136 Daniel B. Rukstalis Department of Urology, Wake Forest University School of Medicine, Winston Salem, NC, USA Human experience has definitively established that cold temperatures kill living tissues. Certainly, arctic explorers and polar bear swim clubs have learned about the manifestations of frostbite as frozen cells become ischemic from exposure to freezing temperatures. The medical applications of such low‐temperature exposure was first developed for the management of malignancy in nineteenth‐century England. Modern technology has provided a mechanism to percutaneously target and ablate clinically localized prostate cancer using the same lethal cold temperatures delivered with needle probes cooled by high‐pressure gas‐based systems. This chapter provides information about the basic principles of cryobiology, current indications for cryotherapy of the prostate, and procedural details, and summarizes the outcomes as reported in the literature. All living cells possess mechanisms for managing exposure to cold temperatures. The limitation of fluid flow across cell membranes, the high concentration of solutes in the cytoplasm and various proteins can minimize the mechanical effect of low temperatures and freezing of water. However, these mechanisms can be ultimately abrogated as the ambient temperature falls below a value of approximately −10 °C. As tissue is exposed to lethally cold temperatures the cells are destroyed through one of several mechanisms. These mechanisms can be summarized into two categories: direct cellular injury and vascular cryogenic injury [1]. Direct cellular injury has been extensively studied in cell culture models and is based on the physics of water and ice formation within the frozen tissue. Two separate mechanisms of ice formation have been described. Initially, ice forms in the extracellular space and propagates through the tissue as temperatures decrease. Since only free water will freeze, the solute concentration rises in the extracellular fluid that has not yet frozen. Intracellular water moves out of the cells in response to this change in osmolarity, causing cellular dehydration with a corresponding increase in the concentration of intracellular solutes. This change disrupts protein function and enzymatic activity and can result in apoptotic cell death [2, 3]. This may be called a solution effect injury. The next direct injury is a result of the development of intracellular ice crystal formation that only develops at very low temperatures (estimated to be below −40 °C). It is also likely that rapid rates of freezing are required to cause freezing of water that is entrapped within the cells before dehydration has occurred. Intracellular ice formation alters cell physiology by disrupting cell membranes and contributes to cell death by direct cryogenic injury. These cells then die through the mechanism of necrosis or direct disruption rather than the programmed cell death described above. Increasing the duration of exposure to lethal temperatures (<−40 °C) may enhance cell destruction since the limited amount of water that remains unfrozen at the periphery may also freeze [4]. Additional cellular damage is created as the tissue is allowed to warm following the initial freeze process. During thawing, recrystallization occurs when the temperature rises above −40 °C. In the recrystallization process smaller ice crystals coalesce into larger structures that can further disrupt cellular membranes and fracture the cells. Moreover, as extracellular ice crystals melt, a hypotonic extracellular environment is created such that free water now flows back into cells, causing cellular edema, swelling, and injury. It has been suggested that passive thawing may be more efficient in prostate cancer destruction. The second category of cryogenic injury is the vascular mechanism. This type of cryogenic injury occurs preferentially in the microcirculation. Vascular endothelial cells are more sensitive to cold‐based injury (as generally understood from experience with frostbite injuries to the extremities of cold weather explorers) and slough into the vessel lumen, resulting in increased vessel permeability and platelet aggregation with thrombosis. This results in tissue ischemia, inflammation, and cell death through necrosis [5]. In addition, thawing and reperfusion injury mediated by the release of free radicals augments the endothelial cell damage and can enhance the inflammatory process with enzymatic degradation of the cellular debris. Cryogenic injury progresses as the temperature drops and is a time‐dependent process. Although cell dehydration occurs at temperatures between 0 °C and −20 °C this is insufficient to produce permanent cellular injury and death. Intracellular ice begins to form at temperatures below −20 °C and is maximal at temperatures below −60 °C, which is uniformly lethal for cancer cells [6]. Importantly, tissue at the periphery of the freeze zone may be exposed to less cold temperatures, despite being included in the frozen tissue, and receive only sublethal injury. In this zone of damage cellular apoptosis is the primary mechanism for cell death and is not uniform. Cryobiologists have attempted to augment the cellular injury that results from exposure of cells to sublethal temperatures in an effort to increase the percentage of cancer cells that suffer programmed cell death. Clarke et al. have demonstrated that several different chemotherapeutic agents can potentiate the lethal impact of freezing cancer cells and may represent the optimal mechanism for destroying all cells within a target tissue volume [7]. The mechanical freeze fracturing of living cancer cells has been demonstrated to release tumor antigens into the microcirculation and initiate an immune response [8, 9]. This potential therapeutic mechanism has been demonstrated in rats treated with cryoablation of a prostate cancer with concomitant administration of BCG [10]. Despite these results, the clinical exploitation of this phenomenon has been limited, although recent studies have suggested that the immune response to the cryoablation of a malignancy within the prostate can be augmented with systemic agents [11, 12]. It remains possible that a multimodality approach using local cancer cryoablation with systemic immune modifiers may result in the treatment of metastatic prostatic cancer in the future. Primary cryoablation of the prostate is considered to be an option for the treatment of localized prostate cancer. The American Urologic Association’s (AUA) Best Practice Statement considered cryosurgery to be an option for patients who either do not desire or are not good candidates for conventional treatment modalities [13]. The European Association of Urology considers cryoablation of the prostate to be investigational at this time [14]. The optimal candidates for primary cryoablation of the prostate for curative intent are men with likely organ‐confined prostatic malignancy with prostate gland volumes between 25 and 80 ml without significant protrusion of the prostate into the bladder or the rectum. The AUA Best Practice Statement indicates that cryoablation is an option for low‐, intermediate‐, and high‐risk clinically localized prostate cancer, setting no apparent limits to prostate specific antigen (PSA) values, clinical stage, or biopsy Gleason score. However, this document does not specifically address the suitability for cryosurgery of high‐risk patients who may require multimodality treatment. It is likely that the optimal clinical stage for prostate cryoablation is cT1 or cT2 tumors. Cryoablation has been evaluated in men with clinical T3 cancers with mixed results [15, 16]. Therefore men with locally advanced prostatic cancers may elect for cryoablation but with the understanding that the risk of incomplete ablation and of associated toxicity is increased. Prostate cryoablation has demonstrated the capability to destroy prostatic tissue with a reduction in the volume of the prostate gland following the procedure, suggesting that this modality can treat men with clinically localized prostate cancer and associated benign prostatic enlargement with voiding dysfunction [17]. Therefore, men with prostate cancer within the setting of benign prostatic enlargement may elect this treatment approach rather than alternatives that do not reduce the volume of prostatic tissue. Salvage prostatic cryosurgery after primary radiation therapy has been proposed as an alternative to salvage radical prostatectomy with the potential for reduced morbidity. Salvage cryoablation has been reported after interstitial brachytherapy as well as external beam therapy [18]. There have been no prospective comparison trials between salvage radical prostatectomy and cryoablation following initial radiation therapy but clinical case series have suggested that the surgically related toxicity is likely reduced with cryoablation [17]. In addition, the oncologic outcome of cryoablation in the salvage setting may be related to the location and volume of persistent malignancy within the prostate gland [19]. Therefore, candidates for salvage prostate cryoablation include men with a small volume of prostatic cancer, as identified on postradiation prostate biopsy, following evaluation for an elevated PSA following first‐line therapy without radiographic evidence of metastatic disease. The optimal PSA level for salvage cryoablation has not been established but is likely similar to that of a salvage radical prostatectomy. A serum PSA value below 4 ng/ml has been associated with the highest likelihood of organ‐confined prostate cancer that can be eradicated with a radical prostatectomy. It is possible that this value is similar for salvage cryoablation [20]. Radiation‐persistent prostatic adenocarcinoma is associated with a higher incidence of seminal vesicle invasion and higher pathologic Gleason sum on prostate biopsy [21]. Although cryoablation is capable of destroying the malignancy irrespective of the histologic grade, successful management of invasive disease within the seminal vesicles is unlikely. Therefore, a seminal vesicle biopsy could be helpful in determining the correct candidate for a salvage cryoablation. As technology has improved over the years, we discuss only the current third‐generation technology, leaving the description of previous techniques (first and second generations) to historical reference. Third‐generation cryotechnology is based on dual‐gas systems exploiting the Joule–Thomson principle of gas expansion to provide heat subtraction and delivery through small‐caliber cryoprobes. The same effect is used in home appliances such as air conditioning systems and refrigerators. Briefly, these systems use pressurized argon and helium gases delivered to the cryoprobe in a closed circuit. When argon gas is allowed to expand through a pinhole opening at the tip of the cryoprobe, the gas changes its internal energy state as the pressure drops and the process consumes energy, thereby reducing the temperature. The inverse process happens during thawing, whereby helium is expanded in the cryoprobe, thus releasing energy and heating the probe. The opposite effects achieved with the two gases derive from different molecular properties (internal energy) of argon and helium gases, based on attractive and repulsive forces of gas molecules. The latest technology introduced an argon‐only system whereby both freezing and thawing phases are achieved by altering the physical properties of argon, thus simplifying the technologic complexity of cryoablation and obviating the need for an additional gas. The cryoablation suite consists of a console that monitors and controls the procedure, argon (and sometimes helium) pressurized gas tanks, a urethral warming device, and peripherals (transrectal stepper‐mounted ultrasound, cryoprobes, and thermocouples). The system’s user interface integrates ultrasonographic imaging that guides cryoprobe positioning and monitors the formation of the iceball, receiving input from the urethral warmer and the temperature probes. Different numbers, positions and configurations of probes allow for sculpturing of the iceball with precision. Cryoprobes and thermocouples are positioned transperineally through a brachytherapy‐like template (Figure 136.1). Currently, thin and ultrathin (17G, 1.5 mm) cryoprobes are available. Iceball formation is monitored both by temperature probe readings and by real‐time ultrasound. Figure 136.1 Transperineal percutaneous prostate cryoablation under ultrasound guidance. Prostate cryoprobes are placed percutaneously into the prostate through a brachytherapy grid under ultrasound guidance. Cryoablation is typically an outpatient procedure and can be performed under general, spinal, or locoregional anesthesia. With the patient in lithotomy position, probes are positioned using the grid under the guidance of transrectal ultrasound. Thermocouples are typically positioned adjacent to the neurovascular bundles, sphincter, and Denonvilliers’ fascia to assist with iceball monitoring. After probe positioning, flexible cystoscopy is used to verify that the probes have not penetrated the urethra or bladder. The urethral warming device is then introduced over a super‐stiff guidewire. Although some surgeons place a suprapubic tube to provide bladder drainage in the postoperative period, a urethral catheter can alternatively be utilized at the end of cryoablation, replacing the urethral warming device. Freezing proceeds in an automated manner, using dual freeze–thaw cycles, monitored by ultrasound and thermocouple readings. Cryoablation results in acute swelling of the prostate that typically resolves in 1–2 weeks, during which time a urethral catheter (or a suprapubic tube) provides bladder drainage. After a successful voiding trial, the catheter can be removed. We recommend assessing voiding ability within one week postoperatively as in our experience most patients are able to spontaneously void by that time. The oncologic outcomes of primary prostate cryoablation have been extensively evaluated in both single‐institution and pooled population studies and are presented in Tables 136.1 and 136.2. The reported clinical series suggest that cryoablation of the prostate can achieve acceptable long‐term disease‐free survival rates that are comparable to alternative options such as radical prostatectomy and radiation therapy. However, there have been no prospective trials that can provide more definitive information about the cancer control rates for cryoablation relative to these more established therapies. In addition, the definition of a successful ablation is variable and no specific PSA value has been established as a clear indicator for disease eradication. A pooled analysis of 1111 men demonstrated that 80% achieved a postcryoablation PSA nadir below 0.4 ng/ml. This achievement was then associated with a 90.4% progression‐free survival for low‐risk men, 81% for intermediate‐risk and 73.6% for men with high‐risk malignancy at 5 years [22]. Another pooled analysis demonstrated similar findings, with 14% of men having persistent cancer on a routine postcryoablation prostate biopsy [23]. Finally, cryoablation resulted in a 59.1% biochemical progression‐free survival at 5 years following therapy in men with high Gleason score prostatic cancer, suggesting that this modality is a rational option for some men with high‐risk disease [24]. Table 136.1 Oncologic outcomes of primary cryoablation.
Cryotherapy of the Prostate
Introduction
Cryobiology: general principles
Cryogenic injury
Cryoimmunology
Indications for cryotherapy of the prostate
Salvage cryoablation
Cryoablation procedure: whole‐gland therapy
Outcomes
Oncologic outcomes of primary whole‐gland ablation
Study
No. of patients
Definition
Biochemical disease‐free survival (%)
1 year
3 years
5 years
7 years
Hubosky et al. [39]
89
ASTRO
94
–
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