Quality of Life in Men Treated for Early Prostate Cancer: A Prospective Patient Preference Cohort Study ()
1. Introduction
Men undergoing treatment for early prostate cancer are faced with a decision about which therapeutic option to choose. This is due to the increasing number of available treatments, each with differing side effects. Patients make their decisions following advice from their specialist, which may be biased towards the treatment they offer [1].
PSA testing and screening programmes have changed the profile of prostate cancer, increasing the proportion of patients with early disease at low risk of becoming symptomatic. In this group of patients, with long life expectancy, treatment-related side effects (urinary, bowel and sexual) are of major concern as they can seriously affect quality of life over years. Therefore quality of life after primary definitive treatment is an important outcome as many would contemplate reduction in life expectancy for treatments with fewer side effects [2,3].
The reliability of health-related quality of life (HRQOL) information in localised prostate cancer is compromised because few randomised controlled trials (RCTs) have compared treatments. Many have been attempted but abandoned due to poor accrual [4]. The only RCT comparing radical prostatectomy to watchful waiting reported a modest survival advantage with surgery [5] and HRQOL data showed important differences in urinary and sexual dysfunction between treatment groups. However, treatment choice had little effect on general HRQOL and no pre-treatment data was available [6].
RCTs are currently underway studying screened populations such as the UK based Protect study, which is evaluating survival and HRQOL after radical prostatectomy, external beam radiotherapy and active surveillance. Accrual was improved using qualitative methods [7] and important data will be provided by these studies in the future.
In view of the limited data currently available from RCTs, non-randomised prospective studies can give important information. Several studies have compared HRQOL after different treatments but unfortunately, most do not include pre-treatment data [8-13] and of those that do, pre-treatment data usually does not directly compare all 3 major treatment options [14-16]. A couple of recent non-randomised cohort studies that compared all three treatments with pre-treatment data have not differentiated patients receiving hormone therapy as part of their treatment [17-19]. Patients receiving hormones for their prostate cancer were excluded from our study to remove the confounding variable of hormone treatment on HRQOL. This was done because for the majority of patients in this early stage group, hormone therapy would not be necessary at the time of treatment decision and hormone treatment has its own side effect profile. This study has used a hypofractionated conformal radiotherapy schedule for the CRT option. In recent years hypofractionated schedules for prostate radiotherapy are becoming more popular as increasing evidence from experimental studies show that prostate cancers have a higher sensitivity to fraction size reflected in a low alpha/beta ratio. This centre has used hypofractionated schedule as standard treatment since 1993 and therefore these patients are a unique cohort in this type of study.
After a pilot study where acceptance to randomisation proved problematic, our investigators embarked upon a prospective audit of outcome in men with early prostate cancer. Treatment choice was based on the individual patient’s preference following full counselling by a urologist, clinical oncologist and uro-oncology nurse practitioner. The rationale for this study design was to minimise investigator-related selection bias and produce a more balanced population by comparison with other longitudinal studies. The aims of this report were to assess the impact of treatment side effects for each of the three main treatments for early prostate cancer: radical prostatectomy (RP), conformal hypofractionated radiotherapy (CRT) and brachytherapy (BT), by measurement of generic and disease-specific HRQOL. Importantly, this study evaluated HRQOL in a non-screened population of men typical of uro-oncology centres in the UK and elsewhere.
2. Materials and Methods
2.1. Patients
Patients were recruited prospectively with full ethical committee approval between 1st Dec 1997 and 1st April 2004 from 7 Urological Cancer centres based in the North West of England. Inclusion criteria included:
1) Biopsy confirmed prostate adenocarcinoma
2) Gleason score ≤ 7;
3) Stage T1/T2;
4) PSA ≤ 20;
5) Patient suitable for radical prostatectomy or radiotherapy;
6) No previous malignancy (except non-melanomatous skin cancers);
7) No previous treatments for prostate cancer (except TURP);
8) No previous treatment with hormone manipulation.
All eligible men recruited were counselled by a clinical oncologist and urological surgeon and received information leaflets about treatment options. Participants had a concluding discussion with a trained specialist nurse and were invited to choose their treatment after a period of reflection.
2.2 Treatment Options
2.2.1. Radical Prostatectomy
Surgery consisted of radical retro-pubic prostatectomy in all cases with nerve-sparing where appropriate and/or possible. No adjuvant treatment was given.
2.2.2. Conformal Radiotherapy—Hypo-Fractionated
All patients choosing conformal radiotherapy received photon beams to the prostate with a standard technique in use in this centre since 1993. Patients were treated supine, without formal immobilisation, with an empty bladder. They were treated with a linear accelerator equipped with a multileaf collimator delivered with 8 - 20 MV x-rays with a four-field technique (opposed anterior and posterior and opposed lateral portals). The planning target volume (PTV) was defined as the clinical target volume (CTV) with the addition of a 1 cm margin anteriorly and laterally and 0.7 cm posteriorly. The tumour stage, Gleason score and PSA of each patient determined inclusion of the seminal vesicles with the CTV as per department protocol. A dose of 50 Gy in 16 fractions over 3 weeks was given to the isocentre without neo/adjuvant hormone manipulation.
2.2.3. Brachytherapy
Brachytherapy using transrectal ultrasound guided permanent seed implant became a treatment option in 2000 in our centre. Additional inclusion criteria were
1) prostate volume ≤ 60 ml and
2) International Prostate Symptom Score (IPSS) score < 16 and
3) No previous TURP.
If these criteria were not met, brachytherapy was not offered. After ultrasound assessment of prostate volume, brachytherapy was performed by transrectal ultrasound guided permanent I-125 seed implant. The dose was 145 Gy prescribed to the peripheral margin of the prostate. Patients did not receive supplementary external beam radiotherapy or neo-adjuvant hormone manipulation/downsizing.
2.3. HRQOL Questionnaires
Self-assessment questionnaires were posted to each patient on four occasions. Pre-treatment measurement preceded the patients’ decision on therapy. Post-treatment assessments occurred at 3, 12 and 24 months. Non-respondents were sent a second reminder questionnaire.
Validated questionnaires measured general and disease specific HRQOL. General HRQOL was measured with the RAND 36-Item Short-Form Health survey version 2 (SF36v2) [20]. This contained 36 questions to assess eight aspects of HRQOL. The University of California, Los Angeles Prostate cancer index (UCLA-PCI) measured disease specific HRQOL [21]. The questions assessed bowel, urinary and sexual function and bother. Each question’s score was linearly translated to a score from 0 to 100, and a median score was obtained for each [21].
Stage, PSA and Gleason grade were recorded prospectively. PSA progression was defined by the 1997 American Society for Therapeutic Radiation Oncology criteria for CRT and brachytherapy patients and by the presence of a serum PSA > 0.2 ng/ml for post-radical prostatectomy patients. Data for patients with biochemical or clinical failure were excluded from the point of PSA progression as this was thought to influence HRQOL. In addition, patients receiving hormone manipulation during the follow up period were excluded from the study for the same reason.
2.4. Statistics
Parametric data (e.g. Age and PSA) was analysed using ANOVA followed by Tukey’s multiple comparison test. Non-parametric data (e.g. comparisons between the three treatment groups for HRQOL, baseline stage and Gleason score) were performed using the Kruskal-Wallis test (KW) unless otherwise stated. The Mann-Whitney U-test (MW) was used for inter-group comparison (if the KW test was significant) with a Bonferroni multiple comparison adjustment to preserve the overall significance level. Chi square tests were performed on all proportional data (e.g. response rates and comorbidity). A non-responder analysis was performed to assess baseline differences from those that responded in each treatment group and here T-test were used for age and PSA whereas Mann-Whitney test were used for stage and Gleason grade. Analysis was not adjusted for baseline differences as the aim was to find relationships between treatment choice and baseline differences.
HRQOL scores at 3, 12 and 24 months were compared with pre-treatment quality of life scores to calculate therapy-specific changes in each of the HRQOL domains. Again Kruskall-Wallis test was used to determine treatment effect on the change in HRQOL scores between each time point and pre-treatment assessments.
The 5% significance level was used in all primary tests. Statistical analyses were performed using SPSS version 11.
2.5. Funding
AstraZeneca contributed towards data management for the initial 6 months.
3. Results
3.1. Study Population
Between 1st December 1997 and 1st April 2004, 490 men registered in the quality of life aspect of the study. Patients who received a different treatment to their original choice were excluded from analysis (n = 38) as this may have affected how they perceived the therapy to work and therefore confound the quality of life results related to the treatment. Despite patients being referred to this study if they were seeking active treatment, 22 men chose active monitoring/watchful waiting and therefore these men too were excluded from analysis. The remaining 430 patients chose and received either RP (n = 217), CRT (n = 161) or Brachytherapy (n = 52). Pre-treatment questionnaire responses were obtained from 354 patients (82.3%), 178 (RP), 129 (CRT) and 47 (BT). There was no significant difference in response rates between treatments: RP (82%), CRT (80%) and BT (90%) (p = 0.2381). Patients were counselled by experts in the radical treatment of localised prostate cancer. These comprised of 10 different urological surgeons, 3 clinical oncologists and 14 specialist nurses.
There was no significant difference in baseline characteristics between patients who responded to pre-treatment questionnaires and non-responders. Table 1 summarises the baseline patient characteristics. There was a significant difference in age between the treatment groups (KWp < 0.0005). Inter-group analysis (Bonferroni significance level a = 0.017) showed that compared to RP and BT groups, CRT patients were significantly older. (Between CRT and RP MWp = 0.0002, between CRT and BT MWp < 0.0005). There was no difference in age between the RP and BT patients (MWp = 0.2201).
3.2. Compliance
Table 2 illustrates the compliance to the questionnaires (i.e. the percentage of patients responding to the questionnaire of the patients given follow up questionnaires) and shows the number of eligible questionnaires at each time point, taking into account patients who died and those who had recurrent disease. Brachytherapy patients had better compliance than the other two groups. However, the questionnaire subsection that fell below 85% compliance was the sexual function and bother questions for patients treated with brachytherapy.