The role of cryotherapy in localized prostate cancer treatment: experience at the Hospital Central Sur de Alta Especialidad, PEMEX

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1 ORIGINAL ARTICLE The role of cryotherapy in localized prostate cancer treatment: experience at the Hospital Central Sur de Alta Schroeder-Ugalde Iván Mauricio, 1 Xochipitécatl-Muñoz D. Juan, 2 Castellanos-Hernández Hibert, 3 Cruz-García-Villa Patricio. 1 Abstract Background: Cryotherapy currently offers the patient a minimally invasive treatment option with low morbidity for localized prostate cancer (CaP). In this study we report the results obtained with the use of cryotherapy in the Hospital Central Sur de Alta Especialidad de PEMEX. Material and methods: The case records of all patients operated on with cryotherapy for CaP at the Hospital Central Sur de Alta Especialidad de PEMEX were reviewed. Thirty-four patients were enrolled in the study and 24 of them had post-cryotherapy biopsies. Of those patients, 19 (79.1%) presented with negative biopsies and five (20.8%) were positive. The patients were classified in three groups according to prostate specific antigen (PSA), Gleason score, and clinical stage. Recurrence rates were 44.4%, 27.7%, and 56.1%, in the low, intermediate, and high-risk groups, respectively. Complications included 22 (64.7%) patients with impotency, four (11.8%) with incontinence, three (8.8%) with stricture, and two (5.9%) with tissue sloughing. There was no Resumen Introducción: En la actualidad la crioterapia ofrece al paciente un tratamiento opcional mínimamente invasivo, con baja morbilidad para el tratamiento del cáncer de próstata (CaP) localizado. En este estudio, reportamos los resultados obtenidos con el uso de la crioterapia en este Hospital. Material y métodos: Se revisaron los expedientes de todos los pacientes operados de crioterapia de CaP, en el Hospital Central Sur de Alta Especialidad de PEMEX. Se incluyeron 34 pacientes, de los 24 pacientes con biopsias poscrioterapia, 19 (79.1%) presentaron biopsias negativas y cinco (20.8%) positivas. Se clasificó a los pacientes en tres grupos de riesgo de acuerdo al antígeno prostático específico (APE), Gleason y estadio clínico. Las tasas de recaída fueron de 44.4%, 27.7% y 56.1%, en los grupos de riesgo bajo, intermedio y alto, respectivamente. Dentro de las complicaciones, se encontraron 22 (64.7%) pacientes con impotencia, cuatro (11.8%) con incontinencia, tres (8.8%) con estenosis y dos (5.9%) con esfacelamiento 1 Urology Resident, Hospital Regional Lic. Adolfo López Mateos, Instituto de Seguridad y Servicios Sociales de los Trabajadores del Estado. Mexico City, Mexico. 2 Head of the Urology Service, Hospital Central Sur de Alta. Mexico City, Mexico. 3 Oncologic Urology Resident, Instituto Nacional de Cancerología. Mexico City, Mexico. Corresponding author: Dr. Iván Mauricio Schroeder Ugalde. Universidad 1321, Colonia Florida, C.P México D.F. México. Telephones: (55) / , mau_shueder@ hotmail.com 162

2 statistical significance between groups, but when analyzed separately, Gleason score was a risk factor for biochemical recurrence. However, comparative studies with large case series have yet to be carried out between cryotherapy and radical prostatectomy, and especially with other minimally invasive treatment modalities. Conclusions: There are still many questions in relation to the follow-up of these patients, and prospective studies with long-term follow-up are needed in order to determine their progression. Keywords: Prostate, cryotherapy, localized prostate cancer, Mexico. de tejido. No se encontró significancia estadística por grupos de riesgo, no obstante, el análisis por separado demostró que el Gleason si es un factor de riesgo para la recaída bioquímica. Sin embargo, aún no se han realizado estudios comparativos de series grandes entre crioterapia y prostatectomía radical, sobre todo con otras modalidades de tratamientos mínimamente invasivos. Conclusiones: Aún quedan muchas interrogantes con respecto al seguimiento de estos pacientes. Hacen falta estudios prospectivos con un seguimiento a largo plazo para determinar la evolución de estos pacientes. Palabras clave: Próstata, crioterapia, cáncer de próstata localizado, México. Introduction No treatment has replaced radical prostatectomy as treatment for localized prostate cancer (CaP). This procedure continues to be the criterion standard because other therapeutic options such as hormonal therapy are not curative, and also because not all cancerous cells can be consistently eradicated with radiation or other energy forms. 1 As the years have gone by, surgical technique has been improving, and the morbidity and mortality of this procedure has been considerably reduced. Even so, an effort has been made to find new less invasive procedures offering similar long-term results. In 1996, The American Urological Association (AUA) recognized cryotherapy as a therapeutic option for localized CaP, and no longer as an experimental one. 2 Today, cryotherapy offers the patient a minimally invasive treatment option with low morbidity, minimal blood loss, shorter hospital stay, and a high negative biopsy rate after treatment. 3 This procedure consists of controlled in situ freezing of prostate tissue for the purpose of producing ablation of part or all of the prostate gland so that disease can be eradicated, while at the same time sparing the anatomic integrity of neighboring structures. Current indications for cryotherapy in CaP include: primary treatment of localized CaP, treatment for biochemical failure after prostatectomy or radiotherapy, and local complication control in patients with disseminated disease. 4 Among the complications, erectile dysfunction occurs in close to 80% of patients, urethral sloughing in 3%, incontinence in 4.4%, pelvic pain in 1.4%, and urinary retention in 2%. 5 The aim of this study was to report the results obtained with cryotherapy in patients with localized CaP in the Hospital Central Sur de Alta Especialidad de PEMEX, to analyze the follow-up according to prostate specific antigen (PSA) results, and to carry out a statistical analysis of the risk factors that can affect biochemical recurrence incidence. Methods The case records were reviewed of all the patients operated on with cryotherapy of the prostate due to organ-confined prostate adenocarcinoma diagnosis within the time frame of July 2007 to September 2011 at the Hospital Central Sur de Alta Especialidad de PEMEX. The variables were: age, associated comorbidities, previous PSA, diagnostic Gleason score, clinical stage, prior use of androgen blockade, and hospital stay. Transrectal biopsies of the prostate were carried out on all patients at the twelfth month of follow-up. Patients were classified into three risk groups in accordance with the D Amico criteria for PSA, Gleason score, and clinical stage. The PSA relation to biochemical recurrence was analyzed as a variable using 0.6 ng/ml as the cut-off point. A PSA curve of the patients without recurrence was made using the antigens at three, six, 12, 24, and 36 months. Procedure complications were reported as independent variables. A descriptive analysis of the data was carried out with measures of central tendency and dispersion and percentages. 163

3 Table 1. Clinical characteristics of the total group of patients Variables Patient total Age 64 (52-75) Comorbidities HBP 12 (35.3%) DM 10 (29.4%) Smoking 4 (11.8%) PSA 10.6 (3.4-40) Gleason score 2 1 (2.9%) 3 3 (8.8%) 4 1 (2.9%) 5 2 (5.9%) 6 9 (26.5%) 7 13 (38.2%) 8 2 (5.9%) 9 2 (5.9%) Stage T1C 14 (41.2%) T2A 12 (35.3%) T2B 8 (23.5%) With prior HB 24 (70.6%) Hospital stay 3.03 (2-6) Number of patients 34 HBO: high blood pressure; DM: diabetes mellitus; PSA: prostate specific antigen; HB: hormonal blockade Results Thirty-seven case records were reviewed of patients that underwent cryotherapy. Three of them did not have a follow-up so they were excluded from the study. The mean age of the 34 patients was 64 years, with a range of 52 to 75 years. In regard to comorbidities, 12 patients (35.3%) had high blood pressure (HBP), 10 patients (29.4%) were diabetic, two patients (5.9%) had heart disease, and four patients (11.8%) had a past medical history of intense smoking. The mean PSA was 10.6 ng/ml with a range of 3.4 to 40 ng/ml. One patient (2.9%) had a Gleason score of 2, three patients (8.8%) had a Gleason score of 3, one patient (2.9%) had a Gleason score of 4, two patients (5.9%) had a Gleason score of 5, nine patients (26.5%) had a Gleason score of 6, 13 patients (38.2%) had a Gleason score of 7, two patients (5.9%) had a Gleason score Figure 1. Patient progression with transrectal biopsy of the prostate Patient total with TRBP*: 24 Positive 5 Negative 19 * BTRP: TRBP: Transrectal Biopsy of the Prostate With recurrence 8 With recurrence 3 Negative Biopsy Without recurrence 11 Positive Biopsy Without recurrence 2 of 8, and two patients (5.9%) had a Gleason score of 9. There were 14 patients (41.2%) with a clinical stage of T1C, 12 patients (35.3%) with stage T2A, and eight patients (23.5%) with T2B. Androgen blockade was given to 24 patients prior to surgery and hospital stay was from two to six days, with a mean of 3.03 days (Table 1). Of the 34 patients, 10 still do not have postoperative prostate biopsy. Of the 24 patients with biopsy, 19 (79.1%) had negative biopsy and five (20.8%) had positive biopsy. In relation to overall recurrence of the 34 patients, 21 (61.7%) did not present with recurrence and 13 (38.2%) had recurrence with a mean follow-up of 18.4 months and a range of six to 42 months (Figure 1). A dispersion curve was made using the PSA values at three, six, 12, 24, and 36 months that showed PSA behavior in relation to the length of time of progression (Figure 2). Patients were classified into three risk groups, obtaining different biochemical recurrence rates. In the low-risk group of nine patients, five (55.5%) did not present with recurrence and four (44.4%) had recurrence at 18.2 months (seven to 28-month range). In the intermediate group of 18 patients, 13 (72.2%) did not present with recurrence and five (27.7%) had recurrence 164

4 Figure 2. Prostatic antigen dispersion Table 2. Risk group correlation Variables With recurrence Without recurrence p PSA Low 26.1% (6) 73.9% (17) Intermediate 71.4% (5) 28.6% (2) High 33.3% (1) 66.7% (2) Gleason score Low 50% (8) 50% (8) Intermediate 7.7% (1) 92.3% (12) High 75% (3) 25% (1) Stage Low 46.2% (12) 53.8% (14) Intermediate 12.5% (1) 87.5% (7) at the follow-up at 19.2 months (11 to 27-month range). In the high-risk group of seven patients, three patients (42.8%) did not present with recurrence and four (56.1%) had recurrence at a mean 15.8 months of follow-up (six to 36-month range) (Table 2). In relation to complications, 22 patients (64.7%) presented with impotency, four (11.8%) with incontinence, three (8.8%) with stricture, and two (5.9%) with sloughing (Figure 3). Discussion Cryosurgery has re-emerged as a technological development and a minimally invasive treatment option, whose use has markedly been on the rise in the last decade. It was originally accepted as rescue treatment for local post-radiotherapy failure and today it is being used more often as primary treatment. 6,7 In this case series we present our experience in the use of cryotherapy as primary treatment for localized CaP, with similar results to those reported in the current medical literature. PSA levels may not descend to undetectable levels immediately after cryotherapy, and the nadir generally presents at three months. However, the nadir to expect after cryotherapy is still not known with certainty. There is no established definition for biochemical recurrence after cryotherapy and cut-off points such as 0.3, 0.4, 0.5, and 1.0 ng/ml have been used in different studies. The American Society for Radiation Oncology s definition of biochemical failure of three consecutive elevations has also been used. Based on available data, the nadir is a prognostic factor for biochemical disease-free survival. PSA levels of 0.6 ng/ml or higher have been associated with a significant biochemical failure rate at 24 months, regardless of risk group, and individuals PSA: prostate specific antigen with these levels require strict follow-up. 8 Therefore, for the purpose of this study, biochemical failure was defined using 0.6 ng/ml with a consecutive elevation as the cut-off point. In a comparative study of cryotherapy and radical prostatectomy published by Castillo-De Lira et al. in 2010, they reported the first postoperative PSA values in both groups as a mean of 2.97 ng/ml with a 0 to 20 ng/ml range. In the cryotherapy group of 30 patients, there was a 40% recurrence rate in which recurrence was considered at values above 0.5 ng/ml. 9 These results are similar to those of our case series in which 38.2% of the patients presented with recurrence at 12 months of follow-up. When patients were classified into risk groups, no statistical significance was found in relation to biochemical recurrence. This was similar to that described in the medical literature in which there were disease-free rates of 60% to 92% for the low-risk group, 61% to 89% for the intermediate risk group, and 36% to 89% for the high risk group. 10 With these results, it can be concluded that cryotherapy is equally effective for all risk groups. A larger patient sample would be required to verify whether Gleason score is really a prognostic risk factor for biochemical failure, because even though 75% of the patients in the high risk group presented with biochemical failure, that was only from a total of four patients. Therefore, for the purpose of this and future studies, other factors such as prostate and tumor volumes should be taken into account. Another important consideration is the role the results of post-cryotherapy transrectal biopsies play in biochemical recurrence, and whether a positive 165

5 Figure 3. Late complications 70.0% 60.0% 50.0% 40.0% 30.0% 20.0% 10.0% 0.0% 11.8% 64.7% 8.8% 5.9% Incontinence Erectile Stricture Sloughing Dysfunction result should be considered as biochemical failure, given that two of the five patients with positive biopsy had a nadir of 0.0 ng/ml and at 24 months of followup they continued to have a PSA under 0.6 ng/ml. According to reports in the medical literature, patients with a nadir above 0.5 ng/ml present with a higher incidence of positive biopsies and a greater incidence of biochemical failure, which can be corroborated in our study in the biochemical failure cases, simply due to the fact that a nadir of 0.5 ng/ml is practically considered to be biochemical failure. However, it is not the same for patients with positive biopsy, and even though we observed that these patients tended to have biochemical failure before patients with negative biopsy did, there are no studies in the literature as to whether this result should lead us to have an expectant behavior or to implement another rescue treatment. In regard to complications in this group, we observed an expected incidence compared with a case series of 23 patients from our same hospital, published in the international literature in 2011, in which 87% of the patients presented with impotency, 8.7% with incontinence, and 13% with stricture. 11 This comparison revealed an improvement in morbidity, with a reduced incidence of impotency and stricture in our study. Conclusions Today, cryotherapy is considered to be a treatment option for localized CaP that offers the advantage of being a minimally invasive procedure with low associated morbidity and a low recurrence percentage compared with other treatment modalities. Large case series comparative studies on cryotherapy and radical prostatectomy, the current criterion standard, have yet to be conducted. The same holds true for comparative studies with other minimally invasive treatments, such as brachytherapy. Although cryotherapy has been earning its place in localized CaP treatment, there are still many questions that need to be answered with respect to the follow-up of these patients. Prospective studies with considerable follow-up are necessary in order to determine the progression of these patients. References 1. Wein A. Campbells Urology. In: Stamey TA. Adenocarcinoma of the prostate. 7th Edition. Philadelphia, EUA. Elsevier Saunders Hobosky SG. 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): Wein A. Campbells Urology. In: Richie JP (editor). Cryotherapy of Prostate Cancer. 9th Edition. Philadelphia, EUA. Elsevier Saunders Pontones Moreno JL. 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:S9-S Jones JS, Rewcastle JC, Donnelly BJ, et al. Whole gland primary prostate cryoablation: initial result from the cryo on-line data registry. J Urol 2008;180(2): Han KR, Cohen JK, Miller RJ, et al. Treatment of organ confined prostate cancer with third generation cryosurgery: preliminary multicenter experience. J Urol 2003;170(4 Pt 1): Levy DA, Pisters LL, Jones JS. Primary Cryoablation Nadir Specific Antigen and Biochemical Failure. J Urol 2009;182(3): Castillo-De Lira HH. Efectividad de la crioterapia para el cáncer de próstata confinado en el órgano. Estudio Comparativo. Rev Mex Urol 2010;70(1): Katz AE, Rewcastle JC. The current and potential role of cryoablation as a primary therapy for localized prostate cancer. Curr Oncol Rep 2003;5(3): Xochipitecatl-Muñoz D Juan. Ablación con criocirugía como manejo en cáncer de próstata. Rev Mex Urol 2011;71(2):