Patient-Reported Quality of Life in Men with Transurethral Resection of the Prostate Undergoing Proton Therapy for Management of Prostate Cancer

Purpose
We report on quality of life (QOL) and early toxicity among men with prostate cancer who underwent transurethral resection of the prostate (TURP) before proton therapy.


Materials and Methods
Between 2006 and 2010, 1,289 patients were treated definitively with proton therapy for prostate cancer at our institution and enrolled on a prospective outcomes-tracking protocol. Ninety-six of the men had received a TURP before proton therapy, while 1,193 men had not. Baseline comorbidities, medications, expanded prostate index composite (EPIC) score, international prostate symptom score (IPSS), and CTCAE vs.3 toxicity assessment were collected prospectively. The Kaplan-Meier product limit method was used to estimate freedom from toxicity.


Results
Men who had TURP before proton therapy had lower baseline EPIC scores for urinary incontinence, bowel summary, and sexual summary compared with the non-TURP group, but no significant difference in urinary obstructive score was observed. After controlling for baseline scores, there was no significant difference in bowel summary or sexual summary scores between the two groups over time. There were, however, differences for urinary irritation/obstruction scores and urinary incontinence scores favoring those patients who did not have a TURP-like procedure. Toxicity assessment showed that the 2-year and 5-year rates of grade 3 genitourinary toxicity in the pretreatment TURP group were 12.3% and 17.2%, respectively.


Conclusions
Pretreatment TURP was associated with both a high incidence of physician-assessed toxicity and inferior patient-reported QOL scores both before and after proton therapy treatment. Studies investigating QOL and toxicity after specific prostate cancer therapies should stratify patients by pretreatment TURP. Longer follow-up is needed to confirm if these differences ever resolve.


Introduction
There are various approaches to the definitive management of localized prostate cancer, including surgery, brachytherapy, and external-beam radiation therapy. All of these treatments result in favorable long-term survival; therefore, quality of life (QOL) and toxicity from treatment have become important considerations during the decision-making process [1][2][3].
Transurethral resection of the prostate (TURP) or TURP-like procedures are a risk factor that may contribute to the treatment decision for prostate cancer. TURP is a procedure that removes portions of the prostate to relieve urinary obstructive symptoms resulting from prostate enlargement, often due to benign prostatic hyperplasia (BPH). Prior studies suggest that men with prostate cancer who undergo TURP may have a greater likelihood of urinary complications after external-beam radiotherapy than men who do not undergo TURP, with rates of grade 3 gentiourinary (GU) toxicity ranging from as low as 3% [4] to as high as 16% [5]. Despite these findings, patient-reported QOL using validated instruments such as the Expanded Prostate Cancer Index Composite (EPIC) have not been well studied in this cohort of patients.
Proton therapy is an effective therapy for localized prostate cancer because it can deliver high doses of conformal radiation while sparing adjacent structures like the bladder and rectum [6]. Early outcomes studies suggest a minimal (1.9%) rate of grade 3 genitourinary (GU) toxicity after proton therapy in a general prostate cancer population [7]. In men with enlarged prostates treated with proton therapy for prostate cancer, the risk appears to be slightly elevated with a 6.4% risk of late grade 3 GU toxicity [8]. Few data exist, however, regarding the impact of a TURP-like procedure on GU toxicity following treatment with proton therapy. The present study investigates early toxicity and patient-reported QOL outcomes following proton therapy among patients who have undergone TURP or a TURPlike procedure.

Methods and Materials Patients
The medical records of 1,289 patients treated with proton therapy for prostate cancer at our institution between 2006 and 2010 were reviewed in accordance with an institutional review board (IRB)-approved treatment protocol and the Health Insurance Portability and Accountability Act. Patients were included in this analysis if they were treated definitively with proton therapy for prostate cancer. Patients were excluded if they had received radiotherapy as salvage therapy or if their radiotherapy included elective treatment to the pelvic lymph node regions. In total, 1,289 patients were eligible for the study.
Patients who were previously treated for urinary retentive or obstructive symptoms with TURP or a TURP-like procedure, such as transurethral microwave therapy (TUMT), transurethral needle ablation (TUNA), or any type of laser surgery on the prostate, were identified. A total of 96 patients had a TURP or TURP-like procedure prior to proton therapy and the vast majority of these patients had procedures done at outside facilities, requiring record retrieval. Of these, patients who had multiple procedures (13%; n=13) were categorized by the last procedure performed before proton therapy. Most of the patients in the cohort (64%; n=62) had a traditional TURP procedure, some patients had a laser utilized in the procedure (24%; n=23), and a minority of the patients either had a TUMT (7%; n=7) or TUNA (5%; n=5).
All patients had pretreatment work-up consisting of computed tomography (CT) of the pelvis, magnetic resonance imaging (MRI) of the pelvis, a bone scan, and an internal pathology review. Patient-and disease-specific characteristics are listed in Table 1.

Treatment
Our protocol for simulation, treatment planning, and delivery of treatment has previously been reported in detail [7]. Briefly, all patients underwent placement of 3 to 4 visicoil fiducials under transrectal ultrasound guidance by the urology team at our institution. Thirty minutes before simulation, patients voided and then drank 16 oz of water. Patients were simulated supine with a vacuum-locked body mold. Patients underwent CT simulation immediately followed by MRI. The CT and MRI images were fused for treatment planning. Prostate and seminal vesicle targets were contoured by the treating physicians. Normal tissues, including bladder, rectum, and bowel, were manually contoured by dosimetrists. The clinical target volume (CTV) included the prostate only for low-risk patients, and the prostate and proximal 2 cm of seminal vesicles for intermediate-and high-risk patients. The planning target volume (PTV) expansion was 6-8 mm beyond the CTV in the superiorinferior axis and 4-5 mm in the axial plane. Beam angles were selected to optimize target coverage and minimize normal-tissue exposure.

Toxicity
Toxicities were recorded for each patient and scored according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE), version 3.0 [9]. Specific attention was paid to GU toxicities. All patients had toxicity assessed and recorded prior to beginning proton therapy, weekly while undergoing proton therapy, and at 6-month intervals following completion of radiotherapy. For our toxicity analysis, the beginning of proton therapy was considered the start date.

Follow-Up and Observed Outcomes
Follow-up care included a medical history and physical examination at 6-month intervals following treatment. EPIC, version 2.2002 [10] questionnaires were conducted before initiating proton therapy and at 6-month intervals following proton therapy. The EPIC-26 summary and subscales were then calculated and reported using a scale of 0 to 100, with higher scores indicating better outcomes. Prostate-specific antigen (PSA) tests were performed at 3-month intervals following proton therapy. For our QOL analysis, the beginning of proton therapy was considered the start date.

Statistical Analysis
SAS and JMP software were used for all statistical computations (SAS Institute, Cary, NC). A Wilcoxon signed-rank sum test was used to determine whether there was a statistically significant increase or decrease in EPIC scores between baseline and 6 months, 1 year, 2 years, and 3 years after treatment. This same series of scores and timepoints was entered into multiple regressions to adjust the effect of pre-treatment TURP by controlling for the baseline score (continuous), risk, use of hormones, diabetes, and age (< vs >60). Fisher's exact test was performed on select items in the EPIC questionnaire related to urinary incontinence, and urinary irritative/obstructive symptoms were dichotomized to differentiate more specific QOL outcomes over time. The Kaplan-Meier product limit function was used to estimate freedom from posttreatment grade 3 GU toxicity. The log-rank test statistic tested whether baseline characteristics predicted for increased risk of grade 3 GU toxicity among the pretreatment TURP patients. These baseline characteristics included age, use of alpha blockers or alpha reductase inhibitors, diabetes, or androgen deprivation therapy (ADT) use. All p values less than 0.05 were considered statistically significant.

Patients
The cohort of patients who had a pretreatment TURP at baseline was quite different from patients who did not have a TURP. Patients in the TURP cohort were significantly older (median age, 72 vs 66 years of age at the start of treatment), had higher-risk disease, more frequently had diabetes, more frequently used 5-alpha reductase inhibitors (5ARIs), and more frequently received ADT as part of treatment ( Table 1).

Quality of Life
The median follow-up time for administration of the EPIC QOL for the cohort was 5.3 years (range, 0.7 to 7.7 years). QOL EPIC-26 scores at baseline, 6 months, 1 year, 2 years, and 3 years were available for 97%, 89%, 88%, 78%, and 74% of the entire patient cohort and are listed by subscale in Table 2. At baseline, the TURP group already had lower median bowel summary, sexual summary, and urinary incontinence subscales compared to the non-TURP group. The urinary irritation/ obstruction subscale was the only score that was not different at baseline. Within the TURP cohort, time from TURP to start of proton therapy (,1 year vs . 1 year) and type of TURP (TURP vs TURP-like procedure) did not impact baseline QOL scores in a statistically significant manner.
After controlling for baseline scores, there was no significant difference in bowel summary or sexual summary scores between the two groups over time. There were, however, differences for urinary irritation/obstruction scores and urinary incontinence scores favoring those patients who did not have a TURP-like procedure ( Table 2).
Specific answers to questions pertaining to urinary incontinence and obstructive symptoms from the EPIC questionnaire are illustrated in Table 3. In particular, at 2 years following treatment more TURP patients leaked urine more than once daily (25.8% vs 11%), had frequent dribbling or no control (10.6% vs 3.4%), and required 1 or more pads/diapers for urinary leakage (15.2% vs 3.7%). Additionally, more TURP patients had moderate or big problems with dripping or leaking urine (17.2% vs 3.9%), bleeding with urination (4.6% vs 1%), and overall urinary function (21.9% vs 9.6%).

Toxicity
A total of 17 of the 96 patients in the TURP group experienced a grade 3 GU toxicity after proton therapy. The 2-year and 5-year cumulative grade 3 GU toxicity rates were 12.3% and 17.2%, respectively [9]. Some patients experienced multiple toxicities. Six patients required another TURP after treatment. Three patients required a urethral dilation procedure, 4 patients required a temporary catheter, 4 patients required hyperbaric oxygen for hematuria, 3 patients required blood transfusions, and 2 patients required cauterization for hematuria. We evaluated whether time to TURP (<1 year vs. >1 year) or type of TURP (TURP vs. TURP-like procedure) had any impact on toxicity rates. No significant difference in toxicity was seen for time to TURP (p=0.3134) or type of TURP (p=0.5769)

Discussion
This study investigated patient-reported QOL and early toxicity in men with TURP undergoing proton therapy for prostate cancer and found that the patients with a prior TURP-like procedure had worse patient-reported QOL outcomes prior to and following proton therapy compared with patients who did not undergo a TURP.
Although both cohorts of patients were treated with proton therapy at the same institution, there were some important differences among the patients that could have contributed to the differences we observed in several of the QOL outcomes. Importantly, the patients who underwent a TURP were older and more likely to have diabetes. Some evidence suggests that older individuals have a higher risk of bowel problems, and other studies have found that older patients with diabetes are at an increased risk of fecal incontinence compared to patients who do not have diabetes [11][12][13]. These characteristics could explain the baseline differences seen in bowel summary score. The reason for decreased sexual QOL scores at baseline among the patients with a prior TURP-like procedure may be multifactorial as well. In addition to advanced age, evidence suggests that decreased sexual function may be attributable to diabetes or ADT use [14,15]. Use of 5ARIs was also more prevalent among the patients with a prior TURP-like procedure. Adverse events related to sexual dysfunction have been reported in up to 8% of patients taking 5ARIs [16].
Urinary irritation/obstruction was the only subscale that was not lower at baseline in the patients with a TURP-like procedure, likely because the TURP-like procedure improved this specific area of urinary function. However, there were significantly worse urinary irritation/ obstruction symptoms following treatment for the TURP group compared with the non-TURP group. This difference is likely due to the higher risk of urethral stricture for TURP patients undergoing radiation, which could cause these types of symptoms. The difference seen in urinary incontinence score at baseline is probably also attributable to the actual TURP procedure, which carries the risk of urinary incontinence [17]. Additional factors, however, may have also contributed to the baseline difference. Diabetes was more prevalent among patients who had a TURP-like procedure (22%) compared with patients who did not (12.3%; p=.0113). A pooled analysis reports that males with diabetes have a significantly increased risk of urinary incontinence (odds ratio=1.4; CI, 1.1-1.6) [18]. Furthermore, ADT use was higher among the patients who underwent a TURP-like procedure (35.4%) compared with patients who did not (16.1%, p,.0001). Patients who received ADT have been reported as having decreased urinary function in comparison to patients undergoing other treatments, such as prostatectomy or radiation therapy [15]. After controlling for ADT, the patients with a prior TURP-like procedure still showed decreased urinary function compared with the general cohort. Importantly, in the present study, the time to TURP and the type of procedure that was used did not impact urinary incontinence scores.
The findings related to the specific questions in Table 3 showing worse urinary incontinence and urinary irritative/ obstructive symptoms over time are notable and may similarly be related to the effect of radiation on susceptible tissue after a TURP-like procedure. Incontinence related to leakage and dribbling requiring use of pads suggests that radiation may exacerbate inadequate sphincter function for these patients with a prior TURP-like procedure. Patients presenting with a prior TURP-like procedure should be made aware of these specific risks during consultation for proton therapy.
Patients with a prior TURP-like procedure experienced more toxicities than observed in earlier proton therapy studies and required various interventions. Most of these patients who experienced a grade 3 toxicity (n=13) required a subsequent TURP, dilation procedure, or catheterization after proton therapy, suggesting a grade 3 GU obstructive rather than a grade 3 GU incontinent pathology after radiation (interfering with ADL; intervention indicated, such as clamp or collagen injections). It is unclear why radiation has such varying effects on patients who underwent similar procedures, especially when none of the pretreatment factors were associated with grade 3 toxicity.

Conclusion
A history of prior TURP-like procedure was strongly associated with reduced QOL outcomes and a higher reported rate of GU toxicity in patients undergoing definitive treatment with proton therapy for prostate cancer. Realistic expectations regarding QOL and toxicity should be communicated to patients with a history of TURP or a TURP-like procedure during consultation for proton therapy. Additionally, these issues should also be considered in a patient contemplating a TURP-like procedure before definitive treatment of prostate cancer with radiation to relieve obstructive symptoms. These observations may guide development of future studies in this cohort.   Table 2 EPIC composite scores over time for TURP and non-TURP patients.  Table 3 Outcomes for specific EPIC questions over time for the TURP and non-TURP patients.