Exerpts from: Prostate Cancer - Cryotherapy
Full article at: http://emedicine.medscape.com/article/458187-overview
Introduction
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History of the Procedure
Cryotherapy-the ablation of tissue by local induction of extremely cold temperatures-has its earliest antecedent in 19th-century London, where Arnott applied ice-salt mixtures to cancers of the breast and cervix.1 The 1966 advent of probes cooled by liquid nitrogen in closed circulation marks the beginning of modern cryotherapy.2 One of the first applications of this new technology was the transurethral cryoablation of benign prostatic hyperplastic tissue,3 followed shortly thereafter by the treatment of prostate cancer via an open perineal approach.4 The transperineal approach was introduced in 1974, initially using a single digitally guided cryoprobe repositioned as needed during the procedure.5
Early series of cryotherapy achieved effective tissue ablation, and complications were considered to be less severe than those of radical surgery at the time. The major impediment to early acceptance of the modality, however, was the inability to accurately monitor cryoprobe placement and ice-ball formation.
Major advances in the past 15 years, which have reinvigorated investigation into the use of cryotherapy for prostate cancer, have included the use of real-time transrectal ultrasonography (TRUS) monitoring of probe placement and freezing,6 the simultaneous use of multiple cryoprobes, and the standard use of urethral warming catheters.7
A significant recent development was the introduction of cryotherapy probes that use argon gas rather than liquid nitrogen. Argon rapidly cools the probe tip to -187°C (-304.6°F) and can be rapidly exchanged with helium at 67°C (152.6°F) for an active thawing phase, producing a faster response to operator input and significantly speeding 2-cycle treatment.8 Moreover, argon-based probes have a much smaller diameter, thus permitting direct, sharp transperineal insertion, avoiding the need for tract dilation and facilitating more conformal cryosurgery by allowing placement of more probes.9
In recent years, cryotherapy has seldom been used in community urological practice despite the initiation of Medicare reimbursement for the procedure in 1999. Among 8685 patients followed as of August 2002 in the Cancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE) registry (a primarily community-based observational database of patients with prostate cancer treated at 35 practice sites across the United States), less than 2% of those diagnosed with prostate cancer since 1996 underwent cryotherapy as primary treatment.10
According to American Urological Association (AUA) polls, the percentage of urologists performing cryosurgery from 1997-2001 remained constant at 2%, but the average annual number of procedures performed by each urologist increased from 4 to 24. In contrast, the percentage of urologists performing brachytherapy over the same period rose from 16% to 51%, with the annual number of procedures per urologist rising from 15 to 16.5.11 However, ongoing technical advances and recently reported results from academic centers suggest that cryotherapy may be poised to capture an increased role in the management of localized prostate cancer.
In 2008, the AUA published a Best Practice Statement on the use of cryosurgery for the treatment of localized prostate cancer.12
Cryobiology
Cryotherapy exerts its antineoplastic effects via numerous proposed pathways, including direct cytolysis via extracellular and intracellular ice crystal formation, intracellular dehydration and pH changes, ischemic necrosis via vascular injury, cryoactivation of antitumor immune responses, and induction of apoptosis. Endothelial damage leads to platelet aggregation and microthrombosis. Histologic changes, including necrosis, hyalinization, and inflammation, can occur for at least one year following treatment, as can residual indolent cancer. Hyalinization may be more prominent in more effectively treated prostates, ie, those with no residual cancer.13
Additional injury occurs during warming, with osmotic cellular swelling and vascular hyperpermeability. Numerous factors affect the efficiency of tissue destruction, including the velocity of cooling, nadir temperature, the duration of freezing, the velocity of thawing, the number of freeze-thaw cycles, and the existence of large blood vessels, which act as heat sinks. In general, a minimum freezing temperature of -40°C (-40°F) for 3 minutes is believed to be necessary for efficient tumor eradication.14,15,16
Primary treatment
A 2008 research summary by the Agency for Healthcare Research and Quality (AHRQ) concluded that, because of the lack of relevant randomized controlled trials, whether cryotherapy is more or less effective than other therapies in the treatment of localized prostate cancer is unknown.17 The Best Practice Statement issued by the AUA concluded that level II-2/3 evidence exists to support offering cryotherapy to men with clinically organ-confined prostate cancer with a negative metastatic evaluation finding. In high-risk men, including those with clinical stage T3 disease, data are more sparse; multimodal therapy may be necessary.12
As with any other treatment for prostate cancer, appropriate patient selection is critical, and preprocedure tumor characteristics are strong indicators of outcome. Patients with low-risk tumor features (ie, serum prostate-specific antigen [PSA] level 10 ng/mL, diagnostic biopsy Gleason score 6, clinical stage T1c or T2a) are expected to have the best outcomes. Patients with higher-grade, more-extensive, or more-advanced disease are at higher risk for local extension, metastatic spread, or both.
In most contemporary series, cryotherapy is associated with higher rates of impotence than other local treatment alternatives; therefore, patients for whom preservation of erectile function is a high priority are probably less-than-ideal candidates. Cryoablation has, however, been used for local disease control in patients with known metastatic disease on systemic therapy who require palliative maneuvers for local symptoms.18
Larger prostates may be more difficult to treat because of the difficulty in achieving a uniformly cold temperature throughout the gland. Neoadjuvant therapy for downsizing the gland may be considered in such patients.
Salvage treatment
The AUA Best Practice Statement concluded that level II-3 evidence supports the consideration of cryotherapy in men in whom radiation therapy has failed, particularly those with biopsy-proven local persistence or recurrence, clinically localized disease, and a PSA level of less than 10 ng/mL.12
Few local treatment alternatives are available for patients who do not achieve a low PSA nadir or who experience a rising PSA level after radiotherapy. Additional brachytherapy19 and radical prostatectomy20 are options; however, most patients in this position undergo systemic androgen deprivation therapy, which may control the cancer for several years but does not offer the possibility of definitive cure. Cryosurgery has recently been established as a viable alternative for patients in whom radiotherapy has failed. Tumor cells resistant to radiotherapy, androgen withdrawal, and chemotherapy may remain vulnerable to the physical trauma of freezing and thawing.
Candidates for such salvage treatment should be carefully selected. In particular, if the goal is cure, the treating physician must be reasonably confident that the failure of radiation is truly attributable to persistent or recurrent local disease rather than to occult metastatic disease. To this end, inclusion criteria for reported series of salvage cryotherapy have generally included imaging tests (nuclear scintigraphy and pelvic cross-sectional imaging [CT scanning or MRI]) to rule out metastases to the bones and pelvic lymph nodes, respectively. However, the sensitivity of these tests, particularly for lymph node involvement, is less than 50%,21 and the likelihood of positive test results despite a low PSA level is quite low.
