SLIDES & TRANSCRIPTS
Saturday, December 6, 2003

Cryotherapy

Jihad Kaouk, M.D.

Now with more interest in nephron sparing surgery, there are several tissue ablative therapies that have been described. Cryotherapy has the most extensive work done on it and studied. Radio frequency ablation has been recently included in the clinical practice.

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Resurgence of visceral cryosurgery came from the improved cryo delivery systems and the superior ultrasounds, and postoperative MRI imaging systems that we have now.

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There are a few landmark studies that helped in the evolution of cryotherapy. Chosey did a report that we need a temperature of minus 19.4 degrees Centigrade to completely achieve a cell death, and this temperature could be achieved at 3.1 millimeter from inside of an ice ball, as presented by Campbell .

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However, tumor cells may be more resistant than normal cells, and may require even lower temperatures, and suggested a minus 40 degrees to achieve a complete job. This minus 40 degrees could be achieved at five to six millimeters inside the ice ball, and this gives us a hint about the surgical margin needed in this procedure.

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Current technology involves one or more probes inserted into the tumor, and rapid cooling by inserting pressurized nitrogen and argon. A core temperature of -180 to -195 degrees Centigrade can be achieved, and this is at the tip of the probe at the center of the ice ball.

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Concerns about dissipating the cold temperature during cryo ablation due to kidney perfusion had been nicely studied by Campbell , and he concluded that renal artery clamping during cryo ablation provides no additional advantage.

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Here I will review the tumoricidal cascade of cryotherapy. Basically we have two main events, the acute and the chronic. In the acute during the freezing, what happens is that the extracellular space will get frozen, causing hypertonicity and shift of fluid from the intracellular to the extracellular compartment. Then the intracellular compartment gets frozen, and this disrupts the organelles and the cell membrane. In a slow thaw cycle following the freezing, what happens is that the extracellular thawing cause hypotonicity, and there would be a shift of fluid inside the cell, and this causes cellular swelling and then cellular rupture.

This is the most important aspect of tumoricidal, and the chronic evidence -- what happens is that there is an intracellular ice formation, causing endothelial cell destruction, and then this causes thrombi and tissue ischemia.

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Here is an animal study that we performed at the clinic. We intentionally formed a large ice ball to include the collecting system in the lower coil in this porcine study.

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Histology documented that at day one, there is necrosis. At day seven there is a complete cell death, and within a month there is resorption of chronic fibrosis scar in place.

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In this same study, you can see the angiogram where the ablated part has no perfusion to it, and more important, you see the collecting system, even if it is involved in the ice ball, it heals by scaring, and there were no urine leaks in any of these animals. Unless you put the probe physically into the collecting system, there will be no leak.

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One advancement for cryotherapy is that this flexible laparoscopic ultrasound probe that makes it feasible to monitor the ice ball by intracorporeal ultrasound during the cryo ablation.

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Here is a 3D simulation of the procedure. In this clip, we will show the procedure, how it is done. It can be done in the retroperitoneal or the transperitoneal approach. This is the direct approach here, where we developed the extraperitoneal space, the retroperitoneal space, using a balloon dissector. We used the direct peritoneal approach for tumors that project posteriorly or posterior lateral. Then if it is anterior we go transperitoneal.

Here is the setting. This is the cryo probe. This is the laparoscope, and this is the ultrasound probe. You will be monitoring the ice ball. This is the edge of the ice ball here, and you can take measurements and insure that you have the good margin, where we intend to have at least half a centimeter of margin on each side of the ice ball. That means you need at least one centimeter extra more than the tumor size. Visually, you can see that the ice ball went beyond the tumor.

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At the Cleveland Clinic now, where we have more than five years follow up, Dr. Andrew McGill started doing cryo ablations in 1997. We have more than 110 cases now, 56 patients, that is 60 tumors, now completed, a minimum of three years. Mean patient age was 65, tumor size 2.3 centimeters, and there were 11 kidneys. Twenty percent of the kidneys were solitary kidneys in this particular group.

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And with minimal blood loss; only one patient had a unit of FFP. We didn't have any significant bleeding in any of the cases. Three hours of operative time and no open conversion.

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The cryo time was 19.5 minutes, temperature was at least -185 degrees, and most of the patients needed one probe, although we used three probes in some of the patients, and the cryo lesion size was 3.6 centimeters.

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Hospital stay was typically overnight, and convalescence takes about two weeks, and there was no effect on their creatinine; it was similar pre-op and post-op.

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There were no urinary fistulae or leaks in any of the cases, and the complications were like a splenic hematoma that appeared ten days later. This is the patient who got the FFP, congestive heart failure, pleural effusion, all treated conservatively with no open conversion in any of them.

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Since we don't have solid data about the surgical margin in this procedure, it is very important to follow them meticulously. What we do here, we do MRIs day one after the procedure, three months, six months, one year and then every year. At six months we get the patient back and do a CT guided biopsy of their ablated area.

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following the patients with MRI, you see the gradual shrinking of the tumor. At three months it is 26 percent, at three years it is 75 percent, and of note, 38 percent of the cryo lesions at three-year MRI were not detectable; they completely disappeared.

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Here is an MRI preoperatively. This is the cryo lesion, and here it is shrinking at three months.

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So 70 percent of these patients came from a CT guided cold biopsy at six months post cryo ablation. We had two renal cell positive biopsies who underwent radical nephrectomies with no local or distant metastasis. Knowing the false negative results of needle biopsies, one should continue following these patients meticulously.

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Here is the histology. This is the pre-op renal cancer, and you can see the extensive fibrosis in the area at the six month biopsy.

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In summary, we have at three years follow up 56 patients who completed a minimum of three years. The cryo lesions decreased by 75 percent, and completely disappeared in 38 percent. We had locally persistent recurrent cancer in only 3.6 percent. Patient survival, 89 percent, cryo ablation specific survival was 100 percent.

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For completion, this procedure is not only done laparoscopically; it has been reported percutaneously. Singleton, Jackson and Zuri do this procedure using an open MRI under general anesthesia, and used two to three millimeter probes. Fifty-five patients reported, and we have no residual tumor in 51 out of the 55. However, seven patients required more than one session of cryo to achieve this result.

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In conclusion, renal cryo ablation is a potentially effective and safe minimally invasive nephron sparing technique for carefully selected cases. Nevertheless, long term results await, and meticulous follow up is very important.

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This is the last slide. For case selection, this is the algorithm we go through. The gold standard for nephron sparing therapy remains open partial nephrectomy, especially for central complex tumors. However, for peripheral smaller tumors, exophytic in a patient who has local morbidity, younger patients, laparoscopic partial nephrectomy is considered. For endophytic high comorbidity, older patient, elevated baseline creatinine, laparoscopic cryo ablation could be done, or percutaneous RFA, as Dr. Walther is going to say.

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Thank you.

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