Approximately 30% of patients who had undergone radical prostatectomy reportedly develop biochemical recurrence (BCR) (1). Salvage radiotherapy (RT) with or without androgen-deprivation therapy (ADT) is recommended for patients with BCR (2). Salvage prostate bed RT (PBRT) alone provides a certain effect on disease control in patients with BCR after radical prostatectomy; however, disease progression occurs in >50% of patients after treatment (3-5). Recent results of the NRG Oncology/RTOG 0534 SPPORT trial have suggested that salvage RT using WPRT and short-term ADT leads to significantly better treatment outcomes than PBRT with or without short-term ADT (6). WPRT as a salvage RT has been commonly performed using a conventional two-step three-dimensional conformal RT (3D-CRT) or intensity-modulated RT (IMRT) technique, consisting of WPRT followed by PBRT (7-9).

Although a previous study has suggested that dose-escalated WPRT can be performed using IMRT (10), the WPRT dose of >50 Gy is not commonly performed (6,11). Recently, a simultaneous integrated boost (SIB) technique using IMRT, which delivers a differential dose per fraction to selected subregions during the same treatment session that prescribes different total doses to target volumes in the same number of fractions, has been increasingly used for the treatment of definitive RT for prostate cancer (12,13). However, the value of dose-escalated WPRT using the SIB technique in patients with postoperative prostate cancer has not been fully evaluated. The present study aimed to investigate the institutional experience of dose-escalated salvage WPRT using the SIB technique in patients with BCR after radical prostatectomy for high-risk prostate cancer.

Patients. The present study was conducted in accordance with the guidelines stipulated in the Declaration of Helsinki and was approved by the Institutional Review Board of our hospital. This study was exempt from the requirement of obtaining informed consent from the patients because of its retrospective design. We enrolled 22 consecutive patients with histologically confirmed high-risk prostate adenocarcinoma who received salvage RT at our institution between September 2015 and March 2018. Among these patients, we excluded one patient from the analysis because he had a history of pelvic inflammation after surgery and underwent PBRT alone. Therefore, the study population ultimately comprised 21 patients with high-risk prostate cancer, as defined by the D'Amico risk classification system.

BCR was defined as a prostate-specific antigen (PSA) level of >0.2 ng/ml with a consecutive increase following radical prostatectomy (14-16). Three (14%) patients received neoadjuvant ADT before prostatectomy. No patient underwent concurrent or adjuvant ADT before or after salvage RT. Prior to salvage RT, computed tomography (CT) and laboratory tests (including an assessment of PSA levels) were performed in all patients.

Radiotherapy. Patients were instructed to void the bladder one hour before CT simulation and subsequent treatments. They were also instructed to void the rectum. Clinical target volume (CTV) of the whole pelvis (CTV56) included the prostate bed, common iliac, external iliac, internal iliac, and obturator lymph node regions based on the RTOG consensus guidelines (17,18). The boost CTV (CTV66) included the prostate bed; the seminal vesicle bed was also included in the boost CTV for patients with seminal vesicle invasion (pT3b). Planning target volumes (PTV) were generated by adding a margin of 6-8 mm to CTV (PTV56 and PTV66). RT was delivered using a 7-field IMRT with the SIB technique. The doses of 56.1 and 66 Gy in 33 fractions were delivered to PTV56 and PTV66, respectively. The RT plans were approved when at least 95% of the PTV received the prescribed dose. The following dose constraints were used for organs at risk: 1) 35% and 65% of the rectal volume received <60 Gy and <40 Gy, respectively; 2) 65% of the bladder wall volume received <40 Gy; 3) 1, 20, and 50 ml of the small bowel received <60, <50, and <40 Gy, respectively; and 4) 1 ml of the large bowel received <65 Gy. For imaging guidance, cone-beam CT imaging was performed for each fraction.

Follow-up. Radiation oncologists examined patients once every week during salvage RT, and radiation oncologists or urologists performed a PSA test at 3-month intervals after salvage RT for 2 years and every 6 months thereafter. Events occurring during and within 6 months of the salvage RT completion were referred to as acute complications, whereas those that developed 6 months or more after salvage RT were termed late complications. The Common Terminology Criteria for Adverse Events version 5.0 by the National Cancer Institute was used to grade the toxicity events.

Statistical analysis. Biochemical progression (BCP) was defined as an increase in the PSA level of ≥0.2 ng/ml above the post-salvage RT nadir with a confirmation of subsequent increase (4,9). The biochemical progression-free survival (BCPFS), overall survival (OS), and cause-specific survival (CSS) rates were calculated from RT initiation using the Kaplan–Meier method. JMP (SAS Institute, Cary, NC, USA) was used for analyses.

The patient characteristics are shown in Table I. The median follow-up duration was 62 months (range=14-98 months). One patient (5%) died of original prostate cancer due to multiple distant metastases of the lung, bone, and liver. During the follow-up period, five patients (24%) developed BCP; of these, two (10%) patients received ADT after BCP confirmation. The 3- and 5-year BCPFS rates were 85% and 72%, respectively, and the 3- and 5-year OS rates were 100% and 94%, respectively. The 3- and 5-year CSS rates were 100% and 94%, respectively (Figure 1).

The treatment-related toxicities are summarized in Table II. Acute ≥G2 and ≥G3 genitourinary (GU) toxicities were observed in one (5%) and 0 (0%) patients, respectively. Acute ≥G2 and ≥G3 gastrointestinal (GI) toxicities were observed in three (14%) and 0 (0%) patients, respectively, and late ≥G2 and ≥G3 GU toxicities in five (24%) and one (5%) patient, respectively. The G3 late toxicity observed in this study was gross hematuria. Late ≥G2 and ≥G3 GI toxicities were not observed in any patient. Grade ≥3 acute and late toxicities other than gross hematuria were not observed in any patient.

In the era of 2D-RT and 3D-CRT, elective nodal irradiation using WPRT with an RT dose of 44-46 Gy at 1.8-2 Gy fractions, which translates to a BED of 72-76.7 Gy₃ as the α/β ratio=3, has been commonly performed for patients with BCR (6,7,11). A modern technique, IMRT, which provides rapid dose drop-off beyond the target volumes, allows dose escalation to the target volumes without increasing the toxicities to normal tissues (19,20). We prescribed a higher RT dose to the whole pelvis with 56.1 Gy in 33 fractions (1.7 Gy per fraction), which translates to a BED of 87.9 Gy₃, to achieve better treatment outcomes. Byun et al. treated 170 high-risk prostate cancer patients with BCR after prostatectomy (11). IMRT was performed with an RT dose of 44-46 Gy for the whole pelvis followed by an RT dose of 20-28.6 Gy for the prostate bed at 2-2.2 Gy fraction. Neoadjuvant, concurrent, or adjuvant ADT was administered with salvage RT in 97 (57%) patients. The 5-year BCPFS, OS, and CSS rates were 39%, 91%, and 97%, respectively. Although we did not perform neoadjuvant, concurrent, or adjuvant ADT, the BCPFS, OS, and CSS rates were comparable to the results of the previous study. This may be due to the dose-escalating prescription for the WPRT.

The problematic toxicities of salvage RT to prostate beds with or without WPRT are GU and GI toxicities (11,21). Alongi et al. evaluated the acute toxicities of WPRT in patients treated with postoperative adjuvant or salvage RT after prostatectomy (21). Of the 172 patients, 81, 37, and 54 patients underwent 3D-CRT, Linac IMRT, and helical tomotherapy (HT), respectively. The median RT dose of WPRT was 50.4 Gy, and the median doses of prostate bed RT were 72.1, 72.5, and 70 Gy for 3D-CRT, Linac IMRT, and HT, respectively. The toxicity rates of 3D-CRT and IMRT (Linac IMRT and HT) for acute ≥G2 upper GI, ≥G2 lower GI, and ≥G2 GU toxicities were 22% and 7% (p=0.004), 9% and 3% (p=0.14), and 12% and 7% (p=0.19), respectively. They found that the risk of acute toxicities following postoperative WPRT delivered by IMRT was reduced as compared with that of 3D-CRT. In the NRG Oncology/RTOG 0534 SPPORT trial, 598 patients underwent salvage RT with short-term ADT (6). WPRT was performed at a dose of 45 Gy at 1.8-Gy fractions followed by PBRT at a dose of 19.8-25.2 Gy. Most patients underwent IMRT (87%). Acute ≥G2 and ≥G3 GU toxicities were observed in 67 (12%) and eight (1%) patients, respectively. Acute ≥G2 and ≥G3 GI toxicities were observed in 38 (7%) and four (1%) patients, respectively. Late ≥G2 and ≥G3 GU toxicities were observed in 223 (40%) and 45 (8%) patients, respectively. Late ≥G2 and ≥G3 GI toxicities were observed in 51 (9%) and eight (1%) patients, respectively. Although our patients underwent WPRT with a higher dose, the toxicities were comparable or better than those in the NRG Oncology/RTOG 0534 SPPORT trial. The combination of higher-dose WPRT using the SIB technique and short-term ADT may provide excellent treatment outcomes.

Study limitations. First, this was a retrospective study with a relatively small number of patients. Second, RT was delivered using fixed-field IMRT, and volumetric modulated arc therapy, which is a more modern and sophisticated RT delivery method that has rapidly become popular in recent years, was not performed. Further investigations are underway to address these limitations.

Dose-escalated salvage WPRT using the SIB technique provides appropriate tumor control without increasing the risk for significant toxicities.

The Authors declare that they have no competing interests in relation to this study.

SM developed the study design, collected, analyzed, and interpreted the data, performed the statistical analysis, and drafted the manuscript. YT developed the study design, analyzed and interpreted the data, and drafted the manuscript. MN, KH, DN, AE, NO, KM, and YN developed the study design and interpreted the data. RI analyzed and interpreted the data. RT developed the study design, collected, analyzed, and interpreted the data, and revised the manuscript. All Authors have read and approved the final version of the manuscript.

No funds, grants, or other support were received.