1. Background
For patients suffering from prostate cancer (PCa), several treatment modalities are available (1-3). An important aspect of counseling patients is to understand the impact of each management option on their quality of life (QoL) (4, 5). Some of these treatments, such as androgen deprivation therapy (ADT) have positive effects on QoL that improve the QoL of patients with moderate to severe voiding dysfunction via decreasing prostate volume and lower urinary tract symptoms (LUTS) (3, 6). Following both radiation therapy (RT) and surgery, LUTS and sexual dysfunction are common (7).
In the field of PCa treatment, when radiotherapy is compared with other treatment modalities, it is of great importance to assess the side effects caused by radiation (8). In comparison with rectal symptoms, post-radiotherapy urinary symptoms affect more patients, particularly with dose escalation, despite the use of more conformal management techniques, thereby drawing much more attention to themselves (9). Risk factors leading to genitourinary (GU) toxicities are not fully understood (10). Currently, there is limited evidence regarding the urinary toxicity of intensity-modulated radiation therapy (IMRT) (11). Urinary symptoms can be influenced by numerous factors, such as dosimetric characteristics and patients' comorbidities, including diabetes mellitus, baseline urinary symptoms, and hypertension (9). On the other hand, urinary symptoms caused by treatment show notable levels of reversibility linked to the contraction of both malignant and benign hypertrophic tissues, which are clinically relevant (12, 13).
In localized PCa subjects treated with brachytherapy, the role of pre-treatment International Prostate Symptom Score (IPSS) in estimating post-treatment urinary morbidities has been widely evaluated (14). Some studies demonstrated that patients, who had a combination of high IPSS before treatment and poor urinary functions, are not the ideal candidates for brachytherapy (15). IPSS was initially utilized as a patient-reported evaluation of benign prostatic hyperplasia symptoms. It benefits from good internal validity. It comprises 7 symptoms, including nocturia, frequency, weak urinary stream, intermittency, incomplete emptying, hesitancy and urgency, and also one QoL due to urinary symptoms (uQoL) question. Each answer is assigned to points from 0 to 5 and the total score can, consequently, range from 0 to 35. The severity of symptoms is, then, divided into 3 categories according to the total score; mild (symptom score less than or equal to 7) moderate (symptom score range 8 - 19), and severe (symptom score range 20 - 35) (16, 17).
2. Objectives
Yet, the pre-treatment IPSS importance and the IPSS time course in the IMRT for PCa, have not been clearly illustrated. The aims of this research were the characterization of the nature and severity of the post-IMRT urinary functions for urinary symptoms of patients with PCa.
3. Methods
3.1. Patients
A total of 127 consecutive cases with clinically-localized PCa (cT1c-cT2c), who underwent IMRT from 2016 to 2019 were enrolled in this prospective study. All subjects received neoadjuvant hormonal therapy.
3.2. Inclusion and Exclusion Criteria
Patients who previously underwent prostatectomy or brachytherapy, intra-prostatic calcification of more than 1 cm, or concomitant anal stricture were excluded from the study.
Eligible patients had newly diagnosed, biopsy-proven with minimum 12-month potential follow-up, untreated, and non-metastatic PCa. No patient underwent transurethral resection of the prostate before IMRT.
3.3. Study Endpoint
Study endpoints included IPSS, urinary toxicities in their early and late forms, prostate-specific antigen (PSA) response, and measures based on sexual function questionnaires.
3.4. Follow-up and IPSS Assessment
IPSSs at baseline, and at 1, 6, and 12 months after IMRT were evaluated. In each follow-up session, medical history and physical examination, PSA values, IPSS, Q max, acute, late toxicity scores according to Radiation Therapy Oncology Group (RTOG), and medication use were accumulated. Late GU toxicities were defined as toxicities recorded 90 days after the last radiotherapy session. The use of alpha-antagonists was documented at each visit.
An increase in IPSS ≥ 12 points was defined as the "obvious deterioration" of LUTS (ODL) (18). This definition is based on the rationale and an increase in IPSS ≥ 12 points during 3 months brings the patients with mild or intermediate levels to the verge of higher IPSS levels.
3.5. Radiation Therapy
Varian Clinac 600C (Varian Inc., California, USA) was utilized to deliver radiotherapy by using an X-ray beam of 6 MV. Using a 9-field technique, patients with localized PCa, who were definitive RT candidates, received hypofractionated (70.2 Gy, 2.7 Gy/fraction) IMRT (19). In these patients, the entire prostate gland and seminal vesicles were defined as clinical target volume (CTV). The extension of CTV of 0.6 cm posteriorly and 1 cm in all other directions was considered planning target volume (20). Three gold fiducial markers were implanted for daily inter-fraction guidance, at least 1 week before simulation. Co-registration with pelvic MRI was done for all patients. The daily setup was verified by an electronic portal imaging device (EPID). Treatment planning was performed, using the Eclipse treatment planning system (Varian Medical System).
All patients discharged urine and, then, drank 250 cc water 1 hour before the CT scan and each treatment (21). Special regimens were given to patients for bowel preparation (22).
Treatment was designed according to a treatment planning; supine positioned CT scan with 3 mm slice thickness.
3.6. Statistics
The effects of subject characteristics and management parameters on the IPSS difference between baseline and 12 months after intervention were analyzed by the Mann-Whitney U test and the multiple linear regression models. Sample medians and ranges were used to describe continuous variables. The Friedman test was used to detect the changes of IPSS from baseline to 12 months after IMRT. The level of statistical significance was set at P < 0.05.
3.7. Ethics
The Ethics Committee of Shahid Beheshti University of Medical Sciences approved the protocol of this study. All the patients were informed of the scientific nature of the study and written informed consent was obtained from all subjects.
4. Results
Baseline characteristics of patient and disease are illustrated in Table 1.
Table 1.Baseline Patient Characteristics
| Parameter | Mean ± SD | Percentage |
|---|---|---|
| Age (y/o) | 71.04 ± 7.1 | |
| Min | 55 y/o | |
| Max | 87 y/o | |
| Median prostate volume (mL) | 38.2 ± 12.1 | |
| Min | 20 | |
| Max | 60 | |
| Bladder volume (mL) | 280.07 ± 54.2 | |
| Min | 160 | |
| Max | 430 | |
| BMI (kg/cm2) | 27.1 ± 4.7 | |
| Min | 19.9 | |
| Max | 37.4 | |
| Gleason sum | 7.1 ± 0.9 | |
| Clinical T stage | ||
| T1 - T2 | 84 | 66.1 |
| T3 - T4 | 43 | 33.9 |
| Risk groups (D’Amico’s) | ||
| Low | 68 | 53.5 |
| Intermediate | 35 | 27.5 |
| High | 24 | 19 |
The IPSS average was the highest at baseline (14.5 ± 6.8). The mean QoL score and IPSS for the entire cohort trend in follow-up visits showed a statistical difference compared with baseline. The mean IPSS score of patients in pretreatment, 3, 6, and 12 months after IMRT were shown in Table 2.
Table 2.The Mean PSA, IPSS, IIEF, and Q Max in Cohort Trend
| Variable | Baseline | 1 Month | 6 Months | 12 Months | P Value |
|---|---|---|---|---|---|
| PSA (ng/dL) | 10 ± 3.2 | 3 ± 1.4 | 0.9 ± 0.8 | 0.2 ± 0.5 | 0.00 |
| IPSS | 13.3 ± 6.1 | 14.5 ± 6.8 | 12.3 ± 5.3 | 10.4 ± 4.2 | 0.00 |
| IPSS QOL | 3.2 ± 1.6 | 2.8 ± 1.2 | 2.5 ± 1 | 1.9 ± 0.7 | 0.01 |
| IPSS i | 7.2 ± 3.4 | 7.4 ± 3.6 | 6.7 ± 3.2 | 5.3 ± 2.3 | 0.00 |
| IPSS o | 6.1 ± 3 | 7.1 ± 3.5 | 5.6 ± 2.3 | 5.1 ± 2 | 0.005 |
| IIEF | 12.7 ± 3.9 | 12.2 ± 3.2 | 13.4 ± 3.6 | 14.5 ± 3.2 | 0.00 |
| Q Max | 15 ± 6.5 | 15.6 ± 5.5 | 18.2 ± 5.2 | 20 ± 4.8 | 0.00 |
Abbreviations: IPSS i, Irritative IPSS; IPSS o, Obstructive IPSS; IIEF, International Index of Erectile Function.
During IMRT, 31 patients (24.4%) started GU medications (alpha-blockers). Of 18 patients (14.1%), who had shown acute Grade 2 urinary toxicity, most of the manifested symptoms were comprised of urinary frequency and dysuria.
5. Discussion
Urinary function, sexual function, and PSA response to treatment play significant roles in the management of post-RT prostate cancer patients (18). In PCa patients, urinary symptoms following radiotherapy are drawing much more attention in comparison with rectal symptoms as they affect more patients (23).
Consistent with previous studies, baseline symptoms had the strongest predictive value for frequency and incontinence (24). In evaluating the radiotherapy effects, some conditions are almost exclusive to urinary symptoms. The LUTS are sometimes unclear from symptoms related to management, and their prevalence is rising with age (25).
In IMRT, for better bladder tolerance, strictly conformal-dynamic techniques of radiotherapy with precise fiducial-based positioning, which are limited exclusively to the prostate gland, may be beneficial (26).
The results of this study proposed a negligible impact on patients’ QoL due to high-dose radiation therapy for PCa. Similar to other studies, decreasing symptoms of endpoints is potentially related to the amelioration of the symptoms after radiotherapy treatment (9, 14, 27).
A study of 368 patients concerning urinary outcomes from Chicago Hospital, who were mainly treated with IMRT with a median dose of 75.6 Gy, showed median IPSS alterations from first to final follow-up worsened by 1 point and improved by 2 and 11 points in patients with mild, moderate, and severe baseline IPSS, respectively (14). A report from Nagoya of 216 subjects treated with IMRT to 74-78 Gy presents comparable outcomes at 2 years with mean IPSS alterations of +1.6, 2.9, and 10.3 from baseline in patients with mild, moderate, and severe baseline IPSS, respectively (10).
A proper assessment of dose-volume GU toxicity depends on the accurate bladder filling between CT simulation and irradiation (10). In the present investigation, all cases discharged urine approximately 1 hour before IMRT and CT simulation; they also defecated every morning when possible. These measures were considered to minimize the effects of variations in the prostate shape and anatomical location.
Some studies have shown acute deterioration of QoL and urinary symptoms based on IPSS (28) that improved within 1 to 2 years after the treatment (29, 30). A study conducted in the Memorial Sloan Kettering Cancer Centre (MSKCC) utilizing IPSS and CTCAE reported urinary outcomes in 268 subjects and showed a decline in dose-escalated IMRT/IGRT (29). In line with the aforementioned study, this cohort study showed improvement in post-treatment median IPSS over time. However, there are differences in sample size, the total dose of radiotherapy, as well as the difference in the dosage of each treatment session, and bladder filling radiotherapy between the present and the MSKCC study.
Over time, the urinary symptom may improve due to the following mechanisms: (1) Using GU medications, (2) Disease burden reduction, (3) Neo-adjuvant RT and/or ADT causing prostate cytoreduction, and (4) patient bias (14, 31).
The most important limitation of this research is the small sample size of the study. Short-term follow-up and the lack of prostate size measurement during the treatment period are other limitations.
5.1. Conclusions
The findings of this study demonstrate that this procedure is safe concerning LUT function. Also, it shows that the majority of GU side effects after primary IMRT for prostate cancer are transient. A rapid increase was observed regarding urinary symptoms peaked at 1 month after IMRT. In most patients in the course of 6 months, symptoms returned to baseline.
The risk of acute urinary retention that was resulted in catheterization was low, although delayed deterioration in obstructive symptoms was common and mostly transient. Factors thought to have an impact on the IPSS changes include GU medications, baseline IPSS, Age, and prostate tumor burden.
