space.13 ing” procedure in which prostate cancer cells may
Typically, a double freeze-thaw technique is used; be “stunned,” but not eradicated and may likely
this includes freezing the neurovascular bundles to represent a source of late prostate cancer failure.
⫺40°C, and the apex to a temperature of approxi- Future research must evaluate the depth of tissue
mately ⫺10°C (greater than the ⫺20°C needed for penetration by the urethral warmer, the absolute
cell death).13 The freezing cycle is complete when minimal temperature and duration necessary for
all prostatic tissue has been frozen as visualized on urethral preservation, and the potential integration
ultrasonography.13 However, Saliken and col- of combined modality therapies (ie, chemical sen-
leagues14 reported that “ultrasound provides no in- sitization/protection and/or biologic response
formation about the temperature distribution modifiers) to minimize the need for urethral warm-
within the ice, nor does it show the extent of freez- ing. In addition, the development of cryotechnol-
ing at the lateral or anterior aspects of the pros- ogy to measure temperature distributions through-
tate,” and thermocouple-based dosimetry repre- out the target volume and not just at specific points
sents isolated “point” temperatures without will significantly improve dosimetric evaluation.
providing information regarding temperature dis-
tributions throughout the target volume, with a
resultant false sense of security regarding the ac- DOES THE CURRENTLY AVAILABLE
tual temperature “dose cloud.” Specifically, blood CRYOABLATIVE TECHNIQUE RESULT IN
vessels may act as “heat sinks,” with adjacent areas OBLITERATION OF MALIGNANT AND
not achieving target temperatures, even though BENIGN ELEMENTS WITHIN THE
they are completely encompassed within the ultra- PROSTATE GLAND?
sound target volume.15 After cryosurgical ablation, few studies have
“Modifications designed to reduce temperature evaluated the long-term histopathologic findings.
side effects could conflict with efforts designed to Residual malignant cells have been reported in 7%
improve eradication of prostate cancer.”16 In a re- to 23% of patients, with focal areas of viable benign
view of Mayo Clinic RP specimens, it was demon- glands present in 45% to 70% of patients.15 In pa-
strated that the mean distance from the urethra to tients receiving neoadjuvant androgen deprivation
the nearest foci of cancer was 3 mm, with 17% of therapy (ADT) in conjunction with salvage cryo-
cancers abutting the urethra. A second study doc- therapy for biopsy-proven EBRT failure, residual
umented that 66% and 45% of prostate cancers prostate cancer, viable benign prostate glands, and
were within 5 mm and 1 mm of the urethra, respec- viable stroma were present in 14%, 42%, and 27%
tively.16,17 The urethra-cancer distance correlated of the specimens, respectively.20 These bother-
with the preoperative prostate-specific antigen some follow-up biopsy results were demonstrated
(PSA) level, biopsy Gleason score, biopsy Gleason despite an inadequate biopsy core technique (four
grade 4 or 5, apical location of the prostate cancer, core) and likely underestimated the actual inci-
transition zone cancer, and greater prostate cancer dence of residual malignancy.20,21 In two contem-
volumes.16,17 Apical prostate cancer was present in porary cryosurgical series, positive biopsies were
74% of the surgical specimens and was more likely documented in 13% and 18% of patients after de-
to have a shorter urethra-cancer distance.17 finitive cryosurgery with or without ADT.22,23 Al-
Although sparing of periurethral tissues from though an attractive aspect of cryotherapy is the
cryoablation may affect the therapeutic efficacy of ability to repeat the procedure in the presence of
10 UROLOGY 66 (1), 2005
PROSTATE CRYOTHERAPY: MORE QUESTIONS
THAN ANSWERS
GREGORY S. MERRICK, KENT E. WALLNER, AND WAYNE M. BUTLER
ecause of the absence of prospective random- prostate cancer in 1968 with the advent of probes
B ized trials comparing the relative efficacy of
various local treatments, the management of clini-
cooled by liquid nitrogen in a closed circulation
system.11 First-generation cryosurgery was per-
cally localized prostate cancer remains one of the formed without transrectal ultrasound guidance or
most controversial topics in oncology. Radical urethral warmers and was plagued by significant
prostatectomy (RP), external beam radiotherapy complications, including urinary incontinence,
(EBRT), and brachytherapy (BT) represent univer- urethral sloughing, and rectourethral fistulas.5,6
sally accepted local approaches. Recently, cryo- These complications were attributed to a lack of
therapy has been resurrected as an additional po- accurate monitoring of the freezing process. Sec-
tential treatment option.1 This resurgence of ond-generation cryosurgery witnessed the devel-
interest in cryotherapy reflects increased interest opment and implementation of transrectal ultra-
in less-invasive forms of therapy and has been fa- sound guidance and urethral warmers.5,8
cilitated by a better understanding of cryobiology, Ultrasound guidance allowed for accurate probe
improved cryotechnology, and a perception placement and real-time monitoring, and urethral
among some that the currently accepted treatment warmers decreased the risk of urethral sloughing.
options are of suboptimal efficacy and/or signifi- Most recently, the implementation of gas-driven
cant morbidity.1– 4
probes in which pressurized gas is used to both
Cryotherapy induces cell death by two main
freeze (argon gas) and actively thaw (helium gas)
mechanisms: direct cellular toxicity from disrup-
using the Joule-Thompson effect heralded the de-
tion of the cellular membrane by iceball crystals
and vascular compromise from thrombosis and velopment of third-generation cryosurgery.5,6 The
ischemia.5 The degree of cell destruction is depen- transition from liquid to gas permitted the use
dent on rapid freezing, the lowest temperature of smaller diameter probes (ie, 17-gauge cryo-
achieved, and slow thawing and is maximized by needles) and facilitated a more conformal cryosur-
two or more freeze-thaw cycles.5–9 During the ini- gical approach secondary to the placement of a
tial freeze cycle, the complete eradication of malig- greater number of probes.5,6
nant cells requires a minimal freezing temperature The goals for all minimally invasive prostate can-
of ⫺40°C for at least 3 minutes.5,8 Tatsutani et al.10 cer therapies include eradication of local disease, a
demonstrated that complete cell death was un- shorter recuperative period, minimal postopera-
likely at temperatures greater than ⫺20°C; temper- tive morbidity, and a reduction in overall cost.1
atures less than ⫺40°C were required to destroy Although cryotherapy has the proven ability to ab-
cells.10 However, cells not destroyed by initial late malignant and benign cells, it has not yet been
freezing to ⫺20°C were eradicated with a second established whether the prostate gland represents
freeze cycle.10 an ideal organ for cryoablative therapy. Although
Cryosurgery was first used in the treatment of long-term results (ie, longer than 10 years) are
available for RP, EBRT, and BT, minimal detailed
G. S. Merrick is a study investigator funded in part by Theragen- information exists regarding optimization of the
ics Corporation. cryoablative technique. Long-term biochemical
From the Schiffler Cancer Center, Wheeling Hospital; Wheel-
ing Jesuit University, Wheeling, West Virginia; Puget Sound control and quality-of-life outcome data for a sig-
Healthcare Corporation; Group Health Cooperative; and Univer- nificant number of patients will not be available for
sity of Washington, Seattle, Washington at least another 5 years. Before the routine use of
Reprint requests: Gregory S. Merrick, M.D., Schiffler Cancer cryosurgery as a mainstream treatment of prostate
Center, Wheeling Hospital, 1 Medical Park, Wheeling, WV
26003-6300. E-mail:
cancer, questions regarding technique, patient se-
Submitted: September 29, 2004, accepted (with revisions): De- lection, thermal dosimetry, local control rates, and
cember 15, 2004 morbidity should be addressed.
© 2005 ELSEVIER INC. UROLOGY 66: 9 –15, 2005 • 0090-4295/05/$30.00
ALL RIGHTS RESERVED doi:10.1016/j.urology.2004.12.039 9
, IS CANCERICIDAL DOSIMETRY ACHIEVED the procedure, the optimal warming regimen re-
WITH PROSTATE CRYOTHERAPY? mains unknown.18 To date, no studies have deter-
mined the volume of periurethral tissue that must
Urethral preservation is critical to prevent mor-
be spared from freezing, and no data exist regard-
bidity in patients treated with cryosurgery. The use
ing the depth of penetration of the urethral
of prostate parenchyma-sparing urethral warming
warmer. During transurethral microwave hyper-
devices has reduced the incidence of incontinence, thermia, Larson et al.19 demonstrated that urethral
urethral sloughing, and irritative voiding symp- cooling resulted in sparing tissue from necrosis for
toms.12 In addition, the implementation of thermo- a distance of 5 mm from the urethral mucosa. In
couples to monitor temperatures at specific sites conjunction with the Mayo Clinic RP data, this
has improved tolerance and intraoperative moni- suggests that periurethral prostate cancer may be
toring during prostate cryotherapy. “spared” in as many as 84% of patients treated with
To ensure preservation of urethral function, a a urethral warming device.17,19 Because the inci-
urethral warmer at a temperature of approximately dence of periurethral and apical malignancy is
38°C should be used before, during, and after cryo- high, it is likely that the currently accepted ther-
surgery.13 In addition, four to six thermocouples mographic dose distributions at the periurethral
are routinely placed in the region of the neurovas- and apical locations may result in a “cancer-spar-
cular bundles, apex, and Denonvilliers space.13 ing” procedure in which prostate cancer cells may
Typically, a double freeze-thaw technique is used; be “stunned,” but not eradicated and may likely
this includes freezing the neurovascular bundles to represent a source of late prostate cancer failure.
⫺40°C, and the apex to a temperature of approxi- Future research must evaluate the depth of tissue
mately ⫺10°C (greater than the ⫺20°C needed for penetration by the urethral warmer, the absolute
cell death).13 The freezing cycle is complete when minimal temperature and duration necessary for
all prostatic tissue has been frozen as visualized on urethral preservation, and the potential integration
ultrasonography.13 However, Saliken and col- of combined modality therapies (ie, chemical sen-
leagues14 reported that “ultrasound provides no in- sitization/protection and/or biologic response
formation about the temperature distribution modifiers) to minimize the need for urethral warm-
within the ice, nor does it show the extent of freez- ing. In addition, the development of cryotechnol-
ing at the lateral or anterior aspects of the pros- ogy to measure temperature distributions through-
tate,” and thermocouple-based dosimetry repre- out the target volume and not just at specific points
sents isolated “point” temperatures without will significantly improve dosimetric evaluation.
providing information regarding temperature dis-
tributions throughout the target volume, with a
resultant false sense of security regarding the ac- DOES THE CURRENTLY AVAILABLE
tual temperature “dose cloud.” Specifically, blood CRYOABLATIVE TECHNIQUE RESULT IN
vessels may act as “heat sinks,” with adjacent areas OBLITERATION OF MALIGNANT AND
not achieving target temperatures, even though BENIGN ELEMENTS WITHIN THE
they are completely encompassed within the ultra- PROSTATE GLAND?
sound target volume.15 After cryosurgical ablation, few studies have
“Modifications designed to reduce temperature evaluated the long-term histopathologic findings.
side effects could conflict with efforts designed to Residual malignant cells have been reported in 7%
improve eradication of prostate cancer.”16 In a re- to 23% of patients, with focal areas of viable benign
view of Mayo Clinic RP specimens, it was demon- glands present in 45% to 70% of patients.15 In pa-
strated that the mean distance from the urethra to tients receiving neoadjuvant androgen deprivation
the nearest foci of cancer was 3 mm, with 17% of therapy (ADT) in conjunction with salvage cryo-
cancers abutting the urethra. A second study doc- therapy for biopsy-proven EBRT failure, residual
umented that 66% and 45% of prostate cancers prostate cancer, viable benign prostate glands, and
were within 5 mm and 1 mm of the urethra, respec- viable stroma were present in 14%, 42%, and 27%
tively.16,17 The urethra-cancer distance correlated of the specimens, respectively.20 These bother-
with the preoperative prostate-specific antigen some follow-up biopsy results were demonstrated
(PSA) level, biopsy Gleason score, biopsy Gleason despite an inadequate biopsy core technique (four
grade 4 or 5, apical location of the prostate cancer, core) and likely underestimated the actual inci-
transition zone cancer, and greater prostate cancer dence of residual malignancy.20,21 In two contem-
volumes.16,17 Apical prostate cancer was present in porary cryosurgical series, positive biopsies were
74% of the surgical specimens and was more likely documented in 13% and 18% of patients after de-
to have a shorter urethra-cancer distance.17 finitive cryosurgery with or without ADT.22,23 Al-
Although sparing of periurethral tissues from though an attractive aspect of cryotherapy is the
cryoablation may affect the therapeutic efficacy of ability to repeat the procedure in the presence of
10 UROLOGY 66 (1), 2005
