Primary cryoablation for Gleason 8, 9, or 10 localized prostate cancer:"Check out this article below about cryotherapy of the prostate. Our Miami urologist, Dr. Amery Wirtshafter contributed many patients to this valuable study evaluating the use of cryoablation for high grade prostate cancer."
Biochemical and local control outcomes from the Cryo OnLine database
registry J. Stephen Jones and John C. Rewcastle1 Glickman Urological
Institute, Cleveland Clinic Foundation, Cleveland, OH, USA 1Department of
Radiology, University of Calgary, Calgary, AB, Canada For correspondence:
Dr. J. Stephen Jones, Glickman Urological Institute, Cleveland Clinic
Foundation, A-100, 9500 Euclid Ave., Cleveland, OH 44195, USA. E-mail:
[email protected] This is an open-access article distributed under the terms
of the Creative Commons Attribution License, which permits unrestricted use,
distribution, and reproduction in any medium, provided the original work is
properly cited. Other Sections? Abstract INTRODUCTION MATERIALS AND METHODS
RESULTS DISCUSSION CONCLUSION REFERENCESAbstract Introduction and Objective:
The increased use of cryoablation as an initial treatment for localized
high-grade prostate cancer has been due to many factors including reports
that cell kill from exposure to cryogenic temperatures is independent of
cellular dedifferentiation and Gleason score. The objective of this study is
to report the outcomes of primary cryoablation when used to treat Gleason 8,
9, or 10 localized prostate cancer at a large number of centers. Materials
and Methods: Data from 1608 patients who underwent primary cryoablation at
27 centers were collected using the Cryo OnLine Database (COLD) registry.
This analysis considers only the 77 patients who had a Gleason score of at
least 8 and a minimum of 24 months of follow-up. Biochemical failure was
defined according to both the original ASTRO definition (three rises) and
the 2006 updated ASTRO (Phoenix) definition of nadir + 2. Biopsy was
performed at the physician's discretion, but most commonly if a patient
had a rising or suspicious prostate specific antigen (PSA). Results: The
average age at treatment was 69.6 ± 8.2 years. Pretreatment PSA was
16.2 ± 17.9 ng/ml and the average Gleason was 8.5 ± 0.6.
Patients were followed for 39.0 ± 18.8 months (range: 24-120 months)
and 5-year follow-up was available for 12 patients. Eight-seven percent of
the patients achieved a PSA nadir < 0.4 ng/ml. Five-year actuarial
biochemical survivals was 64.4 ± 6.0% and 44.6 ± 8.0% for the
ASTRO and Phoenix definitions, respectively. A total of 47 underwent
posttreatment biopsy. Of these, 12 showed evidence of disease resulting in a
positive biopsy rate for those who underwent biopsy of 25.5%. This yields a
positive biopsy rate of the entire population of 15.6% (12/77). Conclusions:
Cryoablation, as a primary treatment for high-grade Gleason prostate cancer
practiced over a wide spectrum of users provides definable biochemical and
local control for a hard to manage patient population with aggressive
disease. Keywords: Cryotherapy, prostate cancer, minimally invasive Other
Sections? Abstract INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION
CONCLUSION REFERENCESINTRODUCTION Despite the well-recognized stage
migration that has led to an improvement in prostate cancer outcomes since
the era of prostate specific antigen (PSA)-based prostate cancer screening
began, patients with high-grade prostate cancer remain at significant risk
of morbidity and mortality.[1] Patients with Gleason score >8 cancer are
often treated with radical prostatectomy or radiotherapy combined with
adjuvant androgen blockade. Some patients have confounding factors limiting
their ability to undergo surgery, including age, anesthetic risks, or simply
refusal of surgical intervention. External beam radiotherapy in combination
with 6-24 months' hormonal ablation offers a nonsurgical alternative,
and brachytherapy or the combination of external beam radiotherapy with
brachytherapy is used for some high-risk patients as well. These options
carry substantial risk of complications, including erectile dysfunction,
incontinence, or damage to the surrounding structures that continue to limit
their acceptance for some patients. Moreover, the efficacy of any modality
decreases in patients with high-grade disease.[1]Cryosurgical ablation has
been used in many centers as a minimally invasive alternative to surgery and
radiation that has the potential to eradicate prostate cancer irrespective
of tumor grade. Unlike radiotherapy, cryoablation appears to reproducibly
kill all cells frozen to lethal temperatures.[2] This has led to the
suggestion that it may be preferentially useful for patients with high-grade
disease.[3]This study reports a relatively large group of patients diagnosed
with Gleason 8, 9, or 10 prostate cancer who underwent cryoablation as their
primary therapy. Patient data were collected with the Cryo OnLine Database
(COLD) registry. Other Sections? Abstract INTRODUCTION MATERIALS AND METHODS
RESULTS DISCUSSION CONCLUSION REFERENCESMATERIALS AND METHODS The COLD
registry is a secure web-based registry consisting of case report forms
designed to collect relevant pre- and post-treatment information for
patients undergoing prostate cryoablation. A central institutional review
board's approval covers the collection and analysis of deidentified
data, additional IRB approval for individual centers has been obtained when
required by institutional policy. Investigators who have entered data into
the COLD registry are listed in the acknowledgments.Only patients with
Gleason score 8 or greater having minimum 24 months follow-up were included
in this analysis. Patients undergoing cryotherapy following failure of prior
definitive radiotherapy or brachytherapy, and those that had undergone
focal, nerve sparing, or nerve warming treatment were excluded. A total of
77 patients from 27 centers were identified meeting the criteria.Biochemical
failure was defined according to both the original ASTRO definition of three
consecutive rises following nadir (referred to as ?ASTRO?), and the second
ASTRO definition of nadir + 2 (referred to as the ?Phoenix? definition).
Biopsy was performed at the physician's discretion, but most commonly
if a patient had a rising or suspicious PSA.Kaplan-Meier analysis was used
to generate curves showing the probability biochemical failure as a function
of time. Statistical analysis was performed with a commercially available
statistical software package (MedCalc, Mariakerke, Belgium). Other Sections?
Abstract INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION CONCLUSION
REFERENCESRESULTS Data were collected from 27 investigators. The average age
of the 77 patients who met the inclusions criteria was 69.6 ± 8.2
years. Pretreatment PSA was 16.2 ± 17.9 ng/ml and the average Gleason
was 8.5 ± 0.6. Patients were followed for 39.0 ± 18.8 months
(range: 24-120 months) and 12 patients had a follow-up of at least 60
months. Posttreatment, 87% of the patients achieved a PSA nadir < 0.4
ng/ml. The 5-year actuarial biochemical survivals are 64.4 ± 6.0% and
44.6 ± 8.0% for the ASTRO and Phoenix definitions, respectively
[Figure 1]. After treatment, 47 underwent biopsy. Of these, 12 showed
evidence of disease. The positive biopsy rate, for those who underwent
posttreatment biopsy was 25.5% and the rate for the entire population was
15.6% (12/77). No fistulas were identified in any of the patients. Figure 1
Kaplan-Meier curve of the cumulative biochemical disease free survival
probability using (a) the ASTRO definition and (b) the Phoenix definition
Other Sections? Abstract INTRODUCTION MATERIALS AND METHODS RESULTS
DISCUSSION CONCLUSION REFERENCESDISCUSSION The COLD registry project is
designed to address the relative paucity of published data regarding
cryotherapy for prostate cancer. It is notable, however, that opinions
regarding the quality and quantity of data published on radical
prostatectomy, external beam radiation, and active surveillance are perhaps
overstated. For example, the Kaplan-Meier 5-year biochemical disease free
survival data for high-risk prostate cancer managed with external beam
radiotherapy as shown in Campbell's Urology textbook is based upon a
surprisingly low six patients with at least 60 months follow-up. Similarly,
the present series reports only 12 patients with results at 5 years. We
believe that both datasets are inadequate to make solid declarations of
long-term efficacy. That being said, the authors do feel it is important to
realize that the data supporting any form of treatment for the high-risk
patient is lacking[1] and that the concept that radiation therapy is clearly
established as a more efficacious treatment for high-risk disease must be
scrutinized.Emerging technologies are often reserved in initial series to
low-risk patients in whom failure to control disease carries less risk of
metastasis and death. For example, most initial brachytherapy series are
heavily weighted toward patients with low-risk disease.[4] Moreover, even
recent radical prostatectomy and radiation series include more low risk than
high-risk patients, but this is at least partially due to high-risk disease
being less common in screened populations.[5,6] In contrast, early pioneers
of cryotherapy advocated the position that if lethal cold temperatures are
achieved, uniform necrosis results and cell death occurs irrespective of
cellular differentiation or Gleason score.[2] In addition, publications
suggesting its potential to treat locally advanced disease has led to the
concept of freezing beyond the prostatic capsule to eliminate extraprostatic
disease that would have resulted in a positive surgical margin had radical
prostatectomy been performed.[7] As a result, cryoablation is often utilized
for the treatment of high-risk localized prostate cancer. Several
publications of intermediate-term results have suggested that the efficacy
of the procedure appears to be equivalent to radiation and surgery for
low-risk prostate cancer and potentially more efficacious for moderate- and
high-risk prostate cancer.[8?11] A summary of the efficacies reported in the
four publications reporting 5 year outcomes exclusively for primary
cryoablation is presented in Table 1. Table 1 Biochemical disease free
survival at 5 years following cryoablation: Reports in the literature As of
yet there is no universally agreed upon definition of biochemical failure
following cryotherapy, but it should be noted that consensus definitions
also remain relatively elusive following radiation or surgery. Radical
prostatectomy completely removes the prostate and should theoretically yield
an undetectable PSA. However, some residual PSA remains detectable in many
patients due to a small number of remaining benign glands. The American
Urological Association (AUA) Guidelines Panel recommended in 2007 that the
definition of biochemical success does not require an undetectable PSA, and
that failure should be a PSA > 0.2 ng/ml confirmed by a second PSA
reading > 0.2.[12] Further, the AUA panel found 166 different published
definitions of biochemical failure, including 99 for patients undergoing
radiation failure. In 1998 the first ASTRO definition of three consecutive
rises, backdated to the midpoint of the first rise, was agreed upon by a
consensus panel and became standard practice. It is the ASTRO definition
that has been used most commonly following cryoablation. This is based on
the similarity of cryoablation and radiation therapy in that both modalities
result in some residual prostatic tissue and low but measurable PSA levels
in most patients. The second ASTRO definition, dubbed the ?Phoenix?
definition, remains somewhat controversial in the eyes of many urologists.
Although it was specified that it was not intended for use with patients
undergoing cryotherapy, we have included our results using this as an
additional definition solely for comparative purposes.[13]Early cryotherapy
experience made it clear that specific thresholds may be meaningless due to
PSA production by residual tissue surrounding the urethra or in a benign
median lobe, and the fact that a PSA of 0.4 is expected when 1 g of prostate
tissue has been preserved in men free of prostate cancer.[14] It is intended
that the data set collected with the COLD registry will be used to create a
scientifically based definition of biochemical failure that is specific to
primary prostate cancer cryoablation as these data accumulate and mature.The
use of negative biopsies as a surrogate for disease control is also
controversial. Regardless of the intervention, sampling error underestimates
disease when using biopsy as a surrogate. This is especially likely when
small volume disease is present, as evidenced by the 61% of men known to
have prostate cancer that have a negative repeat sextant biopsy when
evaluated on an active surveillance protocol.[15] Seventeen percent of
patients with known prostate cancer on an active surveillance protocol have
a negative biopsy even when saturation biopsy is performed.[16] Some authors
suggest that histological evidence of malignancy identified on biopsy should
not be regarded as cancer in some postradiation settings.[17] In contrast,
following cryoablation, histological results tend to fall into one of three
definitive categories: fibrous tissue (scar) indicating tumor eradication,
benign prostate tissue, or prostate cancer.[18] When cryotherapy was first
investigated most patients underwent posttreatment biopsy to confirm local
control. However, due to high-negative biopsy rates (82-98%)[8,9] most
practitioners now utilize biopsy only to investigate suspicious PSA values
or patterns.[19] It is not possible to know what the positive biopsy rate
would be for those not determined to warrant biopsy by the treating
physicians, but previous series have suggested that the likelihood of
residual disease is low as demonstrated in the table.The primary limitation
of this series is the retrospective nature of a registry. There is the
potential that patients with unfavorable features are not voluntarily
reported to the registry, or that unfavorable outcomes are inaccurately
reported. Our experience in dealing directly with the physician members and
with internal audit is that we have found no evidence that there is any case
selection, and to our knowledge all cases of the enrolling physicians are
included. In addition, a wide variety of surgical techniques is possible
with the large number of institutions participating. However, a primary goal
of the COLD registry is to determine outcomes in ?the real world? without
the inherent reporting bias of single surgeon series. These data suggest
that bDFS and complication rates are consistent with earlier single-center
reports. CONCLUSION The biochemical and local control of cryoablation for
high Gleason score prostate cancer appear to be consistent both with early
reports of cryoablation and with large series reporting experience with
radiation and surgery. Improving data available on all treatment modalities
for localized prostate cancer is mandatory for patients to make an informed
decision on therapy. Acknowledgments This analysis is based on data entered
into the COLD registry. The contributing investigators include: AN Avallone,
Grand Rapids, MI; DK Bahn, Ventura, CA; BT Brown, Daytona Beach, FL; A
Cantwell, Daytona Beach, FL; DO Chinn, Arcadia, CA; M Chinn, Arcadia, CA; R
Chopra, Port Orange, FL; FC Derrick, Charleston, SC; M Dineen, Daytona
Beach, FL; HB Epstein, St. Augustine, FL; J Foley, Easton, MD; RW Given,
Norfolk, VA; M Grable, Orange City, FL; RF Graves, Scottsbluff, NE; JM
Greenberg, Tucson, AZ; R Kahnoski, Grand Rapids, MI; AE Katz, New York, NY;
DL Laub, Santa Barbara, CA; MA Melser, Port Charlotte, FL; M Merrell,
Daytona Beach, FL; KR Orton, Tucson, AZ; TH Patterson, Galesburg, IL; R
Regan, Daytona Beach, FL; GS Rosenberg, Hackensack, NJ; SM Scionti, Hilton
Head Island, SC; J Wescott, Daytona Beach, FL; AR Wirtshafter, Miami Beach,
FL. Footnotes Source of Support: The COLD registry is supported through an
educational grant from Endocare, Inc. Conflict of Interest: None declared.
Other Sections:
Abstract
INTRODUCTION
MATERIALS AND
METHODS
RESULTS
DISCUSSION
CONCLUSION REFERENCES
REFERENCES
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