Comparison of health-related quality of life and prostate-associated symptoms after primary and salvage cryotherapy for prostate cancer
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- Anastasiadis, A.G., Sachdev, R., Salomon, L. et al. J Cancer Res Clin Oncol (2003) 129: 676. doi:10.1007/s00432-003-0472-4
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Recent advances in cryosurgery of the prostate have led to the ability to treat tumors successfully with decreased morbidity. The patients’ perspectives of this relatively new technique, however, have not yet been addressed. The purpose of this study was to compare health related quality of life (QoL) as well as prostate-associated symptoms in patients after primary and salvage cryoablation for clinically localized prostate cancer using a self-administered questionnaire.
A total of 131 consecutive patients who underwent cryoablation of the prostate between 1997 and 2001 were included in this confidential mailing study. The patients were either (a) patients with localized prostate cancer with contraindications for radical surgery, including patients refusing other forms of therapy, or (b) had locally recurrent prostate cancer after failure of radiation therapy. All patients received 3 months of neoadjuvant androgen deprivation therapy prior to cryosurgery and were surgically treated by the same surgeon using an argon-based system. We used the EORTC QLQ-C30, a commonly used, multidimensional instrument together with a supplementing, prostate-cancer-specific module.
Eighty-one of the 131 patients (response rate 62%) returned the questionnaires. The two groups were comparable regarding age (mean age 72.8 vs 70.1 for the primary and the salvage group, respectively; p=0.22). The overall QoL scores were high in both groups. Primary cryotherapy patients fared significantly better regarding physical (p=0.005) and social (p=0.024) functioning compared with salvage cryotherapy patients. The most prominent prostate-related symptom in both patient groups was sexual dysfunction, followed by urinary symptoms, which were significantly more severe in the salvage group (p=0.001). Incontinence rates were 5.9 and 10% in the primary and the salvage group, respectively. Severe erectile dysfunction was reported in 86 and 90% of the primary and the salvage group, respectively.
The present study demonstrates that, in selected patients, cryotherapy is a treatment option which has a functional outcome comparable to traditionally used prostate cancer treatments. More information regarding QoL is necessary for appropriate patient counseling and individual decision-making in the presence of various treatment alternatives.
KeywordsProstate cancerCryotherapyQuality of lifeFunctional resultsSexual dysfunction
According to the latest report of the American Cancer Society, the number of estimated new prostate cancer cases in the U.S. will increase to 220,900 in 2003 (American Cancer Society 2003). Although prostate cancer deaths are decreasing due to earlier diagnosis in men without symptoms, the number of affected men under the age of 65 years has continued to increase (American Cancer Society 2003). These observations demonstrate that the number of prostate cancer survivors is increasing, including younger patients.
Primary treatment of clinically organ-confined prostate cancer includes radical prostatectomy and radiation therapy (external beam radiotherapy and brachytherapy). Unfortunately, both treatment modalities are not optimal in cancer treatment, especially in poorly differentiated tumors, and can result in significant morbidity, adversely affecting the quality of life (QoL) of the patient (Bahn et al. 2002; Moul 1999). After failure of local treatment, options for salvage therapy with curative intent include salvage prostatectomy, salvage cryoablation, and salvage brachytherapy (Chin et al. 2001; Izawa et al. 2002).
Recent reports emphasize the importance of QoL aspects in the evaluation of the efficacy of different treatment modalities (Robinson et al. 2002; Tefilli et al. 1998). This seems especially true for prostate cancer patients in whom improvements of surgical and nonsurgical management, multiple treatment alternatives, early age at diagnosis, and the distress of sexual dysfunction and urinary and bowel problems after treatment all underline the significance of QoL (Robinson et al. 2002; Tefilli et al. 1998).
Cryosurgery as a treatment for localized prostate cancer was first described in the 1960s with initially encouraging outcome (Gonder et al. 1966); however, the technique was subsequently abandoned due to significant morbidity. With the introduction of ultrasound guidance and ultrasound monitoring in prostate surgery, percutaneous cryoablation was reintroduced in 1993, and a number of improvements of the technique have followed (Onik et al. 1993). Technical advances of the procedure, including new cryogenic technologies, a urethral warming device, and thermosensor monitoring, have been shown to decrease morbidity and to improve results (Robinson et al. 2002). The 5-year results are now available, showing promising oncological and functional outcome (Donnelly et al. 2002; Robinson et al. 2002).
We have been performing cryoablation of the prostate using an argon-based system since 1997, and the safety and effectiveness of the procedure has been reported in previous prospective studies (De La Taille et al. 2000a; De La Taille et al. 2000b; Ghafar et al. 2001); however, results in cancer treatment should not only be reported in terms of disease-free survival, but also in terms of treatment side effects and health-related QoL issues, especially when new therapeutic modalities are introduced and have to be compared with existing therapies (Shrader-Bogen et al. 1997).
The information on patient-reported QoL in this patient group is limited. The goal of this cross-sectional questionnaire study was therefore to compare health-related QoL as well as sexual, urinary, and bowel symptoms in patients who underwent either primary or salvage cryotherapy of the prostate after failure of radiation therapy. For this purpose, we used a widely accepted, validated, and reliable instrument, the EORTC QLQ-C30, together with a supplementing, prostate-cancer-specific module.
Materials and methods
The study was initiated after Institutional Review Board approval. Between 1997 and 2001, 131 patients underwent cryoablation of the prostate, either as a primary treatment for localized prostate cancer (n=89) or after radiation therapy failure (n=42). All patients had biopsy-confirmed prostate cancer with no seminal vesicle invasion and all had a negative bone scan. Prior to cryotherapy, patients underwent either a laparoscopic or open lymph node dissection. Only patients without evidence of disease in the lymph nodes were eligible for cryotherapy. All patients received 3 months of combined hormonal therapy before the procedure.
The procedure was performed by a single surgeon (A.E.K.). The technique has been recently described by Ghafar et al. (2001). The CRYOcare system (Endocare, Irvine, Calif.), which applies argon and helium gases to freeze and thaw tissue, was used for all procedures. Cryosurgery was performed under spinal anesthesia. Patients received an enema on the morning of the procedure and 500 mg metronidazole intravenously at the start of the procedure. Under flexible cystoscopic guidance, a 10-F suprapubic catheter was placed and the bladder remained distended. A urethral warming catheter (CMSI, Baltimore, Md.) was inserted before freezing the tissue. The catheter was warmed to 38°C and remained in place for 2 h after the procedure. Before the start of the freezing cycle, six cryoprobes were placed into the prostate under transrectal ultrasound guidance, including two anterior, two posteromedial, and two posterolateral probes. Simultaneously, thermocouple devices or temperature monitor probes were placed adjacent to each of the two neurovascular bundles, the apex, Denonvillier’s space, and the external sphincter. Freezing was initiated by activating the two anterior probes, which was followed by the two posterior probes. A double freeze–thaw technique was applied in all cases. The outer edge of the ice ball had a hyperechoic appearance and was readily visualized on transrectal ultrasound. Freezing was completed when the temperature was less than −40°C at each neurovascular bundle, apical temperature was less than −10°C, and all prostatic tissue appeared to have frozen, as visualized on ultrasound.
Patients were discharged home the following morning. They received 500 mg Ciprofloxacin twice a day for 5 days. The suprapubic tube remained open and patients were instructed to clamp the tube on the fourth postoperative day. The removal of the tube was performed in the office 1 week after the procedure.
Questionnaires were mailed to the 131 above-mentioned patients at least 6 months after cryosurgery. The mailing included a cover letter, an information sheet, the questionnaire, and a postage-paid envelope. The information sheet ensured data confidentiality. The questionnaire included the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 version 3.0 (30 questions; Aaronson et al. 1993) as well as a prostate-cancer-specific module (19 questions; Borghede and Sullivan 1996). The questionnaire included four pages and we estimated that 10 min would be needed to complete the questionnaire. Prior to distributing the QLQ-C30 questionnaires, permission was obtained from the EORTC Data Center in Brussels, Belgium.
The EORTC QLQ-C30 is a widely used, reliable, and validated instrument for measuring QoL in cancer patients. It was designed to be cancer specific, multidimensional in structure, appropriate for self-administration, applicable across a range of cultural settings, and suitable for use with additional site- or treatment-specific modules (Fayers and Bottomley 2002). It has been used in clinical trials, cross-sectional, and longitudinal surveys in over 12,000 patients worldwide, and has been translated into over 40 languages (Fayers and Bottomley 2002). The most recent version, 3.0, was used in the present study.
The QLQ-C30 is composed of both multi-item scales and single-item measures; these include five functional scales (physical functioning, role functioning, emotional functioning, cognitive functioning, and social functioning), three symptom scales (fatigue, nausea and vomiting, and pain), a global health status/QoL scale, and six single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). All of the scales and single item measures range in score from 0 to 100. A high score for a functional scale represents a high/healthy level of functioning and a high score for the health status/QoL represents a high QoL, but a high score for a symptom scale or item represents a high level of symptomatology or problems (Fayers et al. 2001).
In addition to the QLQ-C30, participants received a multidimensional, prostate-cancer-specific, self-administered instrument to supplement the core questionnaire. This supplement has been validated in a single institution (Borghede and Sullivan 1996) and is composed of three scales including sexual function (four items), as well as urinary (five items) and bowel (eight items) symptoms (Appendix 1).
Statistical analysis was performed using a standard statistical software program (SPSS Base 10.0, SPSS Inc., Chicago, Ill.). Student’s t-test was used for comparison of means between the two groups. The p values less than 0.05 were considered statistically significant.
Overall, 81 of the 131 patients returned the questionnaires (62%). The response rate was higher in the salvage group (30 of 42, 71%) compared with the primary treatment group (51 of 89, 57%). The mean age of the respondents treated by primary and salvage cryotherapy was 72.8 and 70.1 years, respectively. The time interval between cryotherapy and the questionnaire was significantly longer in the primary group compared with the salvage group (25.6 vs 11.4 months, respectively; p=0.001).
Traditionally, the evaluation of a cancer treatment has been limited to overall and disease-free survival, local and distant recurrence, and treatment-associated toxicity; however, with improvement of surgical and nonsurgical therapies and increased patient survival in many malignancies, it becomes clear that treatment side effects and health related QoL are important end points in clinical cancer trials (Efficace et al. 2003; Tefilli et al. 1998). Prostate cancer is a good example of a malignancy in which mortality rates are decreasing over the past years, patients are diagnosed at a younger age, and alternative therapeutic options are available (American Cancer Society 2003). When offering different options and informing the patient, physicians should be able to address typical side effects and QoL aspects, allowing a more informed decision.
The main treatment options for localized prostate cancer have included radical prostatectomy and external beam radiotherapy. More recently, novel treatments or modifications have been introduced, including brachytherapy, 3D conformal radiotherapy, thermotherapy, and cryosurgery (Long et al. 2001). Reports on the oncological outcome after cryosurgery have been published elsewhere (Bahn et al. 2002; Chin et al. 2001; De la Taille et al. 2000a; De la Taille et al. 2000b; Donnelly et al. 2002; Ellis 2002; Ghafar et al. 2001; Izawa et al. 2002; Long et al. 2001). Studies on QoL after cryotherapy, however, are still scant in the literature.
Reported studies about QoL using the EORTC QLQ-C30 questionnaire in patients with clinically localized prostate cancer. RRP radical retropubic prostatectomy, RT radiotherapy, QoL GlobalHealth/Quality of Life, PF physical functioning, RF role functioning, EF emotional functioning, CF cognitive functioning, SF social functioning
Mean time after treatment
Borghede and Sullivan (1996)
RT (three-field technique)
Fransson et al. (2001)
RT (4-field technique)
In addition to the QLQ-C30, the patients received a prostate-cancer-specific module, addressing sexual, urinary, and bowel symptoms. Salvage patients had a significantly worse score in urinary symptoms than patients after primary cryotherapy. This is not surprising, since salvage patients already had radiation therapy prior to cryosurgery. As previously mentioned, however, the time interval between treatment and completion of the questionnaire was significantly shorter in the salvage group, and it might be possible that an improvement of urinary function would occur over a longer time period after treatment.
Erectile dysfunction (ED) was a major side effect of cryosurgery. Eighty-six percent of the primary cryotherapy patients and 90% of the salvage patients reported being limited in their ability to have or maintain an erection. The ED rates have been reported to be 90, 93, and 96% after salvage radiation therapy, primary cryosurgery, and salvage prostatectomy, respectively (Long et al. 2001; Tefilli et al. 1998). Although ED seems to be inevitable due to freezing of the apex, including the neurovascular bundles during cryosurgery, nerve regeneration, albeit very slow, is possible after cryotherapy (Donnelly et al. 2002). In a longitudinal study, a slow recovery of erectile function after 36 months was reported in up to 47% of the patients, most of them with the use of sexual aids (Donnelly et al. 2002). One way to approach ED after cryosurgery is the use of “focal nerve-sparing cryosurgery,” in which one neurovascular bundle is spared, as recently proposed by Onik et al. (2002). In their preliminary study, they treated 9 patients with focal, unilateral nerve-sparing cryosurgery. After a mean follow-up of 36 months, all patients had a stable PSA and negative biopsies. Seven of the 9 patients reported to be potent. In their report, the authors have appreciated the problem of multifocality in many prostate cancers and encouraged their patients to undergo repeated biopsies at a stable PSA level. Standardized, validated instruments should be used in future studies to interpret and compare functional results appropriately.
Incontinence, another typical side effect, was reported more frequently by salvage patients, and the question “Are you troubled by leakage of urine?” was answered “Very much” by 5.9% of the primary cryotherapy patients and by 10% of the salvage patients. A previous study about incontinence rates in a retrospective, 5-year, multi-institutional pooled analysis in 975 patients after primary cryotherapy revealed an incontinence rate of 7.5% (Long et al. 2001); however, specific techniques of the cryotechnique (e.g., number of cryoprobes, number of freeze–thaw cycles) varied among different institutions. A recently reported study by Donnelly et al. (2002) in 76 patients revealed an incontinence rate of 1.3%. In another study by Perrotte et al. (1999), this time in 112 salvage patients, some degree of urinary leakage was reported by 72% of the patients. Inconsistency in the definitions of incontinence, the use of non-standardized questionnaires, and differences in the cryotechnique can make the direct comparison of these results problematic.
Despite the reported side effects, the overall QoL and functioning scores in the present population were comparable to traditional prostate cancer therapies; however, patient selection, the cross-sectional nature of the survey of a patient population from a single institution, and missing preoperative data deserve mention. Finally, as mentioned previously, the different time intervals after treatment between the two groups should be taken into consideration when interpreting the presented data.
Recent studies have demonstrated safety and feasibility of cryotherapy for prostate cancer, and first reports regarding oncological and functional outcome show promising results. Technical advances of the cryotechnique have led to significant improvement of treatment-related side effects (e.g., decrease in incontinence rates after the introduction of urethral warming catheters). Further prospective, multi-institutional studies are, however, necessary to add more data on QoL issues and help us in defining the most appropriate therapy for the individual patient.