Comparison of Physician-recorded Toxicities and Patient-reported Outcomes of Five Different Radiotherapy Methods for Prostate Cancer

Patients and Methods

Patients. Medical records of non-metastatic prostate cancer (cT1-T4, N0, M0) patients from four institutions were reviewed retrospectively between 2005 and 2018. In this study, patients aged ≥20 years who were treated with either BT or EBRT were included. The exclusion criteria were as follows: patients treated with palliative intent, those who received EBRT using three-dimensional conformal radiation therapy, those who received elective pelvic radiotherapy, those who received a combination of BT and EBRT, and those with a short follow-up (<1 year). Finally, a total of 496 patients were included. Patients were classified into risk groups according to the National Comprehensive Cancer Network guidelines (3). Radiotherapy alone was offered to low-risk patients (clinical stage T1-T2a, prostate-specific antigen [PSA] <10 ng/ml, and Gleason score of 6). In contrast, intermediate- to high-risk patients received neoadjuvant/adjuvant androgen deprivation therapy (ADT). ADT included luteinising hormone-releasing hormone agonists and/or anti-androgen, and it was used for longer periods in high-risk patients. This study was approved by the appropriate institutional review board, and the need for informed consent was waived.

Radiotherapy. Patients were treated with one of the following five radiotherapy methods in the four institutions: HDR-BT, LDR-BT, CFRT, MHRT, or UHRT. Patients in the EBRT group were treated with a linear accelerator or CyberKnife (Accuray Inc., Sunnyvale, CA, USA). Details of the radiotherapy methods are as follows.

HDR-BT. HDR-BT was performed as monotherapy using an HDR Iridium-192 source with 370 GBq (10 Ci) activity. A total of 49 Gy in 7 fx was delivered over four days. Treatment was accomplished within one implant session under continuous epidural anesthesia, and irradiation was administered twice daily with an interval of at least six hours. Needle insertion was performed under transrectal ultrasound guidance; however, the treatment planning was based on computed tomography (CT). The clinical target volume (CTV) included the whole prostate gland and medial seminal vesicles with a 0- to 5-mm margin except for a 0- to 3-mm margin for the rectal side.

In most cases, the planning target volume (PTV) equalled CTV, and the prescribed dose was delivered to 95% of the PTV (D95). Dose constraints for organs at risk were as follows: the maximum dose to the entire urethra should be <125% of the prescription dose, preferably <110%, and the maximum dose to the entire rectal mucosa should be <100% PD dose, preferably <80%. The dose–volume constraint for the rectum was D5cc <55% of the prescription dose.

LDR-BT. LDR-BT was performed as monotherapy using I-125 seeds with mostly 13.1 MBq (0.35 mCi) activity. The prescribed dose was 145 Gy. All patients underwent transrectal ultrasound preplanning 3-4 weeks before implantation to determine the number of seeds. Then, the actual implant was performed according to intraoperative planning under general anaesthesia. The CTV was defined as the prostate itself, which was also equal to the PTV. VariSeed 7.1 (Varian Medical Systems, Palo Alto, CA, USA) was used as the treatment planning system. The percent volumes of the PTV receiving 100% of the prescribed dose (V100%) were planned to be ≥95%, preferably ≥99%. Dose constraints for organs at risk were as follows: V100% for the rectum should be =0%, V150% for the urethra should be =0%, and D30% for the urethra should be <200 Gy, preferably <180 Gy. Post-planning using CT and magnetic resonance imaging was performed 1 month after treatment, and dosimetric parameters were evaluated. Note that patients in the LDR-BT group received only prophylactic alpha-blocker treatment for GU toxicity for approximately one year after radiotherapy.

CFRT. In principle, the prescribed dose was 78 Gy in 39 fx. In contrast, the dose for low-risk patients and/or those receiving anticoagulants was reduced to 74 Gy in 37 fx. The CTV was defined as the whole-prostate gland and proximal seminal vesicle, while the CTV was only the prostate in low-risk patients. The PTV1 included CTV with a 7-mm margin except for the rectal side, where a 4-mm margin was added. PTV2 was defined as the seminal vesicle with a 5-mm margin, excluding PTV1. The prescribed doses were delivered to PTV1 (D95), and 64 Gy were delivered to PTV2. Only in seminal vesicle invasion cases, 74 or 78 Gy were administered to both PTV1 and PTV2. The dose constraints were as follows: D2% of the PTV should be <107%. V70 covers <10% of the rectum, and V60 covers <18%. V70 covers <16% of the entire bladder, and V60 covers <25%. D2% of the penile bulb should be <70%. Both the target volume and normal organ structures were contoured using a treatment planning system (Eclipse, Varian Medical System). All patients were treated with a linear accelerator (TrueBeam STx, Varian Medical Systems).

MHRT. The prescription dose for MHRT was 70 Gy in 28 fx. The CTV was defined as the whole prostate gland and proximal seminal vesicle regardless of the risk group. Furthermore, the CTV included the entire seminal vesicle in seminal vesicle invasion cases. The PTV included the CTV with a 5-mm margin except for a 4-mm margin for the rectal side. The prescribed dose was adjusted to deliver 50% of the PTV (D50). The dose constraints were as follows: D95 of the PTV was >95%, and D2% was <105%. The maximum dose to the rectum should be <101%, and the percentage covered by D20% should be <54% and that by V40% should be <37%. The maximum dose to the entire bladder should be <103%, and the percentage covered by D20% should be <63% and that by V40% should be <28%. Most patients (n=55) were treated with a linear accelerator, represented by TrueBeam (Varian Medical Systems). The Eclipse (Varian Medical System) was used for treatment planning. In contrast, 42 patients were treated using CyberKnife M6 (Accuray Inc.). All patients treated using CyberKnife were implanted with three gold fiducial markers owing to its incorporation of near real-time kV imaging of the prostate 2 weeks before treatment.

UHRT. A total dose of 36.25 Gy was prescribed for five consecutive days, excluding the days when the hospital was closed. The definition of CTV was the same as that in MHRT. Patients in the UHRT group had more thorough nutritional guidance and urinary/defecation management. Compared with other EBRT groups, the daily setup for UHRT was performed with greater care. Therefore, the CTV margin was very tight; the PTV included the CTV with a 5-mm margin except for a 3-mm margin for the rectal side. In addition, the part that overlapped with the rectal bladder mucosa was removed by 1 mm. The prescription dose was adjusted to D95 with a 75%-85% isodose line to meet the dose constraints. The dose constraints were as follows: the percentage of the rectum that should be covered by D0.5cc was <102% and that by D5cc was <77%. The percentage of the entire bladder that should be covered by V50% was <35 cc and that by V100% was <5 cc. Multiplan (Accuray Inc.) was used as the planning system. Treatment was performed using CyberKnife M6 (Accuray Inc.), except in three cases where TrueBeam STx was used. Only one periprostatic hydrogel spacer (SpaceOAR; Augmenix Inc., Boston, MA, USA) for EBRT was used in the UHRT group.

Evaluation of outcomes. The date of the event was measured from the date of commencement of radiotherapy. Biochemically, no evidence of disease (bNED) was defined according to the Phoenix definition, as an absolute nadir PSA level +2 ng/ml increase (14). Both physician-recorded toxicities and patient-reported outcomes were evaluated. Physician-recorded toxicities were assessed by four observers according to the National Cancer Institute Common Toxicity Criteria for Adverse Events (version 5.0). To reduce observer bias as much as possible, toxicity assessments were discussed in advance and only grade ≥2 events were evaluated. Acute toxicity was defined as symptoms that were observed during or less than 6 months after radiotherapy treatment. Late toxicity was defined as any event persisting or occurring 6 months after completing radiotherapy. Patient-reported outcomes were evaluated to supplement the understanding of GU toxicity transitions, especially in the acute phase. These were evaluated based on the International Prostate Symptom Score (IPSS) and quality of life (QOL) score. The scores were recorded at the time of radiotherapy, then 1 week, 4 weeks, and 3 months, and thereafter every 3 months until 1 year after radiotherapy and were directly proportional to the patient’s displeasure level.

Statistical analysis. All statistical analyses were performed using EZR version 1.33 (Saitama Medical Center, Jichi Medical University, Saitama, Japan) based on the R and R commander (The R Foundation for Statistical Computing, Vienna, Austria) (15). Multiple comparisons of percentages were performed using Fisher’s exact tests with post-hoc Bonferroni analyses and a one-way analysis of variance (ANOVA) was performed to analyse the incidence acute toxicity. A comparison of IPSS transitions was performed using repeated-measures ANOVA. The Kaplan–Meier method was used to estimate bNED rates and the cumulative incidence of toxicities, and comparisons were performed using log-rank tests or Gray’s tests with post-hoc Bonferroni analyses. Cox’s proportional hazard model was used for the univariate and multivariate analyses, which were used to determine the factors that contributed to the cumulative incidence of late GI/GU toxicity. p-Values <0.05 were considered statistically significant. Factors showing a difference with p<0.1 in the univariate analysis were included the multivariate analysis.