
==== Front
J Radiat Res
J Radiat Res
jrr
Journal of Radiation Research
0449-3060
1349-9157
Oxford University Press

39154370
10.1093/jrr/rrae056
rrae056
Oncology/Medicine
AcademicSubjects/MED00870
AcademicSubjects/SCI00960
Impact of neoadjuvant androgen deprivation therapy on toxicity in intensity-modulated radiation therapy for prostate cancer
Serizawa Itsuko Department of Radiation Oncology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo 135-8550, Japan

Kozuka Takuyo Department of Radiology, University of Tokyo Hospital, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan

Soyano Takashi Department of Radiation Oncology, National Hospital Organization Tokyo Medical Center, 2-5-1 Higashigaoka, Meguro-ku, Tokyo 152-0021, Japan

Sasamura Kazuma Department of Radiology, Musashino Red Cross Hospital, 1-26-1 Kyonancho, Musashino City, Tokyo 180-8610, Japan

Kamima Tatsuya Department of Radiation Oncology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo 135-8550, Japan

Kunogi Hiroaki Department of Radiation Oncology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo 135-8550, Japan

Numao Noboru Department of Genitourinary Oncology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo 135-8550, Japan

Yamamoto Shinya Department of Genitourinary Oncology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo 135-8550, Japan

Yonese Junji Department of Genitourinary Oncology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo 135-8550, Japan

Yoshioka Yasuo Department of Radiation Oncology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo 135-8550, Japan

Corresponding author. Department of Radiation Oncology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo 135-8550, Japan. Tel: +81-3-3520-0111; Fax: +81-3-3570-0343; Email: itsuko.serizawa@jfcr.or.jp
9 2024
17 8 2024
17 8 2024
65 5 693700
17 4 2024
02 6 2024
12 7 2024
© The Author(s) 2024. Published by Oxford University Press on behalf of The Japanese Radiation Research Society and Japanese Society for Radiation Oncology.
2024
https://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (https://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com

Abstract

This study aimed to compare toxicities, prostate volume and dosimetry, between patients who underwent intensity-modulated radiation therapy (IMRT) combined with ≥3 months of neoadjuvant androgen deprivation therapy (NADT) and those without NADT for prostate cancer. In total, 449 patients with intermediate- and high-risk prostate cancer received 78 Gy IMRT in 39 fractions, of which 129 were treated without any ADT (non-ADT group) and 320 with NADT ≥3 months (NADT group). Adverse events and dose-volume indices were compared between the two groups retrospectively. The NADT group had a lower rate of acute grade 2 gastrointestinal (GI) toxicities (17% vs 25%, P = 0.063) and late grade 2 GI toxicities (P = 0.055), including a significantly lower rate of late grade 2 rectal hemorrhage (P = 0.033), compared with the non-ADT group. There were no cases of late grade 3 or higher GI toxicities. The average volume of the prostate in the NADT group was 38% smaller than that in the non-ADT group (43.7 vs 27.0 cm3, P < 0.001). Bladder V40Gy and V50Gy, and rectum V40Gy, V50Gy, V60Gy and V70Gy were significantly smaller in the NADT group. In the NADT group, no significant difference was observed in adverse events or dosimetry between the subgroups with NADT ≥12 and <12 months. Acute and late rectal toxicities were reduced by NADT within ≥3 months in accordance with reduced prostate volume and improved rectal dosimetry. This suggests a merit of administering neoadjuvant ADT ≥3 months for reducing rectal toxicities.

prostate carcinoma
NADT
IMRT
radiotherapy
==== Body
pmcINTRODUCTION

Radiation therapy (RT) is a standard treatment for localized or locally advanced prostate cancer [1]. For intermediate- or high-risk prostate cancer, the addition of androgen deprivation therapy (ADT) to RT reduces the biochemical failure rate and increases the disease-specific survival or overall survival rate compared with RT alone [2–5]. Typically, ADT is administered for 4–6 months preceding RT (neoadjuvant ADT: NADT) for intermediate-risk prostate cancer; 1.5–3 years ADT is administered for high-risk prostate cancer, including 4–6 months of NADT, concurrent and adjuvant ADT [1–5].

Sequencing of ADT, or prolongation of NADT, remains controversial. Using a method of an individual patient meta-analysis, several studies have compared the effect of NADT with that of adjuvant ADT, or the effect of prolongation of the NADT duration with that of the adjuvant ADT duration. Spratt et al. [6] reported improved outcomes of progression-free survival and metastasis-free survival in the adjuvant ADT group compared with the NADT group. Kishan et al. [7] showed that prolonging the adjuvant component of ADT offered a significantly improved metastasis-free survival; however, NADT extension offered no clear benefit, suggesting that the routine use of prolonged NADT is not recommended.

In contrast, NADT reduces the prostate volume at the time of RT and consequently adverse events following RT due to reduced target volume and radiation dose to the organs at risk [8–10]. Some of these studies have examined only dose-volume histogram (DVH) parameters with or without acute toxicity data, lacking long-term toxicity data [8, 9]; others used three-dimensional conformal RT with or without multiple prescription doses [8–10] and included a small number of patients with a long-term follow-up period [8]. Herein, we included a significant number of patients with long-term follow-up, all of whom received intensity-modulated radiation therapy (IMRT) with a uniform prescription dose administered using a uniform treatment-planning method, including a group that received NADT and another that did not. This study examined the effect of NADT on the toxicity of RT by comparing two groups who did and did not receive NADT, retrospectively in the whole cohort of intermediate- and high-risk prostate cancer who received IMRT with a uniform dose. We hypothesized that NADT can reduce the prostate volume at the time of IMRT, consequently reducing the irradiation dose to the bladder and rectum and decreasing the rate of acute and/or late genitourinary (GU) and/or gastrointestinal (GI) toxicities.

METHODS AND MATERIALS

Between January 2007 and August 2014, 566 patients with T1c-T3aN0M0 prostate cancer were treated with 78 Gy IMRT in 39 fractions at our hospital. All patients had biopsy-proven adenocarcinoma and were staged using the 2018 Union for International Cancer Control Staging System after bone scintigraphy, pelvic computed tomography (CT) and prostate magnetic resonance imaging (MRI). We classified those with T1c-T2a, prostate-specific antigen (PSA) <10 ng/mL and Gleason score (GS) ≤6 as low-risk, T2b-c, PSA 10–20 or GS 7 as intermediate-risk and T3a, PSA >20 ng/mL or GS ≥ 8 as high-risk patients according to the National Comprehensive Cancer Network guidelines [11].

Of the 566 patients, we excluded 60 who had been inserted fiducial markers, 15 with a follow-up period of <2 years, seven who had been diagnosed with castration-resistant prostate cancer (CRPC) at the time of IMRT and six who had been treated with high-intensity focused ultrasound or holmium enucleation of the prostate before IMRT. NADT was defined as ADT administered prior to the first day of IMRT. We also excluded 22 patients who received NADT for only 1 or 2 months, three patients who received concurrent or concomitant ADT and four patients whose duration of ADT was missing. None of the patients received whole pelvic RT or perirectal spacers.

The remaining 449 patients were the subjects of this report, and will be included in the analysis hereafter. All of them were intermediate- or high-risk patients who underwent IMRT using 78 Gy in 39 fractions and with a minimum follow-up period of 2 years. Of those, 320 patients who received NADT ≥3 months were defined as the NADT group, and the other 129 patients without any ADT were defined as the non-ADT group (Supplementary Fig. 1).

ADT comprises a luteinizing hormone-releasing hormone (LHRH) agonist and an antiandrogen. NADT was administered for 6 months before IMRT; for high-risk patients only, adjuvant ADT was continued so that the total duration of ADT was 2 years. Their characteristics are presented in Table 1. This retrospective study was approved by the institutional review board of our hospital (approved number: 2020-GA-1214).

Table 1 Patient characteristics

	Non-ADT group	NADT group	P value	
No. of patients	129	320		
Age (years)			0.067	
 Median	69	71		
 Range	49–83	51–84		
Hypertension	41 (32%)	130 (41%)	0.087	
Lipid metabolic disorder	23 (18%)	53 (17%)	0.781	
Heart disease	19 (15%)	51 (16%)	0.776	
Diabetes	30 (23%)	59 (18%)	0.295	
Use of anticoagulant	28 (22%)	85 (27%)	0.336	
Collagen disease	2 (1.6%)	4 (1.3%)	0.617	
T classification			<0.001	
 T1	61 (47%)	63 (20%)		
 T2	68 (53%)	127 (40%)	
 T3a	0 (0%)	130 (41%)	
Gleason score			<0.001	
 ≤6	16 (12%)	11 (3%)		
 7	95 (74%)	133 (42%)	
 ≥8	18 (14%)	176 (55%)	
Pretreatment PSA (ng/ml)		<0.001	
 <10	79 (61%)	121 (38%)		
 10–20	47 (36%)	100 (31%)	
 ≥20	3 (2%)	99 (31%)	
 Median	8.27	12.5		
 Range	2.42–25	1.87–499		
NCCN risk			<0.001	
 Intermediate	109 (84%)	80 (25%)		
 High	20 (16%)	240 (75%)	
ADT (neoadjuvant + adjuvant)		<0.001	
 >20 months	0 (0%)	81 (25%)		
 6–20 months	0 (0%)	214 (67%)	
 3–6 months	0 (0%)	25 (8%)	
 0 month	129 (100%)	0 (0%)	
CAB	-	306 (96%)		
LHRH	-	13 (4%)		
Antiandrogen	-	1 (0%)		
Follow-up (months)			0.035	
 Median	110	99		
 Range	26–153	26–155		

Treatment planning

A glycerin enema was administered 1 h before treatment planning using CT acquisition. CT and MRI were performed after 1 h of urine storage on the same day. IMRT was delivered using 10-MV photon beams. The beam was delivered using Clinac 21EX (Varian Medical Systems, Palo Alto, CA, USA) linear accelerator. We applied a five-field IMRT technique. The clinical target volume (CTV) was defined as the prostate gland (and any extracapsular lesion) plus a 5-mm margin. The proximal seminal vesicles were added, and the rectal and bladder volumes were eliminated from the CTV. The planning target volume (PTV) was defined as the CTV plus a 5-mm margin. The modified PTV was defined as the difference between PTV and the rectal area. A prescribed dose of 78 Gy was administered to 95% volume of the modified PTV. RT planning was performed using the Eclipse Treatment Planning System (Varian Medical Systems, Palo Alto, CA, USA). The data on prostate volume and all dosimetric parameters were obtained from the records of radiotherapy treatment planning retrospectively.

The 4 mm inner volumes of the entire bladder and the rectum were defined as the bladder and rectal wall, respectively, and used to evaluate the dosimetric indices. The percentage of rectum wall volume or bladder wall receiving more than 40, 50, 60 and 70Gy was defined as V40Gy, V50Gy, V60Gy and V70Gy, respectively.

Analysis

Adverse events were evaluated using the Common Terminology Criteria for Adverse Events version 4.0. Acute toxicity was defined as symptoms observed during or after treatment that completely resolved 3 months post-treatment. Treatment-related toxicity that persisted or occurred >3 months post-treatment completion was considered late toxicity.

The chi-squared test and t-test were used to compare the occurrence rates of acute adverse events and the parameters of the DVHs. The Kaplan–Meier method was used to show the actuarial rates of late adverse events, while the log-rank test was used to determine the significant differences between the groups. A P value of <0.05 was considered statistically significant, while the P values ≥0.05 and <0.1 were considered to have a tendency toward significance. All statistical analyses were performed using IBM SPSS Statistics version 24.0.

RESULTS

The median follow-up periods for the non-ADT and NADT groups were 110 and 99 months, respectively, which were significantly different (P = 0.045). In the non-ADT group, 109 (83%) and 23 (17%) participants were intermediate- and high-risk patients, respectively, while in the NADT group, 80 (25%) and 240 (75%) were intermediate- and high-risk patients, respectively (P < 0.001). In the NADT group, 306 patients (96%) received combined androgen blockade (CAB), 13 (4%) received LHRH alone and one (0%) received antiandrogen alone. Comorbidities were compared between the non-ADT group and the NADT group, but no significant difference was observed; only hypertension was more frequent in the NADT group (P = 0.087, Table 1).

Figure 1(a) shows box-and-whisker plots of the prostate volume comparing the non-ADT and NADT groups. Prostate volumes were significantly different among the two groups, with an average ± standard deviation (SD) of 43.7 ± 15.6 and 27.0 ± 12.5 cm3, respectively (P < 0.001). The volume of the prostate in the NADT group was 38% smaller than that in the non-ADT group.

Fig. 1 (a) Box-and-whisker plots showing prostate volume comparing the non-ADT and NADT groups. The center line of each box and the x-mark represent the median and mean values, respectively. The upper and lower edges represent the 25th and 75th percentiles, respectively. (b) Box-and-whisker plots showing the V40Gy, V50Gy, V60Gy and V70Gy for bladder and rectal walls, comparing the non-ADT and the NADT groups.

The center line of each box and the x-mark represent the median and mean values, respectively. The upper and lower edges represent the 25th and 75th percentiles, respectively.

Figure 1(b) shows box-and-whisker plots of the V40Gy, V50Gy, V60Gy and V70Gy for the bladder and rectal walls, comparing the non-ADT and the NADT groups. The V40Gy and V50Gy of the bladder wall were significantly larger in the non-ADT group with an average ± SD of 42.7 ± 12.7 and 34.9 ± 10.6% than in the NADT group with 39.3 ± 11.4 and 32.7 ± 9.4% (P = 0.010 and P = 0.039), respectively. The V40Gy, V50Gy, V60Gy and V70Gy of rectal walls were significantly larger in the non-ADT group with an average ± SD of 52.1 ± 6.3, 38.1 ± 4.7, 28.9 ± 3.6 and 20.2 ± 2.7% than in the NADT group 46.9 ± 7.8, 34.2 ± 5.1, 26.2 ± 3.9, 18.4 ± 3.0% (P < 0.001, P < 0.001, P < 0.001 and P < 0.001) (Table 2a).

Table 2 (a) Dosimetric parameters comparing the non-ADT group and the NADT group

	Non-ADT group	NADT group	P value	
Number of patients	129	320		
Prostate volume (cm3)				
Average	43.7	27.0	<0.001	
Range	21.5–122.4	10.5–102		
		38% volume reduction		
Bladder wall (%)				
V40	42.7 (17.6–88.5)	39.3 (11.5–80.6)	0.010	
V50	34.9 (13.3–82.3)	32.7 (9.6–67.7)	0.039	
V60	28.7 (10.6–72.8)	27.1 (8–58.7)	0.082	
V70	23.9 (8.6–61.3)	22.4 (6.6–45.5)	0.060	
Rectum wall (%)				
V40	52.1 (33.8–61.7)	46.9 (20.4–69.4)	<0.001	
V50	38.1 (26.3–47.0)	34.2 (7.6–49.7)	<0.001	
V60	28.9 (20.7–36.2)	26.2 (1.2–38.9)	<0.001	
V70	20.2 (13.4–25.9)	18.4 (0–26.4)	<0.001	
Figures are averages (ranges).

No patient showed grade ≥3 GU or GI acute adverse event. Figure 2 shows the occurrence rates of acute adverse events of grade 2 GU and grade 2 GI. The occurrence rate of acute grade 2 GU was 54 and 49% (P = 0.404) in the non-ADT group and NADT groups, respectively. No significant difference in the occurrence rate of grade 2 GU was observed between the two groups. The occurrence rate of acute grade 2 GI was 25 and 17% (P = 0.063) in the non-ADT and NADT groups, respectively. The NADT group showed a lower tendency rate of acute grade 2 GI than the non-ADT group.

Fig. 2 Occurrence rates of acute adverse events in the non-ADT and the NADT groups. GU, genitourinary; GI, gastrointestinal.

As for late adverse events, no patient showed grade ≥4 late adverse event. Two patients in the non-ADT group (1.6%) and seven patients in the NADT group (2.2%) showed late grade 3 GU adverse events, whereas no patient showed late grade 3 GI adverse event. Figure 3 shows the occurrence rates of late adverse events of grade ≥2 GU, grade ≥ 2 hematuria, grade 2 GI and grade 2 rectal hemorrhage in the non-ADT and NADT groups. The actuarial occurrence rates of late grade ≥2 GU and grade ≥2 hematuria were 24 and 1% at 5 years and 32 and 2% at 10 years in the non-ADT group, while those of the NADT group were 26 and 2% at 5 years and 32 and 6% at 10 years. The actuarial occurrence rates of grade 2 GI and grade 2 rectal hemorrhage were 7 and 4% at 5 years and 8 and 4% at 10 years in the non-ADT group, and 4 and 1% at 5 years and 4 and 1% at 10 years in the NADT group.

Fig. 3 Occurrence rates of late adverse events in the non-ADT and the NADT groups. (a) Grade ≥2 GU toxicities. (b) Grade ≥2 Hematuria. (c) Grade 2 GI toxicities. (d) Grade 2 Rectal hemorrhage. GU, genitourinary; GI, gastrointestinal.

Compared with the non-ADT group, the NADT group showed a lower tendency rate of late grade 2 GI (P = 0.055) and a significantly lower occurrence rate of grade 2 rectal hemorrhage (P = 0.033).

No significant difference in the occurrence rate of GU was observed between the two groups.

To examine the effect of the duration of NADT on the prostate volume, DVH parameters and occurrence rates of adverse events, we divided the NADT group into two subgroups and compared them, namely patients with NADT for ≥3 months but <12 months (NADT 3–12 m group) and patients with NADT for ≥12 months (NADT ≥12 m group). Supplementary Fig. 2(a) shows box-and-whisker plots of the prostate volume comparing the NADT 3–12 m group and the NADT ≥12 m group. Prostate volume was significantly different among the two groups, with an average ± SD of 27.7 ± 12.8 and 23.8 ± 10.3 cm3, respectively (P = 0.019). The prostate volume in the NADT ≥12 m group was 14% smaller than that in the NADT 3–12 m group. Supplementary Fig. 2(b) shows box-and-whisker plots of the V40Gy, V50Gy, V60Gy and V70Gy for bladder and rectal walls, comparing the NADT 3–12 m and NADT ≥12 m groups. No significant difference regarding V40Gy, V50Gy, V60Gy and V70Gy for bladder and rectal walls was observed between the two groups. The mean of V40Gy, V50Gy, V60Gy and V70Gy for bladder and rectal walls was slightly higher in the NADT ≥12 m than in the NADT 3–12 m groups, which were inversely different from expected (Table 2b). Supplementary Figs 3 and 4 show the occurrence rates of acute and late adverse events in the NADT 3–12 m and NADT ≥12 m groups. No significant difference in acute and late GU/GI was observed.

Table 2 (b) Dosimetric parameters comparing the NADT 3-12 m group and the NADT > 12 m group

	NADT 3–12 m group	NADT ≥12 m group	P value	
Number of patients	269	51		
Prostate volume (cm3)			0.019	
Average	27.7	23.8		
Range	13.5–102	10.5–61.4		
Bladder wall (%)				
V40Gy	39.0 (11.5–75.9)	41.2 (18.7–80.6)	0.215	
V50Gy	32.4 (9.6–67.7)	34.3 (15.5–66)	0.175	
V60Gy	26.9 (8–58.7)	28.5 (12.8–50.2)	0.170	
V70Gy	22.3 (6.6–45.5)	23.4 (10.6–35.7)	0.208	
Rectum wall (%)				
V40Gy	46.9 (20.4–69.4)	47.1 (31.3–59.4)	0.834	
V50Gy	34.1 (7.6–49.7)	34.3 (24.2–44.7)	0.841	
V60Gy	26.2 (1.2–38.9)	26.4 (16.5–34.4)	0.676	
V70Gy	18.3 (0–26.4)	18.5 (10.6–23.4)	0.604	
Figures are averages (ranges).

DISCUSSION

In this retrospective study, we demonstrated that the mean prostate volume at the timing of the IMRT initiation was 43.7 cm3 for the non-ADT group and 27.0 cm3 for the NADT group, a 38% volume reduction by neoadjuvant ADT with ≥3 months. V40Gy and V50Gy for the bladder and V40Gy, V50Gy, V60Gy and V70Gy for the rectal walls of the NADT group were significantly smaller than those of the non-ADT group. A significant difference was observed in the incidence rates of late grade 2 rectal hemorrhages in the non-ADT and NADT groups (P = 0.033). Moreover, there was a tendency in the incidence rates of acute and late grade 2 GI toxicities (P = 0.063 and 0.055).

The effect of NADT on prostate volume change was discussed in the 1990s. Yang et al. [8] performed a 3-month NADT for seven patients with bulky clinical Stage C prostate cancer. The mean volumes of prostate before and after NADT were 129.1 ± 32.9 SD and 73.0 ± 29.5 SD cm3 (43.5% reduction). The volume of the rectum and bladder receiving 80% of the prescribed dose was reduced in five of seven patients from a mean of 83.2 to 59.9 cm3 (P = 0.045) and 74.5 to 40.2 cm3 (P = 0.045). However, the correlation between the reduction in prostate size and the amount of rectum or bladder treated was not linear. Forman et al. [12] compared the size of the prostate and the DVH parameters of the bladder and rectum between the pre-NADT (non-clinical use) treatment planning and the post-NADT (actually used) treatment planning of 20 patients with T1 or T2 prostate carcinoma who received 3 months of Lupron before RT. The average volume of the prostate was reduced by 37%. Consequently, the volume of the bladder receiving at least 40, 52 and 64 Gy was reduced by an average of 15, 18 and 20%, respectively, and the volume of the rectum receiving at least 40, 52 and 64 Gy was reduced by an average of 13, 20 and 34%, respectively. Zelefsky et al. [10] analyzed 214 patients treated with NADT for 3 months before RT with a median dose of 70.2 Gy and showed that the 3-year actuarial grade 2 late GI and GU toxicity rates were 6 and 18%, respectively. The DVH and target volume of 45 patients were prospectively evaluated with pre- and post-NADT planning CT. The median volume of the target was reduced by 27%, and the median reduction of the rectal and bladder volumes receiving 95% of the prescription dose (D95) was reduced by 18 and 46%, respectively. The prostate volume reduction rate of the current study (38%) was consistent with previous reports (27–43.5%). Notably, these reports used three-dimensional conformal RT as the irradiation technique, and, to the best of our knowledge, this study is the first to examine NADT with IMRT using a uniform prescription dose of 78 Gy in 39 fractions for intermediate- and high-risk prostate cancer and analyze the prostate volume, DVH parameters and acute/late adverse events for all cases consistently.

In addition, the median follow-up period in our study was very long (99 months). Herein, we compared two cohorts comprising the non-ADT and NADT patient groups, differently from the above-mentioned three reports comparing the same patient at pre-NADT and post-NADT timings.

Concerning the optimal duration of NADT, Langenhuijsen et al. [13] repeated CT scan examination every 3 months for cT2-3 N0/xM0 prostate cancer patients and measured prostate volume until 9 months following treatment with NADT. The authors showed that a significant prostate volume reduction was achieved after 3 months of NADT, maximum reduction after 6 months and no significant reduction between 6 and 9 months. Lilleby et al. evaluated changes in the volume of the cancerous prostatic gland during ADT [14]. As compared with the pre-treatment situation, the prostate gland was reduced in size by 18, 35 and 46% at 1, 6 and 12 months, respectively. The authors suggested that NADT should be given for at least 6 months to achieve the maximal effect on patients in downsizing the volume of the cancerous prostate gland. In this study, we first eliminated the patients who received NADT with <3 months, since such a short period is insufficient to observe the impact and previous studies adopted NADT duration of ≥3 months. Next, we determined whether a substantially longer duration of NADT had any benefit that would counterbalance patients’ burden. Although our data showed that the volume of the prostate in the NADT ≥12 m group was 14% smaller than that in the NADT 3–12 m group, no significant difference in the DVH parameters was observed between the two groups. Contrarily, the means of V40Gy, V50Gy, V60Gy and V70Gy for bladder and rectal walls were slightly higher in the NADT ≥12 m group than in the NADT 3–12 m group. No significant difference in acute and late GU/GI was observed between the two groups. Although the reason why the DVH parameters did not improve the NADT ≥12 m group is unknown, despite the further reduced prostate volume, we considered that NADT ≥12 months was not beneficial and do not recommend it.

Recently, sequencing of ADT with RT for prostate cancer has been discussed. In an individual patient meta-analysis, Spratt et al. [6] concluded that adjuvant short-term ADT combined with prostate-directed RT conferred superior progression-free survival and reduced the incidence of biochemical relapse and distant metastasis compared with neoadjuvant and concurrent ADT. No significant differences were observed in either late grade 3–5 GI (2% vs 3%, P = 0.33) or GU (5% vs 5%, P = 0.76) toxicity between the neoadjuvant versus adjuvant groups. Ma et al. [15] also analyzed individual patient data from 12 randomized trials that included patients receiving neoadjuvant/concurrent or concurrent/adjuvant short-term ADT (4–6 months) with RT obtained from the Meta-Analysis of Randomized trials in Cancer of the Prostate consortium. The authors revealed that concurrent/adjuvant ADT was associated with significantly improved metastasis-free survival, distant metastasis, prostate cancer-specific mortality and overall survival when prostate-only RT was administered.

The RT oncology group (RTOG 9413) [16] and Ottawa 0101 [17], which form the basis of these trials, only listed grade ≥3 adverse events. No data regarding grade 2 GU and GI were available. Hence, our study, which examined grade 2 toxicity, is novel. However, when we administer NADT, we should consider some risk that the patient may miss the appropriate period for receiving IMRT. That is, there is a possibility that the tumor may become CRPC during the period of NADT. Actually, one of the seven patients, who were excluded from this analysis by the reason of CRPC, had developed castration-resistance 5 months after starting NADT before receiving IMRT. He may have lost the chance to receive IMRT while the tumor was castration-sensitive. One should recognize such trade-off between reducing grade 2 toxicity, if any, by NADT and missing the appropriate time to receive IMRT before the tumor become CRPC during the NADT period.

The study has some limitations. First, this study was retrospective in nature and involved significant inherent heterogeneity. The ratio of intermediate−/high-risk patients in the non-ADT and NADT groups significantly differed (84%/16% in the non-ADT group vs 25%/75% in the NADP group). We did not consider administering NADT before 2010, partly due to poor adherence to the guidelines for intermediate- and high-risk prostate cancer at that time. Therefore, the non-ADT group comprised earlier cases compared with the NADT group, had a significantly longer observation period (110 months vs 99 months, P = 0.035) and comprised more cases of intermediate-risk naturally. However, since our method of treatment planning for intermediate- and high-risk patients (without T3b) was the same, it seemed unlikely that the different ratios of intermediate−/high-risk affected the toxicity outcome. The irradiation technique during this study period was not target-matching image-guided RT, but rather bone-matching without implanted fiducial markers or without cone-beam CT registration, which differed from our present practice. This suggests that the results of this study are applicable since we currently use a smaller CTV-to-PTV margin based on an implanted fiducial marker registration. Finally, NADT itself may cause toxicity. Because we investigated only GU and GI toxicity in this report, there remains some possibility of underestimation for toxicity of the NADT group, for example, in sexual function.

In conclusion, with NADT ≥3 months, rectal toxicity grade 2 was significantly reduced, which could be explained by the reduced prostate volume and improved DVH parameters. NADT ≥12 months was not meaningful, and hence not recommended. Our results indicate that NADT for 3–12 months has an adverse-events-reducing effect.

CONFLICT OF INTEREST

There is no conflict of interest. All authors have approved the submission of the manuscript.

FUNDING

None.

Supplementary Material

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