Cryotherapy effectiveness in organ-confined prostate cancer: a comparative study

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1 ORIGINAL ARTICLE Cryotherapy effectiveness in organ-confined prostate cancer: a comparative study Castillo-de Lira HH, 1 Venegas-Ocampo PJ, 1 Robles-Scott MA., 1 Gutiérrez-Ochoa J, 1 Landa-Soler M, 1 Xochipiltécatl-Muñoz JD. 2 ABSTRACT RESUMEN Objective: To evaluate cryotherapy as a safe and valid treatment alternative equivalent to radical prostatectomy in localized prostate cancer management. Materials and methods: A clinical retrospective study was carried out in which 60 case records from the years of patients diagnosed with localized prostate cancer who underwent cryotherapy (30 patients) or radical prostatectomy (30 patients) were reviewed. The following variables were analyzed: age, Gleason grade, clinical stage, prostate volume, prostate specific antigen (PSA) levels, surgery duration, bleeding, hospital stay and Results: In the cryotherapy group, surgery duration was a mean 3.5 hours, bleeding was between ml with a mean 51 ml and hospital stay was a mean 4.13 days. In the radical prostatectomy group, surgery duration was 3.90 hours, bleeding was from ,500 ml with a mean 2680 ml and hospital stay was a mean 5.07 days. Complications presented in 100% of patients that underwent cryotherapy, the most frequent of which was perineal ecchymosis. In the radical prostatectomy group complications presented in 30% of patients. Conclusions: The advantages of cryotherapy over radical prostatectomy are reduced blood loss and less Objetivo: Evaluar a la crioterapia como un tratamiento alternativo válido, seguro y probablemente equivalente a la prostatectomía radical para el manejo del cáncer de próstata localizado. Material y métodos: Se realizó un estudio clínico retrospectivo con revisión de 60 expedientes de pacientes con diagnóstico de cáncer de próstata localizado sometidos a crioterapia (30 pacientes) o prostatectomía radical (30 pacientes) durante el periodo de enero de 2006 a enero de 2009 y luego se analizaron variables como edad, grado de Gleason, estadio clínico, volumen prostático, niveles de antígeno prostático, tiempo quirúrgico, sangrado, estancia hospitalaria y complicaciones. Resultados: El tiempo quirúrgico en el grupo de crioterapia tuvo una media de 3.5 h y en el grupo de prostatectomía radical, de 3.9 h. El sangrado del grupo de crioterapia tuvo valores entre 30 y 100 ml con una media de 51 y el grupo de prostatectomía radical de entre 800 y ml con una media de Asimismo, la estancia hospitalaria del grupo de crioterapia tuvo una media de 4.13 días y el grupo de prostatectomía radical de Las complicaciones se presentaron en 100% de los pacientes sometidos a crioterapia, de las cuales la más frecuente fue la equimosis perineal en comparación con la prostatectomía radical, donde las complicaciones se presentaron en 30% de los pacientes. 1 Urology Division, Lic. Adólfo López Mateos Regional Hospital ISSSTE, Mexico City 2 Urology Division, Hospital Central Sur de Alta Especialidad PEMEX Picacho, Mexico City Corresponding author: Dr. Hervey Humberto Castillo de Lira. Avenida Cuauhtémoc 919, Interior 201, Colonia Narvarte Poniente, Delegación Benito Juárez. México, D. F. Telephone: castillodelira@hotmail.com. 6

2 serious complications during and after the procedure. Adequate patient selection is necessary for both procedures in order to choose the most appropriate and effective treatment and consequently obtain better results for each patient. Key words: prostate cancer, cryotherapy, radical prostatectomy, prostate antigen. Conclusiones: Las ventajas de la crioterapia con respecto a la prostatectomía radical son una menor pérdida sanguínea, así como que las complicaciones son de un carácter menor durante y después de la realización de este procedimiento. Es necesaria una adecuada selección de los pacientes sometidos a cualquiera de ambos procedimientos con el fin de obtener los mejores resultados y seleccionar el tratamiento más apropiado y efectivo para cada uno de los pacientes. Palabras clave: cáncer de próstata, crioterapia, prostatectomía radical, antígeno prostático, México. INTRODUCTION Prostate cancer (CaP) is the most common noncutaneous cancer and is the second cause of death from cancer in men in the United States. 1 CaP prevalence increases with age. 2 The wide use of CaP monitoring with prostate specific antigen (PSA) and digital rectal examination (DRE) has allowed for early detection, finding localized disease in 90% of cases. 1 Radical prostatectomy consists of complete removal of the prostate gland and the seminal vesicles and usually includes modified dissection of the pelvic lymph nodes. 3 No treatment has replaced radical prostatectomy and it continues to be the gold standard due to the fact that hormonal therapy and chemotherapy are not curative and that not all cancerous cells can be consistently eradicated by radiation and other energy forms. 1 The ideal candidate for radical prostatectomy is a healthy patient with no comorbidities, with disease localized in the prostate and with a life expectancy of at least 10 years. The principal advantage of radical prostatectomy is that it offers the possibility of cure with minimal collateral damage to surrounding tissues and in addition it enables more adequate staging through surgical specimen examination. 1 The main disadvantages of radical prostatectomy are the need for hospitalization and recuperation period, the possibility of incomplete tumor resection and the risk of erectile dysfunction and urinary incontinence. 3,4 The overall percentage of early complications after radical prostatectomy in the hands of an experienced surgeon is less than 10%. 1 Early complications include hemorrhage, urinary fistula, rectal, vascular, ureteral or nerve damage, thromboembolic or cardiovascular events, lymphocele or problems with surgical wound. 1 The most common late complications are erectile dysfunction, urinary incontinence and urethral stricture. 3 Free-from-disease survival expectancy with radical prostatectomy varies from 80-88% for 5 years and 69-75% for 10 years. 5 In 1996 cryoablation of the prostate was recognized as a CaP treatment option by the American Urological Association (AUA) and stopped being considered experimental. 6 Prostatic cryosurgery consists of controlled in situ freezing of prostatic tissue for the purpose of ablating part or all of the prostate gland, eliminating the disease while at the same time conserving the anatomical integrity of the neighboring structures. 7 The destructive effects of cryosurgery can be grouped to include two mechanisms: cellular damage and vascular damage. 8 Transrectal ultrasound cryotherapy of the prostate can be carried out through the transperineal percutaneous placement of multiple small-caliber cryocatheters. The extent of the freezing can be controlled with precision through thermal devices. Prostatic and neighboring tissue destruction can be visualized in real time and urethral effacement is avoided through the use of urethral heaters. 7 Present indications for cryosurgery in CaP include: primary localized CaP treatment, post-prostatectomy or post-radiotherapy biochemical failure treatment and local complication control in patients with disseminated disease. 7 7

3 Erectile dysfunction occurs in almost 80% of patients, urethral effacement in 3%, incontinence in 4.4%, pelvic pain in 1.4% and urinary retention in 2%. 8 Less than 0.2% of patients develop urethrorectal fistula and close to 5% of patients require transurethral resection due to the presence of infravesical obstruction. 9,10 Cryotherapy offers the patient a minimally invasive treatment with low morbidity, minimal blood loss, short hospital stay and high indices of negative posttreatment biopsies. 11 MATERIALS AND METHODS STUDY GROUP Thirty male patients diagnosed with organ-confined CaP at the Hospital Central Sur de Alta Especialidad PEMEX Picacho who underwent cryotherapy and 30 male patients diagnosed with histopathological organ-confined CaP at the Hospital Lic. Adolfo López Mateos del ISSSTE who underwent radical prostatectomy were included in the study. The patients were stratified into 3 groups: low, intermediate and high parameters prior to procedure including prostate specific antigen (PSA) levels, clinical stage and Gleason grade. Low risk: (T1a-T2a, N0, M0) Gleason 6 or PSA < 10 ng/ml Intermediate risk: (T2b, N0, M0) Gleason of 7 or PSA ng/ml High risk: T2c, Gleason > 7 or PSA > 20 ng/ml Treatment success was defined as attaining a PSA nadir 0.5 ng/ml. A basic retrospective clinical study was carried out in which 60 case records were reviewed. Statistical analysis was done using the Windows SPSS 15.0 program and the following variables were evaluated: age, Gleason grade, clinical stage, prostate volume, PSA levels, surgery duration, bleeding, hospital stay and Inclusion criteria: Male patients between the ages of 50 and 70 years with histopathological organ-confined CaP diagnosis, no evidence of metastatic disease and patients with clinical data of localized disease. Exclusion criteria: Male patients who did not fit the age category of years, patients histopathologically diagnosed with non-organ-confined CaP and patients with evidence of metastatic disease and with clinical data of non-localized disease. RESULTS A total of 60 patients diagnosed with organ-confined CaP were included in the study. Thirty of those patients underwent cryotherapy and another 30 underwent radical prostatectomy. The parameters analyzed were: age, Gleason grade, clinical stage, prostate volume, PSA levels, surgery duration, bleeding, hospital stay and In the cryotherapy group (Group 1) age was from years with a mean years and in the radical prostatectomy group (Group 2) age was from years with a mean years (Tables 1 and 2). Prostate volume in Group 1 was from grams with a mean grams and in Group 2 was from grams with a mean grams (Tables 1 and 2). Initial PSA levels in Group 1 were between 5.40 and 40 ng/ml with a mean ng/ml and PSA values after treatment were from 0 to 20 ng/ml with a mean 2.97 ng/ml (Tables 1 and 2). In Group 2 initial PSA levels were between 3 and 56.7ng/mL with a mean ng/ml and after treatment were between 0 and 1.5 ng/ml with a mean ng/ml (Tables 1 and 2). Surgery duration in Group 1 varied from 3-5 hours with a mean 3.5 hours and in Group 2 from 3-5 hours with a mean 3.90 hours (Tables 1 and 2). Bleeding in Group 1 was between 30 and 100 ml with a mean 51 ml and in Group 2 between 800 and ml with a mean 2680 ml. Hospital stay in Group 1 was from 3-7 days with a mean 4.13 days and in Group 2 from 4-8 days with a mean 5.07 days (Tables 1 and 2). In Group 1, 14 patients (23.3%) had a Gleason grade between 6 and 7 and 2 patients (6.7%) had a Gleason grade of 4. In Group 2, 10 patients (33.3%) presented with a Gleason grade of 6, 7 patients (23.3%) had a Gleason grade of 7, 6 patients (20%) had a Gleason grade of 4, 5 patients (16.7%) had a grade of 7, 1 patient (3.3%) had a grade of 3 and 1 patient (3.3%) had a grade of 8. In Group 1, 24 patients (80%) presented with stage T1c N0 M0, 3 patients (10%) with stage T2a N0 M0 and 3 patients (10%) with stage T2b N0 M0. In Group 2, 25 patients (83.3%) had stage T1c N0 M0, 4 patients (13.3%) had stage T2b N0 M0 and 1 patient (3.3%) had stage T2c N0 M0. In Group 1, 12 patients (40%) were in the intermediate risk group, 10 (33.3%) were in the low risk group and 8 (26.7%) were in the high risk group. In Group 2, 15 patients (50%) were in the low risk group, 13 patients (43.3%) were in the intermediate risk group and 2 patients (6.7%) were in the high risk group. 8

4 Table 1. Statistical characteristics of prostatectomy with cryother Standar N Minimum Maximum Mean Asymmetry Kurtosis deviation AGE Volume Initial PSA PSA nadir Surgery duration Bleeding Hospital stay Valid N (according to list) 30 Table 2. Statistical characteristics of radical prostatectomy group N Minimum Maximum Mean Standar deviation Asymmetry Kurtosis AGE Volume Initial PSA PSA nadir Surgery duration Bleeding Hospital stay Valid N (according to list) 30 Complications presented in 100% of patients in Group 1. The most common was perineal ecchymosis in 19 patients (83.3%) and 11 patients (36.7%) presented with 2 or more procedure-related In Group 2, 30% of patients presented with Impotence was the most frequent complication and presented in 5 patients (16.7%) followed by urinary incontinence in 2 patients (6.7%) and by hypovolemic shock requiring intensive care in 2 patients (6.7%). DISCUSSION In both groups studied age was within the range of life expectancy above 10 years. The majority of patients were under 65 years of age, underlining the importance of an effective curative procedure in an effort to completely eradicate pathology in these patients presenting with localized disease. One of the limitations of cryotherapy in CaP management has been gland volume. The freezingdefreezing cycle has been observed to be more effective in small prostates than in large ones. In the present study the majority of prostates had a similar volume and did not vary between groups. In the postoperative control, treatment response in relation to low PSA levels showed that response was more favorable in Group 2 with only 2 patients with levels above 0.5 ng/ml. In Group 1, 12 patients presented with biochemical failure, in other words, PSA levels were above 0.5 ng/ml. The above could be related to the fact that 26.7% of patients selected for cryotherapy were in the 9

5 high risk group compared with 6.7% in the radical prostatectomy group. One of the points to be stressed is the fact that 100% of CT patients presented with some type of postoperative complication while only 30% of patients in the RP group did. This could be due to the variables that were selected as It should be pointed out that even though the cryotherapy group presented with a higher percentage of complications, the majority of the complications were minor, such as perineal ecchymosis. In contrast two patients in the radical prostatectomy group had to be admitted to the intensive care service because of complications during surgical procedure. An advantage of cryotherapy is minimal blood loss during the procedure with a mean 51 ml. During radical prostatectomy mean blood loss was 2680 ml and hemoderivative transfusion was imperative. In regard to surgery duration no significant difference was observed between the two procedures when taking cryotherapy learning curve and surgeon s skill into consideration. With respect to hospital stay, cryotherapy patients required a shorter time with a mean 4.13 days compared with a mean 5.07 days for radical prostatectomy patients. CONCLUSIONS Radical prostatectomy continues to be the treatment of choice in organ-confined prostate cancer in adequately selected patients. Random studies with adequate sample size and inferred statistical analysis are required for comparing both techniques and hopefully will continue to be carried out. In the hands of the experienced surgeon, morbidity and mortality in radical prostatectomy are greatly reduced and therefore, even though it is considered major surgery, complication indices are low. A learning curve is necessary for a procedure such as cryotherapy as well as experience in transrectal ultrasound in order to have a higher success rate using this procedure. The advantages of cryotherapy over radical prostatectomy are less blood loss and consequent hemoderivative use and less serious complications during and after surgery. Adequate patient selection for both procedures with individual risk assignation for each patient is necessary in order to obtain the best results and to select the most appropriate treatment for each patient. BIBLIOGRAPHY 1. Thomas A. Stamey, John E Mc-Neal. Adenocarcinoma of the prostate. Elsevier. Philadelphia, PA, EUA. Campbell s Urology 7th Edition. 2007;(Cap. 29): Eggener SE, Scardino PT, Carroll PR. Focal therapy for localized prostate cancer: a critical appraisal of rationale and modalities. J Urol 2007;178(6): Richie JP, D Amico AV. Prostate Cancer. Urologic oncology. Elsevier Saunders. 8th Edition 2005;(Cap. 26): Johansen TE. Crioterapia prostática como tratamiento primario en pacientes con cáncer de próstata. Actas Urol Esp 2007;31(6): Speight JL, Roach M. New techniques and management options for localized prostate cancer. Rev Urol 2006;8(Suppl 2):S Hubosky SG, Fabrizio MD. Single center experience with third-generation cryosurgery for management of organ-confined prostate cancer: critical evaluation of short-term outcomes, complications, and patient quality of life. J Endourol 2007;21(12): Pontones Moreno JL, Morera Martínez JF, Vera Donoso CD. Criocirugía en el tratamiento del cáncer de próstata. Actas Urol Esp 2007;31(3): Theodorescu D. Cancer cryotherapy: evolution and biology. Rev Urol 2004;6(Suppl 4):S Pisters LL, Rewcastle JC, Donnelly BJ, Lugnani FM, Katz AE, Jones JS. Salvage prostate cryoablation: initial results from the cryo on-line data registry. J Urol 2008;180(2): Aus G, Abbou CC, Bolla M, Heidenreich A. Guidelines on prostate cancer, European Association of Urology, Guidelines Milán, Italia Richie JP, D Amico AV. Cryotherapy of Prostate Cancer. Elsevier. Philadelphia, PA. EUA. Campbell s Urology. 9th Edition 2007;(Cap. 101): Jones JS, Rewcastle JC, Donnelly BJ. Whole gland primary prostate cryoablation: initial results from the cryo on-line data registry. J Urol 2008;180(2):