Hypofractionated radiation therapy combined with androgen deprivation therapy for clinically node-positive prostate cancer

Tae Hoon Lee; Hongryull Pyo; Gyu Sang Yoo; Seong Soo Jeon; Seong Il Seo; Byong Chang Jeong; Hwang Gyun Jeon; Hyun Hwan Sung; Minyong Kang; Wan Song; Jae Hoon Chung; Bong Kyung Bae; Won Park

doi:10.3857/roj.2024.00080

Radiation Oncology Journal > Volume 42(2); 2024 > Article

Lee, Pyo, Yoo, Jeon, Seo, Jeong, Jeon, Sung, Kang, Song, Chung, Bae, and Park: Hypofractionated radiation therapy combined with androgen deprivation therapy for clinically node-positive prostate cancer

Original Article

Radiation Oncology Journal 2024; 42(2): 139-147.

Published online: June 25, 2024

DOI: https://doi.org/10.3857/roj.2024.00080

Hypofractionated radiation therapy combined with androgen deprivation therapy for clinically node-positive prostate cancer

Tae Hoon Lee¹, Hongryull Pyo¹, Gyu Sang Yoo², Seong Soo Jeon³, Seong Il Seo³, Byong Chang Jeong³, Hwang Gyun Jeon³, Hyun Hwan Sung³, Minyong Kang³, Wan Song³, Jae Hoon Chung³, Bong Kyung Bae⁴, Won Park¹

¹Department of Radiation Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea

²Department of Radiation Oncology, Chungbuk National University Hospital, Cheongju, Republic of Korea

³Department of Urology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea

⁴Department of Radiation Oncology, Kyungpook National University Chilgok Hospital, Daegu, Republic of Korea

Correspondence: Won Park Department of Radiation Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul 06351, Republic of Korea
Tel: +82-2-3410-2616 Fax: +82-2-3410-2619 E-mail: wonro.park@samsung.com

Received January 23, 2024 Revised February 14, 2024 Accepted February 20, 2024

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 unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Purpose

This study aimed to analyze the treatment outcomes of combined definitive radiation therapy (RT) and androgen deprivation therapy (ADT) for clinically node-positive prostate cancer.

Materials and Methods

Medical records of 60 patients with clinically suspected metastatic lymph nodes on radiological examination were retrospectively analyzed. Eight patients (13.3%) were suspected to have metastatic common iliac or para-aortic lymph nodes. All patients underwent definitive RT with a dose fractionation of 70 Gy in 28 fractions. ADT was initiated 2–3 months before RT and continued for at least 2 years. Biochemical failure rate (BFR), clinical failure rate (CFR), overall survival (OS), and prostate cancer-specific survival (PCSS) were calculated, and genitourinary and gastrointestinal adverse events were recorded.

Results

The median follow-up period was 5.47 years. The 5-year BFR, CFR, OS, and PCSS rates were 19.1%, 11.3%, 89.0%, and 98.2%, respectively. The median duration of ADT was 2.30 years. BFR and CFR increased after 3 years, and 11 out of 14 biochemical failures occurred after the cessation of ADT. Grade 2 and beyond late genitourinary and gastrointestinal toxicity rates were 5.0% and 13.3%, respectively. However, only two grade 3 adverse events were reported, and no grade 4–5 adverse events were reported. Patients with non-regional lymph node metastases did not have worse BFR, CFR, or adverse event rates.

Conclusion

This study reported the efficacy and tolerable toxicity of hypofractionated definitive RT combined with ADT for clinically node-positive prostate cancer. Additionally, selected patients with adjacent non-regional lymph node metastases might be able to undergo definitive RT combined with ADT.

Keywords: Prostatic neoplasms, Lymph nodes, Radiotherapy, Androgen suppression

Introduction

Prostate cancer is ranked the second most common cancer in men after lung cancer by GLOBOCAN [1]. However, prostate cancer with regional or distant metastases is relatively uncommon. Between 2003 and 2017, only 11% of patients newly diagnosed with prostate cancer in the United States had a regional disease [2]. Radiation therapy (RT) is one of the most common treatment for prostate cancer [3]. Current clinical guidelines recommend definitive RT combined with androgen deprivation therapy (ADT) as a preferred treatment for clinically node-positive prostate cancer, although ADT alone is also acceptable [4-6]. This recommendation is largely based on population-based retrospective studies [7-9], as randomized evidence is currently lacking. However, a post hoc analysis of the control arm of the STAMPEDE trial provided an additional evidence with increased survival rates for RT [10]. Retrospective studies have also shown favorable clinical outcomes and toxicity rates of definitive RT for this disease entity [11-13]. Despite these findings, real-world experiences are still needed because of the disease’s relative rarity.

Since 2008, our institution has been treating clinically node-positive prostate cancer, including cases with adjacent non-regional lymph node metastases, such as common iliac and abdominal para-aortic lymph node metastases, using hypofractionated RT combined with ADT. This study aims to analyze the treatment outcomes, patterns of recurrence, and adverse events of definitive RT combined with ADT for clinically node-positive prostate cancer based on our institutional experience.

Materials and Methods

1. Study population

This study was approved by the Institutional Review Board of Samsung Medical Center (Approval No. 2023-04-110) before gathering the patients’ information. The requirement for informed consent was waived because of the retrospective nature of the study. The medical records of patients with clinically node-positive prostate cancer who underwent definitive RT combined with ADT between January 2008 and November 2018 were reviewed. Eligible patients underwent definitive RT with intensity-modulated radiation therapy (IMRT) technique or proton therapy at a total dose of 70 Gy with a fraction size of 2.5 Gy. Patients who underwent a follow-up of less than a year and who did not undergo ADT were excluded. Therefore, 60 patients were included and analyzed in this study.

2. Treatment

Patients with histologically confirmed prostate cancer were referred to the radiation oncology department when a lymph node-metastasis was suspected on clinical examination and when the patient preferred RT. Definitive RT was not recommended for patients with an expected survival rate of less than 5 years. The staging procedure included computed tomography (CT), magnetic resonance imaging (MRI), and bone scanning. Positron emission tomography (PET)/CT scans were not routinely performed during the study period. Suspected lymph nodes were evaluated based on MRI and CT features, such as size, changes from previous scans, response to ADT, and contrast uptake. Furthermore, selected patients with suspected adjacent non-regional lymph nodes, such as the common iliac and para-aortic nodes, were referred to the department when the definitive RT field could cover all suspected diseases.

Patients, who were scheduled to undergo definitive RT, started ADT 2–3 months before the initiation of RT. ADT comprised a gonadotropin-releasing hormone agonist (GnRH) and an antiandrogen. It was administered for at least 2 years and could be extended at the discretion of the treating clinicians. Suspected lymph nodes were assessed before initiating RT using MRI and CT to determine their responsiveness at 2–3 months after ADT. The suspected lymph nodes of all patients showed more than a partial response after the initial 2–3 months of ADT.

For RT planning, patients initially underwent simulation CT and MRI scans. A rectal balloon was routinely placed during the simulation CT and MRI scans and the treatment sessions for reproducibility. As stated in the eligibility criteria, IMRT technique or proton therapy was used. RT was delivered to the prostate and regional lymph nodes. High-risk clinical target volumes (HR-CTV) included the prostate, seminal vesicles, and residual metastatic lymph nodes. The seminal vesicles could be partially or completely omitted from the HR-CTV when they showed no evidence of invasion. Low-risk CTV (LR-CTV) included the obturator, external iliac, internal iliac, and presacral lymph nodes. The LR-CTV were extended to comprise additional suspected lymph nodes located outside the routinely irradiated regional lymph node areas. CTV were delineated based on previously published guidelines [14,15]. The planning target volume (PTV) was constructed by expanding the CTV by 3–10 mm. The prescribed dose was 70 Gy in 28 fractions for the HR-PTV and 50.4 Gy in 28 fractions for the LR-PTV. The plan was optimized to cover 95% of the PTV with 100% of the prescribed dose. A simultaneous integrated boost technique was used to differentiate the dose between the HR- and LR-CTV. The dose to the metastatic lymph nodes was often limited owing to an unacceptable radiation dose to the bowel.

Patients were evaluated for acute toxicity at the outpatient clinic a month after RT completion. Subsequently, they were monitored using prostate-specific antigen (PSA) tests every 3–6 months.

3. Endpoints and statistics

The oncological outcomes analyzed in this study were biochemical failure rate (BFR), clinical failure rate (CFR), overall survival (OS), and prostate cancer-specific survival (PCSS). Biochemical failure was defined as a rise in the PSA level by at least 2.0 ng/mL from the PSA nadir after undergoing RT, or administration of salvage ADT. Clinical failure was defined as an evidence of disease progression on physical or radiological examination. An event for OS was defined as a patient’s death from any cause. An event for PCSS was defined as a prostate cancer-related death, evaluated by a board-certified radiation oncologist. The actuarial rates for these oncological outcomes were calculated using the Kaplan–Meier method. The actuarial rates of oncological outcomes were compared between regional and non-regional lymph node metastasis using the log-rank test. Genitourinary and gastrointestinal toxicities were graded according to the Common Terminology Criteria for Adverse Events version 5.0. Adverse events that occurred within 3 months from RT completion were considered acute adverse events, whereas others were considered late adverse events. Univariate and multivariate analyses were conducted to evaluate the potential association between oncological outcomes and variables based on the Cox proportional hazards model. These analyses were conducted only for BFR and CFR because OS and PCSS had a limited number of events. A p-value lower than 0.05 was considered statistically significant. All statistical analyses were conducted using the R software (version 4.2.1; The R Foundation for Statistical Computing, Vienna, Austria).

Results

1. Patient characteristics and treatment

Patient characteristics and treatment specifics are summarized in Table 1. The median follow-up period for the included patients was 5.5 years (range, 1.3 to 13.8). The median age at diagnosis was 68 years (range, 51 to 81), and all patients had good performance status (Eastern Cooperative Oncology Group performance status 0–1) at presentation to the radiation oncology department. The disease had several high-risk features. Most patients presented with high PSA levels at diagnosis (median, 39.11 ng/mL; range, 4.05 to 370.2). All patients had a cT3-4 disease, and 85.0% had a Gleason score of 8 or higher. Regarding the nodal disease burden, the median number of suspected lymph nodes was 3 (range, 1 to 6), and the median maximum size of the suspected lymph nodes was 11.68 mm (range, 3.14 to 45.63). Eight patients (13.3%) had suspected non-regional lymph node metastases, including metastases to the common iliac (10.0%) and para-aortic (3.3%) lymph nodes. Most patients (98.3%) underwent IMRT with photon beam therapy, while one patient (1.7%) received proton therapy. ADT mostly comprised leuprorelin and bicalutamide (96.7%), and the median duration of ADT administration was 2.3 years (range, 1.2 to 11.1).

2. Oncological outcomes and patterns of failure

The actuarial rates of BFR, CFR, OS, and PCSS are shown in Fig. 1. The 3-, 5-, and 7-year BFR rates were 5.2%, 19.1%, and 35.6%, respectively, while the 3-, 5-, and 7-year CFR rates were 3.2%, 11.3%, and 23.1%, respectively. The 3-, 5-, and 7-year OS rates were 96.6%, 89.0%, and 83.4%, respectively, and the 3-, 5-, and 7-year PCSS rates were 100%, 98.2%, and 95.3%, respectively. The Kaplan–Meier curves of BFR and CFR showed an increase in the estimated incidence rates after 3 years. The actuarial rates of BFR, CFR, OS, and PCSS according to regional and non-regional lymph node metastasis are illustrated in Fig. 2. Significantly lower PCSS was associated with non-regional lymph node metastasis (p = 0.001), while other oncological outcomes did not show a significant difference based on lymph node metastasis status.

Patterns of failure are summarized in Table 2. Biochemical failure occurred in 14 patients (23.3%), and clinical failure occurred in 10 patients (16.7%). Among the clinical failures, three local failures (5.0%), one regional failure (1.6%), and nine distant failures (15.0%) were detected. No significant difference in patterns of failure according to regional and non-regional lymph node metastasis was reported. Moreover, all clinical failures occurred either simultaneously with (n = 8) or after (n = 2; 4.6 and 33.7 months from biochemical failure) biochemical failures. Of the 14 biochemical failures, 11 occurred after the cessation of ADT, while three occurred during ADT. The median ADT duration of 11 patients who experienced biochemical failure after cessation of ADT was 1.9 years (range, 1.3 to 2.3 years). The median duration from the last ADT administration to the biochemical failure was 2.5 years (range, 1.0 to 4.7 years).

3. Adverse events

The highest grades of genitourinary and gastrointestinal adverse events are summarized in Table 3. Acute genitourinary adverse events were reported in 25.0% of the patients, whereas late gastrointestinal adverse events were reported in 35.0%. However, no grade 4 or 5 adverse events were reported. No statistically significant differences in adverse events between patients with regional lymph node metastasis only and those with non-regional lymph node metastasis were reported. Two cases of late gastrointestinal adverse events were recorded as severe toxicities (grade 3 or beyond). One patient experienced grade 3 hematochezia 20 months after RT completion and visited a local institution to undergo transfusion and argon plasma coagulation. Although the patient did not experience additional severe adverse events, intermittent hematochezia persisted. The other patient experienced grade 3 hematochezia 22 months after RT completion and visited our institution to undergo routine sigmoidoscopy, in which, bleeding was detected during enema, and low hemoglobin levels were confirmed by blood tests. Sigmoidoscopy was performed after transfusion, and multiple angiodysplasias were detected. The patient underwent argon plasma coagulation and did not report any hematochezia afterwards.

4. Univariate and multivariate analyses

The results of the univariate and multivariate analyses of BFR and CFR based on the Cox proportional hazards ratio are summarized in Table 4. In the univariate analysis of BFR, a clinical T stage (cT4 vs. cT3; hazard ratio = 3.057; 95% confidence interval 1.102–8.481; p = 0.032) was significantly associated with BFR. However, in the multivariate analysis of BFR, a significant association with the clinical T stage was no longer maintained. No variables were significantly associated with CFR in either the univariate or multivariate analyses.

Discussion and Conclusion

This study reported our 10-year experience with definitive hypofractionated RT combined with ADT for clinically node-positive prostate cancer. The RT and ADT methodologies used in this study were homogeneous. All patients underwent definitive RT to the prostate and corresponding lymph nodes with a dose-fractionation scheme of 70 Gy in 28 fractions and long-term ADT comprising a GnRH agonist and antiandrogen. The study reported excellent survival and acceptable toxicity rates, with no grade 4–5 adverse events. Two grade 3 late gastrointestinal adverse events (hematochezia) occurred 20–22 months after RT completion. However, these events were managed by argon plasma coagulation.

Although the clinical approach should differ between node-positive prostate cancer and prostate cancer with distant metastasis, both disease entities are grouped as stage IV according to the American Joint Committee on Cancer (AJCC) [16]. Some clinicians might treat clinically node-positive prostate cancer with systemic therapy alone rather than with a curative approach, as the disease is not confined to the prostate [9]. However, previous studies have shown that a better prognosis can be achieved by using definitive RT. Several population-based studies have reported better survival rates with local treatments, such as RT and surgery, which could improve survival rates in clinically node-positive diseases [7-9,17-19]. However, these studies were not conclusive because of their retrospective nature, unbalanced characteristics between comparison groups, and limited information on treatments. Although being a post hoc analysis, data from the control arm of the prospective STAMPEDE trial also showed better survival rates with definitive RT [10]. Along with the current study, several retrospective analyses reported favorable oncological outcomes and manageable toxicities [11-13,20]. Although randomized evidence is needed for clarification, clinicians should not hesitate to recommend definitive RT for patients with clinically node-positive prostate cancer who have sufficient expected survival. A prospective randomized phase III COHORT trial (NCT03241537) is currently underway to determine the optimal treatment strategy for the disease. The COHORT trial has been designed to compare the differences in recurrence-free survival rates between ADT alone and ADT combined with RT. Enrollment has been completed for the trial, and we anticipate that the results will provide high-level evidence for managing the disease.

Interestingly, according to the Kaplan–Meier curves of BFR and CFR, most biochemical and clinical failures occurred 3 years after the initiation of the treatment. In this study, long-term ADT for at least 2 years was recommended; moreover, the use of ADT could be extended. Accordingly, 78.6% of the biochemical failures in this study occurred after the cessation of ADT. This indicated that the extended or lifelong use of ADT for node-positive prostate cancer might result in fewer recurrences. However, a potential association between the extended use of ADT and PCSS could not be established based on the data from this study. In a previous randomized trial, long-term adjuvant ADT had clinical benefits for high-risk localized prostate cancer compared with short-term ADT. The 5-year results of DART01/05 showed that 2-year adjuvant ADT was associated with a better OS than did 4 months of ADT [21]. A statistically significant increase in OS in the overall cohort was not sustained in the 10-year follow-up data; however, a clinically relevant benefit was found in a subgroup of high-risk patients [22]. This finding could be extrapolated to clinically node-positive prostate cancers treated with definitive RT. However, the continuation of adjuvant ADT for more than 2–3 years could be controversial. Various randomized trials have compared intermittent and continuous ADT in both non-metastatic and metastatic diseases [23]. Although some of these trials did not meet pre-specified statistical criteria, no significant difference in OS was reported [24-26]. Although the extended use of ADT might decrease the recurrence rate, its survival benefit should be identified before using it as a routine practice, as it has adverse effects that can impair the quality of life [27].

In this study, eight patients had suspected metastatic common iliac and para-aortic lymph nodes, which were not considered as regional lymph nodes according to the AJCC staging system [16]. No significant differences in failure rates or adverse events were observed between patients with regional and non-regional lymph node metastases. However, the patients with non-regional lymph node metastases included in this study were from a selected population, and the RT field was not significantly different from that of the routine practice for most of these patients. Of the eight patients, six had suspected common iliac lymph nodes that could be irradiated with a slight extension of the routine RT field. One patient had a suspected lower para-aortic lymph node. The LR-CTV were extended to the L4-5 level, which was still not extraordinarily enormous for the CTV.

This study had some limitations, mainly owing to its retrospective nature. The analyzed cohort size was small, and only a few events occurred, which might have hindered the statistical power of the study. Events related to oncological outcomes and adverse events might be under-reported, especially for PCSS, owing to the premature discontinuation of follow-up and the ambiguous causes of death in mortality reports. Additionally, the diagnosis of clinically node-positive prostate cancer might not have been sufficiently accurate, as the nodal staging procedure only included MRI and CT without PET/CT or pathological confirmation. Despite these limitations, this study retained its value as a patient cohort that received homogenous treatment, and the results showed that the use of moderately hypofractionated RT combined with ADT comprising a GnRH agonist and an antiandrogen has been a comparable and safe definitive treatment strategy for clinically node-positive prostate cancer.

In conclusion, this study demonstrated that use of definitive RT combined with ADT for clinically node-positive prostate cancer is a viable treatment option with decent efficacy, as indicated by the 7-year PCSS rate of 95.3%. The reported rates of grade 2 and beyond late genitourinary and gastrointestinal toxicities were 5.0% and 13.3%, respectively. However, only two grade 3 events were recorded, and all adverse events were manageable. No grade 4–5 adverse events were reported. Most biochemical failures occurred after the cessation of ADT, and the prolongation of ADT may presumably decrease the failure rate, although its effect to PCSS was unclear. Furthermore, selected patients with adjacent non-regional lymph node metastases such as common iliac and para-aortic lymph node metastases may be candidates for definitive RT. We eagerly await the results of the COHORT trial, a prospective study designed to evaluate the role of definitive RT combined with ADT for clinically node-positive prostate cancer. More studies are required to clarify the clinical efficacy of prolonged ADT, exceeding 2–3 years.

Statement of Ethics

This study was approved by the Institutional Review Board of Samsung Medical Center (Approval No. 2023-04-110).

Conflict of Interest

No potential conflict of interest relevant to this article was reported.

Funding

None.

Author Contributions

Conceptualization, HP, GSY, WP; Investigation and methodology, THL, HP, GSY, BKB, WP; Project administration, THL, SSJ, SIS, WP; Resources, HP, GSY, SSJ, SIS, BCJ, HGJ, HHS, MK, WS, JHC, WP; Supervision, SSJ, SIS, WP; Writing of the original draft, THL, WP; Writing of the review and editing, THL, WP; Software, THL, BKB; Validation, THL, WP; Formal analysis, THL, BKB; Data curation, THL, BKB, WP; Visualization, THL. All the authors have proofread the final version.

Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Fig. 1.

The Kaplan–Meier curves of (A) biochemical failure rate, (B) clinical failure rate, (C) overall survival, and (D) prostate cancer-specific survival.

Fig. 2.

The Kaplan–Meier curves of (A) biochemical failure rate, (B) clinical failure rate, (C) overall survival, and (D) prostate cancer-specific survival according to regional and non-regional lymph node metastasis.

Table 1.

Patient characteristics and treatment (n = 60)

Variable	Value
Age at diagnosis (yr)	68 (51–81)
ECOG performance status
0	48 (80.0)
1	12 (20.0)
PSA at diagnosis (ng/mL)	39.11 (4.05–370.2)
Clinical T stage
cT3a	9 (15.0)
cT3b	34 (56.7)
cT4	17 (28.3)
Gleason score
6	1 (1.7)
7	8 (13.3)
8	27 (45.0)
9	22 (36.7)
10	2 (3.3)
Number of suspected lymph nodes	3 (1–6)
Maximum size of suspected lymph nodes (mm)	11.68 (3.14–45.63)
Non-regional lymph node metastasis	8 (13.3)
Common iliac lymph nodes	6 (10.0)
Para-aortic lymph nodes	2 (3.3)
Radiation therapy modality
Intensity-modulated radiation therapy	59 (98.3)
Proton therapy	1 (1.7)
Androgen deprivation therapy regimen
Leuprorelin and bicalutamide	58 (96.7)
Goserelin and bicalutamide	2 (3.3)
Duration of androgen deprivation therapy (yr)	2.3 (1.2–11.1)

Values are presented as median (range) or number (%).

ECOG, Eastern Cooperative Oncology Group; PSA, prostate-specific antigen.

Table 2.

Patterns of failure

Adverse events	All patients (n = 60)	Subgroup analysis
Adverse events	All patients (n = 60)	Pelvic regional lymph node only (n = 52)	Non-regional lymph node (n = 8)	p-value^*
Biochemical failure	14 (23.3)	11 (21.2)	3 (37.5)	0.570
Clinical failure	10 (16.7)	8 (15.4)	2 (25.0)	0.865
Local failure	3 (5.0)	3 (5.8)	0 (0)	1.000
Regional failure	1 (1.6)	1 (1.9)	0 (0)	1.000
Distant failure	9 (15.0)	7 (13.5)	2 (25.0)	0.750

Values are presented as number (%).

^* Calculated with chi-squared test.

Table 3.

Highest grades of genitourinary and gastrointestinal adverse events

Adverse events	All patients (n = 60)	Subgroup analysis
Adverse events	All patients (n = 60)	Pelvic regional lymph node only (n = 52)	Non-regional lymph node (n = 8)	p-value^*
Acute genitourinary				0.215
0	45 (75.0)	37 (71.2)	8 (100)
1	9 (15.0)	9 (17.3)	0 (0)
2	6 (10.0)	6 (11.5)	0 (0)
Acute gastrointestinal				1.000
0	57 (95.0)	49 (94.2)	8 (100)
1	3 (5.0)	3 (5.8)	0 (0)
Late genitourinary				0.288
0	48 (80.0)	41 (78.9)	7 (87.5)
1	9 (15.0)	9 (17.3)	0 (0)
2	3 (5.0)	2 (3.8)	1 (12.5)
Late gastrointestinal				0.432
0	39 (65.0)	35 (67.3)	4 (50.0)
1	13 (21.7)	11 (21.2)	2 (25.0)
2	6 (10.0)	4 (7.7)	2 (25.0)
3	2 (3.3)	2 (3.8)	0 (0)

Values are presented as number (%).

^* Calculated with chi-squared test.

Table 4.

Univariate and multivariate analyses of biochemical and clinical failure rates

Variable (comparison vs. reference)	Biochemical failure rate (number of events = 14)				Clinical failure rate (number of events = 10)
	Univariate		Multivariate		Univariate		Multivariate
	HR (95% CI)	p-value	HR (95% CI)	p-value	HR (95% CI)	p-value	HR (95% CI)	p-value
Age at diagnosis (continuous, per year)	0.960 (0.893–1.032)	0.267	0.949 (0.866–1.040)	0.261	0.958 (0.880–1.043)	0.324	0.965 (0.872–1.068)	0.491
PSA level at diagnosis (per 1 ng/mL)	1.005 (1.000–1.010)	0.072	1.006 (0.999–1.012)	0.079	1.003 (0.996–1.011)	0.383	1.004 (0.996–1.011)	0.376
Clinical T stage (cT4 vs. cT3)	3.388 (1.179–9.734)	0.024^*	2.549 (0.595–10.92)	0.207	3.397 (0.962–11.99)	0.056	2.579 (0.479–13.87)	0.270
Gleason score (9–10 vs. 6–8)	2.959 (0.991–8.838)	0.052	2.502 (0.690–9.066)	0.163	2.381 (0.671–8.457)	0.180	1.752 (0.401–7.656)	0.456
Number of suspected lymph nodes (continuous, per 1)	1.051 (0.771–1.433)	0.753	0.799 (0.472–1.351)	0.402	1.091 (0.759–1.568)	0.637	0.982 (0.575–1.678)	0.947
Maximum size of suspected lymph nodes (continuous, per mm)	1.014 (0.958–1.072)	0.637	1.059 (0.964–1.164)	0.230	1.009 (0.941–1.081)	0.808	1.020 (0.918–1.134)	0.712
Non-regional lymph node metastasis (yes vs. no)	1.554 (0.429–5.632)	0.503	1.896 (0.359–10.00)	0.451	1.441 (0.302–6.883)	0.647	1.801 (0.250–12.98)	0.559

PSA, prostate-specific antigen; HR, hazard ratio; CI, confidence interval.

^* p<0.05.

References

1. Sung H, Ferlay J, Siegel RL, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2021;71:209–49.

2. Siegel DA, O'Neil ME, Richards TB, Dowling NF, Weir HK. Prostate cancer incidence and survival, by stage and race/ethnicity: United States, 2001-2017. MMWR Morb Mortal Wkly Rep 2020;69:1473–80.

3. Kim E, Jang WI, Yang K, et al. Clinical utilization of radiation therapy in Korea between 2017 and 2019. Radiat Oncol J 2022;40:251–9.

4. National Comprehensive Cancer Network. NCCN Guidelines: prostate cancer [Internet]. Plymouth Meeting, PA: National Comprehensive Cancer Network; c2024 [cited 2024 Apr 10]. Available from: https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1459.

5. Parker C, Castro E, Fizazi K, et al. Prostate cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2020;31:1119–34.

6. Lieng H, Kneebone A, Hayden AJ, et al. Radiotherapy for node-positive prostate cancer: 2019 recommendations of the Australian and New Zealand Radiation Oncology Genito-Urinary group. Radiother Oncol 2019;140:68–75.

7. Tward JD, Kokeny KE, Shrieve DC. Radiation therapy for clinically node-positive prostate adenocarcinoma is correlated with improved overall and prostate cancer-specific survival. Pract Radiat Oncol 2013;3:234–40.

8. Rusthoven CG, Carlson JA, Waxweiler TV, et al. The impact of definitive local therapy for lymph node-positive prostate cancer: a population-based study. Int J Radiat Oncol Biol Phys 2014;88:1064–73.

9. Lin CC, Gray PJ, Jemal A, Efstathiou JA. Androgen deprivation with or without radiation therapy for clinically node-positive prostate cancer. J Natl Cancer Inst 2015;107:djv119.

10. James ND, Spears MR, Clarke NW, et al. Failure-free survival and radiotherapy in patients with newly diagnosed nonmetastatic prostate cancer: data from patients in the control arm of the STAMPEDE trial. JAMA Oncol 2016;2:348–57.

11. Lilleby W, Narrang A, Tafjord G, et al. Favorable outcomes in locally advanced and node positive prostate cancer patients treated with combined pelvic IMRT and androgen deprivation therapy. Radiat Oncol 2015;10:232.

12. Mallick I, Das A, Arunsingh M. Moderately hypofractionated radiotherapy in node-positive prostate cancer. Clin Oncol (R Coll Radiol) 2019;31:260–4.

13. Onishi M, Kawamura H, Murata K, et al. Intensity-modulated radiation therapy with simultaneous integrated boost for clinically node-positive prostate cancer: a single-institutional retrospective study. Cancers (Basel) 2021;13:3868.

14. Lawton CA, Michalski J, El-Naqa I, et al. RTOG GU Radiation oncology specialists reach consensus on pelvic lymph node volumes for high-risk prostate cancer. Int J Radiat Oncol Biol Phys 2009;74:383–7.

15. Harris VA, Staffurth J, Naismith O, et al. Consensus guidelines and contouring atlas for pelvic node delineation in prostate and pelvic node intensity modulated radiation therapy. Int J Radiat Oncol Biol Phys 2015;92:874–83.

16. American Joint Committee on Cancer. AJCC cancer staging manual. 8th ed. Cham, Switzerland: Springer International Publishing; 2017.

17. Zagars GK, Pollack A, von Eschenbach AC. Addition of radiation therapy to androgen ablation improves outcome for subclinically node-positive prostate cancer. Urology 2001;58:233–9.

18. Seisen T, Vetterlein MW, Karabon P, et al. Efficacy of local treatment in prostate cancer patients with clinically pelvic lymph node-positive disease at initial diagnosis. Eur Urol 2018;73:452–61.

19. Bryant AK, Kader AK, McKay RR, et al. Definitive radiation therapy and survival in clinically node-positive prostate cancer. Int J Radiat Oncol Biol Phys 2018;101:1188–93.

20. Fonteyne V, De Gersem W, De Neve W, et al. Hypofractionated intensity-modulated arc therapy for lymph node metastasized prostate cancer. Int J Radiat Oncol Biol Phys 2009;75:1013–20.

21. Zapatero A, Guerrero A, Maldonado X, et al. High-dose radiotherapy with short-term or long-term androgen deprivation in localized prostate cancer (DART01/05 GICOR): a randomised, controlled, phase 3 trial. Lancet Oncol 2015;16:320–7.

22. Zapatero A, Guerrero A, Maldonado X, et al. High-dose radiotherapy and risk-adapted androgen deprivation in localised prostate cancer (DART 01/05): 10-year results of a phase 3 randomised, controlled trial. Lancet Oncol 2022;23:671–81.

23. Perera M, Roberts MJ, Klotz L, et al. Intermittent versus continuous androgen deprivation therapy for advanced prostate cancer. Nat Rev Urol 2020;17:469–81.

24. Crook JM, O'Callaghan CJ, Duncan G, et al. Intermittent androgen suppression for rising PSA level after radiotherapy. N Engl J Med 2012;367:895–903.

25. Hussain M, Tangen CM, Berry DL, et al. Intermittent versus continuous androgen deprivation in prostate cancer. N Engl J Med 2013;368:1314–25.

26. Schulman C, Cornel E, Matveev V, et al. Intermittent versus continuous androgen deprivation therapy in patients with relapsing or locally advanced prostate cancer: a phase 3b randomised study (ICELAND). Eur Urol 2016;69:720–7.

27. Nguyen PL, Alibhai SM, Basaria S, et al. Adverse effects of androgen deprivation therapy and strategies to mitigate them. Eur Urol 2015;67:825–36.