Quality of Life of Metastatic Prostate Cancer Patients Treated with Prostate Radiotherapy

doi:10.21203/rs.3.rs-3128164/v1

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Research Article

Quality of Life of Metastatic Prostate Cancer Patients Treated with Prostate Radiotherapy

https://doi.org/10.21203/rs.3.rs-3128164/v1

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Journal Publication

published 02 Oct, 2023

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Background

The impact of prostate radiotherapy on patient-reported health-related quality of life (HRQoL) significantly influences the outcomes of metastatic prostate cancer. We measured and compared HRQoL of metastatic prostate cancer patients who received cytoreductive prostate radiotherapy.

Methods

Between November 23, 2020, and November 21, 2022, we recruited 70 metastatic prostate cancer patients at the Department of Clinical Oncology at Suez Canal University Hospital. Patients were eligible if they had synchronous and metachronous histopathological confirmed metastatic adenocarcinoma and an Eastern Cooperative Oncology Group performance status ≤ 2. Random allocation was performed for either definitive local radiotherapy concurrent with the standard androgen deprivation therapy (ADT) or to the standard ADT alone. Definitive radiotherapy was delivered conventionally (70 Gy/35 fractions) or through the hypofractionated regimen (55 Gy/20 fractions). Patients completed the comprehensive European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-PR25) at baseline, then at three-month intervals for one year. The primary endpoint was patient-reported HRQoL, with secondary endpoints including toxicity and radiographic progression-free survival (rPFS). Mean HRQoL scores between groups were compared using the independent samples t-test.

Results

We observed clinically significant improvements in urinary and bowel functions between baseline, 3-month, 6-month, and 12-month intervals after receiving definitive prostate radiotherapy. Patients in the radiotherapy group had significantly lower urinary symptoms scores than the control group. However, sexual activity and functioning showed significant deterioration.

Conclusion

Cytoreductive prostate radiotherapy in metastatic prostate cancer patients significantly improved urinary functioning, preserved bowel functioning but was associated with worsening of sexual functioning.

Trial Registration

This trial was registered on (27/04/2023) with pactr.samrc.ac.za, PACTR202305854600529, URL: https://pactr.samrc.ac.za/TrialDisplay.aspx?TrialID=25510

ADT

Cytoreductive

HRQoL

Metastatic prostate cancer

Prostate radiotherapy

Prostate cancer has been globally expanding placing a high burden on patient reported health related quality of life (HRQoL). Recently, prostate cancer has become the second mostly diagnosed male cancer with a rising incidence by 3% annually for the last 5 years. According to SEER data, an estimated 288,300 new prostate cancer patients will be diagnosed in 2023 representing approximately 14% of all new cancer cases (1). Metastatic disease accounts for 6–8% of newly diagnosed prostate cancer cases (2).

Upfront combination treatments that have been greatly encouraged and adopted in the management of metastatic prostate cancer patients have negatively impacted upon health-related quality of life (HRQoL) (3). Short-term and long-term HRQoL should be considered before choosing the most tailored treatment for metastatic prostate cancer patients (4).

Prostate-directed radiotherapy is a new standard practice that has shown substantial benefits in delaying disease progression and improving survival outcomes (5, 6). However, combining prostate radiotherapy with the standard androgen-deprivation therapy affects patients’ physical, emotional, sexual, and social health. Ultimately, HRQoL after local radiotherapy depends on the total dose, fractionation regimen and the dose received by the critical organs (7).

Early genitourinary toxicities may include obstructive and irritative symptoms such as frequency, nocturia and urgency. Early gastrointestinal toxicities include diarrhea, rectal bleeding, and abdominal pain. These symptoms typically disappear within 4–8 weeks after finishing prostate radiotherapy. However, some patients might suffer from proctitis with rectal bleeding as a late rectal toxicity. Less commonly patients might suffer hematuria as a late bladder toxicity (8).

Undoubtedly, assessing health-related quality of life facilitates improved treatment outcomes. Focusing on reporting various quality of life domains, including urinary, sexual and bowel functions for each patient is associated with improved survival outcomes. Thus, standardizing HRQoL assessment tools, their scoring and interpretation in metastatic prostate cancer patients receiving prostate radiotherapy is necessary to optimize treatment outcomes and improve patients’ adherence to treatment and health care facilities (9). In addition to using validated patient-reported outcome measures (PROMs) to evaluate HRQoL, reporting radiotherapy-related adverse events is complementary to assess patients’ tolerability and treatment efficacy. This study aimed to assess the impact of delivering cytoreductive local radiotherapy concurrently with ADT on patient reported HRQoL.

Study design and conduct

A phase III randomized controlled study was conducted from November 2020 to November 2022 at the Clinical Oncology Department, Suez Canal University Hospital in Ismailia, Egypt. The study aimed to assess the patient-reported HRQoL and toxicity profile in metastatic prostate cancer patients who received local prostate-directed radiotherapy concurrent with ADT. The study protocol was approved by the Research Ethics Committee at the Faculty of Medicine, Suez Canal University prior to its commencement. All patients provided written informed consent before enrollment and had the right to withdraw from the study at any time.

Patients

This study included eligible patients who had de-novo or metachronous metastatic prostate cancer with histologically proven adenocarcinoma and a performance score ≤ 2 according to the Eastern Cooperative Oncology Group (ECOG) performance scale, with or without nodal involvement, low metastatic burden prostate cancer (< 4 bone metastases), or high metastatic burden prostate cancer (≥ 4 bone metastases at least 1 beyond spine or pelvis, ± visceral metastases) according to CHAARETED definition. Patients were excluded if they had a second neoplasm, ECOG performance score > 2, underwent radical prostatectomy, received prior pelvic radiotherapy, or had cerebral metastases. We recruited and enrolled 70 patients at our institution between November 2020 and November 2022. Then, 63 patients were randomly allocated to receive either prostate radiotherapy concurrent with ADT (Prostate RT group) or the standard ADT (control group).

Randomization and masking

Randomization was conducted using computer generated block randomization with a block size of 4 which consisted of 2 treatments with 2 patients per treatment. Stratification of patients at randomization was not performed, and allocation was not masked due to the nature of the intervention.

Intervention

All patients with metastatic prostate cancer received the standard ADT (Gonadotropin hormone–releasing hormone agonist ± bicalutamide) or underwent orchiectomy 2 months prior to randomization. Local external beam radiotherapy was administered as one of two regimens either: conventional regimen 70 Gy in 35 daily fractions of 2 Gy over 7 weeks, or hypofractionated regimen 55 Gy in 20 daily fractions of 2.75 Gy over 4 weeks. Patients were simulated in supine position with an empty rectum and comfortably full bladder. Pelvic immobilization was maintained using knee support. Planning CT scans were acquired without intravenous contrast. We employed forward planned three-dimensional (3D) conformal radiotherapy with planning target volume (PTV) that encompassed the prostate with a 10 mm margin circumferentially, except posteriorly (6 mm) and the proximal 2 cm of seminal vesicles. Elective pelvic nodal irradiation was not included in the field. Patients were followed-up weekly during radiotherapy, then 1 month after finishing radiotherapy, then every 3 months for a year.

All patients were then requested to complete the European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire Prostate Module (EORTC-QLQ-PR25) at baseline and then every 3 months throughout the study. This module consists of multi-item scales designed to measure prostate cancer-specific health-related quality of life outcomes (Supplementary File. 1). The module comprises 25 questions, all of which should be completed by the patient. We used this questionnaire to assess baseline HRQoL in metastatic prostate cancer patients receiving standard of care and to determine changes in patient-reported HRQoL after prostate radiotherapy (10). The questions in the prostate cancer module are grouped into symptom scales and functional scales. The symptoms scales assess urinary symptoms (Questions 1–7,9), incontinence aid (Question 8), bowel symptoms (Questions 10–13) and hormonal treatment-related symptoms (Questions 14–19). The functional scales consist of questions related to sexual activity (Questions 20,21) and sexual functioning (Questions 22–25). Scoring of the EORTC QLQ-PR25 was carried out according to the provided EORTC scoring manual. The calculated raw score for each scale is linearly transformed into a scale from 0-100 points (Supplementary File. 2). Higher scores on symptomatic scales indicate greater symptom severity whereas higher scores on functioning scales indicate better levels of functioning.

During treatment, early and late genitourinary and gastrointestinal toxicity symptoms were reported weekly. After treatment, these symptoms were reported every 3 months during regular follow-up visits or when serious adverse events occurred, and these events were graded according to the Radiation Therapy Oncology Group (RTOG) scale. Early toxicity was recorded within the first 90 days post-radiation while late toxicity was recorded after 90 days. The metastatic burden of the disease was assessed through CT and bone scans and classified according to the CHAARTED definition. High metastatic burden disease was defined as four or more bone lesions with one or more outside the vertebral bodies or pelvis or visceral metastases, or both. Low metastatic burden disease was associated with less than four bone lesions not extending beyond the spine or pelvis. Radiographic response after radiation was monitored every 6 months using CT chest and pelvi-abdominal scans and evaluated based on the RECIST 1.1 criteria (11).

Endpoints

The primary endpoint of this study was patient-reported health-related quality of life (HRQoL). Secondary endpoints included early and late radiation toxicity for the prostate-radiotherapy group and radiographic progression-free survival.

Statistical Analysis

Statistical analysis was conducted using the Statistical Package for Social Science (SPSS), version 28 (IBM Corporation, Armonk, NY, USA). The independent t-test was used to compare mean HRQoL scores between groups while the Friedman’s test was used to compare mean HRQoL scores over one year. The Fisher’s exact test and Pearson’s Chi square test were conducted to test for the significance of association between variables. Radiographic progression-free survival was measured using Cox Regression analysis and the Log-Rank test was used for comparison between study groups. The hazard ratio and its 95% confidence interval were calculated using multivariate Cox regression to determine the association between variables and radiographic progression-free survival. The statistical significance for radiographic progression-free survival was measured using the Wilcoxon signed rank test. Post-hoc survival analysis was conducted to correlate radiographic progression-free survival with the metastatic burden of the disease. Additionally, exploratory subgroup analysis was performed to compare the median radiographic progression-free survival time among different subgroups. Subgroup analyses were pre-specified for the baseline metastatic volume (low vs high), the response to androgen deprivation (castration sensitive vs resistant) and the received radiotherapy regimen (conventional 70Gy vs hypofractionated 55Gy). All statistical tests were two-sided, and p-values of < 0.05 were considered statistically significant.

From November 23, 2020, to November 21, 2022, a total of 63 patients were enrolled and randomly assigned to either the control group receiving standard ADT (n = 29) or the radiotherapy group receiving standard ADT and radiotherapy (n = 34). Among the radiotherapy group, 20 patients received the hypofractionated radiation schedule, while the remaining 14 patients received the conventional fractionation schedule. Only one patient in the conventional fractionation group stopped treatment after receiving 11 sessions due to severe cardiac comorbidity (Fig. 1). The study groups were well balanced regarding baseline sociodemographic and clinicopathological characteristics.

The median age of patients was 70 years (IQR 66–75). The most common histopathological variant in both study groups was acinar adenocarcinoma (88.9%). The most frequent histological grade observed was GS 8–10 (47.6%). The most common pathological stages were T3 (38.1%) and N0 (61.9%). The most common site of metastases was bone (69.8%). The radiotherapy group had a significantly higher incidence of nodal positive disease (p = 0.035). High-volume metastatic disease was present in 63.5% of patients in both groups, and most patients had synchronous metastatic disease (85.7%). Most patients in both groups had an ECOG performance score of 1 (65.1%). Clinically, most patients suffered frequency (87.3%), urgency (95.2%), difficulty (88.9%), and dysuria (84.1%). Patients in the control group had significantly more skeletal-related events than those in the radiotherapy group (62.1%, p = 0.001). The median duration of androgen deprivation therapy was 4.25 months (IQR 2.5-9) for the radiotherapy group and 2.8 months (IQR 1.94-7) for the control group. Most patients received combined GnRH agonist and bicalutamide (71.4%). The majority of patients were castrate sensitive (68.3%), while 31.7% were castrate resistant. Docetaxel was received by 25.4% of patients in both groups, whereas 22.2% received abiraterone acetate. Very few patients received enzalutamide (4.8%) (Table 1).

Table 1

Sociodemographic and clinicopathological characteristics among study groups
Variables	Prostate RT group n = 34 (54%)	Control group n = 29 (46%)	P-value
Age (years) < 65	10 (29.4%)	4 (13.8%)	0.224 ^f
> 65	24 (70.6%)	25 (86.2%)
Median (IQR)	68 (64–72)	73 (68.5–79.5)
Marital status Married	24 (70.6%)	14 (48.3%)	0.068 ^f
Single	10 (29.4%)	15 (51.7%)
Residence Rural	10 (29.4%)	11 (37.9%)	0.478
Urban	24 (70.6%)	18 (62.1%)
Histopathological variant Acinar adenocarcinoma	32 (94.1%)	24 (82.8%)	0.233 ^f
Others	2 (5.9%)	5 (17.2%)	0.233 ^f
GS ≤ 7	12 (35.3%)	4 (13.8%)	0.081 ^f
8–10	22 (64.7%)	25 (86.2%)	0.081 ^f
T Stage T2	13 (38.2%)	8 (27.6%)	0.371
T ≥ 3	21 (61.8%)	21 (72.4%)	0.371
N Stage N0	17 (50%)	22 (75.9%)	0.035*
N+	17 (50%)	7 (24.1%)	0.035*
Site of metastases Bones	23 (67.6%)	21 (72.4%)	0.628 ^f
Lungs	2 (5.9%)	-
> 1 site	9 (26.5%)	8 (27.6%)
Metastatic burden High metastatic burden	18 (52.9%)	22 (75.9%)	0.060
Low metastatic burden	16 (47.1%)	7 (24.1%)	0.060
Timing of Metastases Synchronous	27 (79.4%)	27 (93.1%)	0.160 ^f
Metachronous	7 (20.6%)	2 (6.9%)	0.160 ^f
Performance status
≤ 1	25 (73.5%)	17 (58.6%)	0.211
2	9 (26.5%)	12 (41.4%)
ADT Duration, median (IQR)	4.25 (2.5-9)	2.8 (1.9-8)	0.073
GnRH agonist only	3 (8.8%)	5 (17.2%)	0.453 ^f
Bicalutamide only	6 (17.6%)	3 (10.3%)	0.488 ^f
Both	25 (73.5%)	21 (72.4%)	0.921
Response to ADT Castration naïve/sensitive	24 (70.6%)	19 (65.5%)	0.666
Castration resistant	10 (29.4%)	10 (34.5%)
Docetaxel	7 (20.6%)	9 (31%)	0.342
Abiraterone acetate	10 (29.4%)	4 (13.8%)	0.224 ^f
Enzalutamide	2 (5.9%)	1 (3.4%)	1.000 ^f
Palliative RT	9 (26.5%)	25 (86.2%)	< 0.001*
Comorbidities	22 (64.7%)	19 (65.5%)	0.946

RT: radiotherapy, IQR: Interquartile range, N+: node positive, ADT: Androgen deprivation therapy, GnRH: Gonadotropin releasing hormone SRE: skeletal-related events, GS: Gleason score.

^f. Fisher's exact test *. Statistically significant p value

After a median follow-up duration of 12 months (IQR 10–14), there was a significant improvement in urinary and bowel functions at 3 months, 6 months, and 12 months intervals compared to baseline. However, there was a statistically significant worsening of ADT related symptoms, sexual activity, and sexual functioning at 3 months, 6 months, and 12 months intervals compared to baseline (Table 2).

Table 2

Quality of life scoring of the prostate radiotherapy group over one year
EORTC QLQ-PR25	Mean (SD)	P-value
Urinary functions Baseline	76.76 (15.1)	< 0.001*
3 months	15.06 (17.32)
6 months	12.02 (15.15)
9 months	12.02 (15.15)
12 months	11.22 (15.17)
Incontinence aid Baseline	14.10 (31.51)	0.144
3 months	10.26 (26.28)
6 months	11.54 (29.73)
9 months	11.54 (29.73
12 months	11.54 (29.73)
Bowel functions Baseline	13.78 (10.26)	< 0.001*
3 months	10.26 (5.92)
6 months	8.79 (5.74)
9 months	8.33 (5.78)
12 months	8.33 (5.78)
ADT-related symptoms Baseline	57.1 (17.11)	< 0.001*
3 months	60.47 (17.87)
6 months	63.03 (17.98)
9 months	64.74 (18.52)
12 months	64.96 (18.51)
Sexual activity Baseline	32.05 (18.81)	< 0.001*
3 months	18.27 (14.72)
6 months	16.34 (14.24)
9 months	13.78 (10.53)
12 months	13.46 (10.56)
Sexual function Baseline	14.10 (12.42)	< 0.001*
3 months	3.53 (5.86)
6 months	3.53 (5.86)
9 months	3.53 (5.86)
12 months	3.53 (5.86)
*. Statistically significant p value

Patients in the prostate radiotherapy group had statistically significantly lower and better scores in urinary symptoms and ADT related symptoms than patients in the control group at 3 months, 6 months, 9 months, and 12 months (p < 0.001) (Table 3).

Table 3

Comparing quality of life domains scoring between study groups
QLQ-PR25 Variables	Prostate RT group	Control group	P-value
QLQ-PR25 Variables	Mean (SD)	Mean (SD)	P-value
QoL Urinary functions
Baseline	78.19 (15.11)	77.44 (14.58)	0.844
3 months	18.75 (20.25)	62.19 (15.67)	< 0.001*
6 months	15.19 (17.33)	59.24 (18.20)	< 0.001*
9 months	12.5 (14.96)	61.04 (20.56)	< 0.001*
12 months	11.22 (15.17)	59.29 (22.89)	< 0.001*
QoL Bowel functioning
Baseline	15.44 (11.26)	8.33 (8.34)	0.707
3 months	12.5 (9.7)	13.58 (14.83)	0.738
6 months	11.02 (8.97)	11.96 (13.02)	0.756
9 months	8.63 (5.78)	13.33 (13.63)	0.108
12 months	15.38 (20.93)	14.08 (17.12)	0.114
QoL Incontinence aid
Baseline	16.67 (83.34)	31.03 (44.48)	0.147
3 months	13.54 (30.36)	25.93 (38.49)	0.173
6 months	11.83 (29.25)	20.29 (31.37)	0.313
9 months	10.71 (28.77)	21.67 (34.67)	0.239
12 months	11.54 (29.73)	28.21 (38.12)	0.142
QoL ADT symptoms
Baseline	58.33 (16.08)	68.01 (10.46)	0.006*
3 months	62.33 (17.04)	75.72 (6.19)	< 0.001*
6 months	64.87 (17.36)	77.05 (4.53)	< 0.001*
9 months	65.87 (18.31)	78.61 (4.52)	0.001*
12 months	64.96 (18.51)	79.06 (5.15)	0.001*
QoL Sexual activity
Baseline	28.92 (18.03)	12.64 (12.32)	< 0.001*
3 months	16.40 (13.96)	9.88 (11.56)	0.058
6 months	14.78 (13.56)	8.7 (12.17)	0.095
9 months	13.1 (10.5)	6.67 (11.34)	0.053
12 months	13.46 (10.56)	7.69 (11)	0.121
QoL Sexual functioning
Baseline	12.26 (11.83)	2.3 (5.41)	< 0.001*
3 months	2.86 (5.44)	2.47 (4.51)	0.765
6 months	2.96 (5.51)	1.89 (3.57)	0.431
9 months	3.27 (5.71)	0.83 (2.56)	0.081
12 months	3.53 (5.86)	0.64 (2.31)	0.097

*. Statistically significant p value derived from independent samples t-test, SD: standard deviation.

QoL: quality of life, RT: radiotherapy, QLQ: quality of life questionnaire, ADT: Androgen deprivation therapy

Furthermore, there was no statistically significant difference between patients who received either fractionation regimens in terms of early or late genitourinary and gastrointestinal events. The most observed significant acute GU toxicity in both fractionation arms was cystitis (G2 in 58.8% and G3 + in 32.3%). Acute G2 hematuria developed in 38.2% and G3 + in 32.3% of patients. Acute G2 urinary obstruction occurred in 2.9% and G3 + in 32.3% of patients (Table 4).

Meanwhile, acute proctitis and abdominal pain were the most common acute GI toxicities in both fractionation schedules, with G2 toxicity occurring in 32.3% of patients and G3 + in 14.7%. Acute G2 diarrhea was reported in 8.8% of patients, and G3 + in 3 patients (8.8%). Patients who received the hypofractionation regimen experienced a higher-grade acute diarrhea. In addition, acute anal fissure/fistula was detected in 3 patients (8.8%), with 2 patients developing acute anal fissure and one patient developing acute perianal fistula. Acute G3 + rectal bleeding developed in 3 patients (8.8%) (Table 4).

The most common late GU toxicities observed in both fractionation schedules were late cystitis and bladder spasm, with G2 toxicity occurring in 6.4% of patients and G3 + in 12.9%. Late hematuria was reported as G2 in 3.2% of patients and G3 + in 12.9%. Four patients (12.9%) developed late G3 + urinary obstruction, and all patients in both arms experienced erectile dysfunction.

The most prevalent late GI toxicities in both fractionation schedules were proctitis and abdominal pain, with G2 toxicity occurring in 3.2% of patients and G3 + in 3.2%. Additionally, late rectovesical fistula developed in 1 patient (3.2%) (Table 4).

Table 4

Incidence of significant genitourinary and gastrointestinal toxicities in patients receiving prostate radiotherapy
Toxicity	Fractionation type		P-value
Toxicity	Conventional n = 14 (41.2%)	Hypofractionation n = 20 (58.8%)	P-value
Acute GU toxicity G2+	12 (85.7%)	19 (95%)	0.555 ^f
Cystitis, bladder spasm G2	9 (75%)	11 (57.9%)	0.452 ^f
G3+	3 (25%)	8 (42.1%)	0.452 ^f
Hematuria G2	6 (66.7%)	(46.7%)	0.423 ^f
G3+	3 (33.3%)	8 (53.3%)	0.423 ^f
Obstruction G2	0 (0%)	(12.5%)	1.000 ^f
G3+	4 (100%)	7 (87.5%)	1.000 ^f
Acute GI toxicity G2+	7 (50%)	9 (45%)	0.774
Diarrhea G2	3 (100%)	-	0.100 ^f
G3+	-	3 (100%)	0.100 ^f
GI upset G2	4 (100%)	1 (25%)	0.143 ^f
G3+	-	3 (75%)	0.143 ^f
Proctitis, Abdominal pain G2	6 (85.7%)	5 (55.6%)	0.308 ^f
G3+	1 (14.3%)	4 (44.4%)	0.308 ^f
Fissure/ fistula G3+	2 (14.3%)	1 (5%)	0.555 ^f
Rectal bleeding G3+	2 (14.3%)	1 (5%)	0.555 ^f
Late GU toxicity G2+	2 (16.7%)	3 (17.6%)	1.000 ^f
Cystitis, bladder spasm G2	1 (33.3%)	1 (33.3%)	1.000 ^f
G3+	2 (66.7%)	2 (66.7%)
Hematuria G2	-	1 (33.3%)	1.000 ^f
G3+	2 (100%)	2 (66.7%)
Obstruction G3+	(16.7%)	2 (11.8%)	1.000 ^f
Erectile dysfunction	11 (100%)	17 (100%)	----
Late GI toxicity G2+	1 (9.1%)	1(5.9%)	1.000 ^f
Proctitis, Abdominal pain G2	-	1 (100%)	1.000 ^f
G3+	1 (100%)	-
Fissure/ fistula G3+	1 (9.1%)	-	0.393 ^f
^f. Fisher's exact test. GU: Genitourinary, GI: Gastrointestinal, G2+: Grade 2 or higher, G3+: Grade 3 or higher

For the radiotherapy group, the median radiographic progression-free survival was not reached, compared to 4.067 months for the control group. The radiotherapy group had a significantly longer radiographic progression-free survival than the control group (not reached vs 4.067 months, Log-rank p < 0.001), with a risk of radiographic progression that was 0.167 times that of the control group (HR: 0.167, 95% CI 0.081–0.344; p < 0.001) (Fig. 2).

Further confirmatory subgroup analysis revealed that low volume metastatic patients in the radiotherapy group had a significantly lower risk of radiographic progression compared to those in the control group (HR: 0.029, 95% CI 0.003–0.244; p = 0.004). Similarly, high-volume metastatic patients in the radiotherapy group had a significantly lower risk of radiographic progression than those in the control group (HR: 0.343, 95% CI 0.160–0.739; p = 0.006). Furthermore, the metastatic castration-sensitive patients who received radiotherapy had a significantly lower risk of radiographic progression than those in the control group (HR: 0.096, 95% CI 0.032–0.292; p < 0.001) (Fig. 3).

The multivariable analysis of radiographic progression-free survival in subgroups receiving prostate radiotherapy showed that radiographic progression-free survival was significantly associated with the low volume metastatic subgroup (adjusted HR: 0.104, 95% CI 0.013–0.857; p = 0.035) but non significantly associated with the castration-sensitive subgroup (adjusted HR: 0.305, 95% CI 0.083–1.117; p = 0.073) or the hypofractionation regimen subgroup (adjusted HR: 0.650, 95% CI 0.185–2.287; p = 0.502) (Table 5).

Table 5

Univariate and Multivariate subgroup analysis of radiographic progression-free survival in prostate radiotherapy group
Subgroup	Univariate				Multivariate
	HR	P-value	95% CI		HR	P-value	95% CI
	HR	P-value	Lower	Upper	HR	P-value	Lower	Upper
Metastatic burden
Low metastatic burden	0.091	0.023*	0.012	0.716	0.104	0.035*	0.013	0.857
High metastatic burden	1				1
Response to ADT
Castration sensitive	0.233	0.021*	0.068	0.805	0.305	0.073	0.083	1.117
Castration resistant	1				1
Fractionation
Hypofractionation	0.740	0.621	0.226	2.433	0.650	0.502	0.185	2.287
Conventional	1				1
*. Statistically significant p value
HR: Hazard ratio, CI: Confidence interval, ADT: Androgen deprivation therapy

We conducted a post-hoc analysis which showed that the median radiographic progression-free survival was significantly higher and not reached in the low volume and castration-sensitive metastatic subgroups compared to the high-volume and castration-resistant metastatic subgroups (p = 0.004, p = 0.012). The risk of radiographic progression among patients in the low volume metastatic subgroup who received prostate radiotherapy was 0.091 times the risk among patients in the high-volume subgroup. No significant difference was found between the two fractionation schedules in terms of median radiographic progression-free survival (p = 0.620).

This study was a randomized controlled trial aimed at investigating the benefits of adding prostate radiotherapy to standard androgen deprivation therapy in metastatic prostate cancer patients. We aimed at evaluating the patient-reported health-related quality of life outcomes and the tolerability of prostate radiotherapy in these patients. In this study, we stratified metastatic prostate cancer patients according to their disease burden, classifying them as either having high or low burden metastatic disease. In contrast, Boevé et al. subgrouped their patients based on the number of bone lesions, with < 5, 5–15, or more bone lesions, as determined by bone scan and conventional imaging. They did not stratify patients at the time of randomization (12). However, Parker et al. also stratified their patients into low and high burden metastatic disease groups based on the metastatic burden at randomization (13).

With regard to radiation dose, we delivered the same conventionally fractionated regimen of 70Gy in 35 fractions over 7 weeks, as prescribed by Boevé et al. Alternatively, we delivered the same hypofractionated regimen of 55Gy in 20 daily fractions over 4 weeks, as prescribed by Parker et al. Apart from the therapeutic benefit, radiobiological rationale, and good local response to the hypofractionated schedule, there were several advantages, such as shortening overall treatment time, saving medical resources, and improving patient convenience (5, 13).

Treating metastatic prostate cancer patients with prostate radiotherapy positively impacted different quality-of-life domains, including urinary and bowel functions. However, the deterioration in sexual activity and functioning developed after a time as a negative consequence of long-term ADT. In contrast, Boevé et al. concluded that patients reported significantly more diarrhea, bowel symptoms, and urinary symptoms after receiving prostate radiotherapy and ADT compared to ADT alone (p < 0.001) (14). Corresponding to our findings, Parker et al. reported that prostate radiotherapy did not negatively impact HRQoL, with no differences in quality-of-life scores over time (6).

Regarding acute and late toxicities, our data showed that acute significant G3 or higher (G3+) genitourinary adverse events were detected in 32.3% of patients in the prostate radiotherapy group. Additionally, acute significant G3 + gastrointestinal adverse events occurred in 14.7% of patients after radiotherapy. On the other hand, late significant G3 + genitourinary adverse events were detected in 12.9%, whereas late significant G3 + gastrointestinal adverse events were seen in 3.2% of patients after radiotherapy. Our study reported more significant G3 + acute and late genitourinary and acute gastrointestinal adverse events than reported by Parker et al. The late significant G3 + genitourinary toxicity was observed in 2% of their patients within 1 year of prostate radiotherapy. Late significant G3 + gastrointestinal toxicities were comparably reported for 3% of their patients (6). This can be attributed to more patients receiving systemic treatment and the absence of the high-precision Intensity modulated radiation therapy (IMRT) technique in our study. Contrary to our study, in which all patients were treated with 3D conformal radiotherapy, Cho et al. reported that 71% of their patients were treated with IMRT, and none of them developed significant gastrointestinal or genitourinary toxicity (15).

Furthermore, the regression analysis demonstrated the significant impact of delivering prostate radiotherapy on radiographic progression-free survival in metastatic prostate cancer patients. Consistent with our findings, Boevé et al. showed that the median progression-free survival was statistically significantly associated with low metastatic volume disease (HR: 0.15, p = 0.005) and castration-sensitive disease (HR: 0.22, p = 0.004) (16).

Our prespecified subgroup analysis revealed that prostate radiotherapy improved progression-free survival in low metastatic volume (HR: 0.029, p = 0.004), high metastatic volume (HR: 0.343, p = 0.006), and metastatic castration-sensitive disease (HR: 0.096, p < 0.001). Meanwhile, Parker et al. found that prostate radiotherapy improved failure-free survival in all patients (HR: 0.76, p < 0.0001) and progression-free survival in patients with low metastatic burden (HR: 0.78, p < 0.0001) after a median follow-up of 37 months (13). Parallel to our data, Parker et al. reported that symptomatic local progression was improved with prostate radiotherapy in the low metastatic burden group (6). However, Burdett et al. showed that there was no improvement in progression-free survival with prostate radiotherapy (17).

Regarding palliative bone-directed radiotherapy, we treated symptomatic patients similarly to the ORIOLE study conducted by Phillips et al. which demonstrated the clinical and survival benefit of additional treatment of all oligometastases (18). Likewise, Cho et al. and Morgan et al. also permitted oligometastases directed radiotherapy in addition to prostate radiotherapy (15, 19). This contradicts Parker et al. and Boevé et al., who did not consider palliative bone-directed radiotherapy (12, 13). Currently, ESTRO recommends metastases-directed radiotherapy strategies and focuses on the role of combination treatments in oligometastatic prostate cancer patients, as declared by Zilli et al. (20) .

There were some limitations in our study. First, the small sample size may affect its external validity. Second, the short follow-up duration may underestimate possible benefits of local radiotherapy and fail to detect chronic long-term radiation-induced effects. Third, the lack of highly advanced precision radiation techniques such as IMRT in our center was an important limitation. Finally, we did not require the use of PSMA-PET due to limited resources in our center, although PSMA-PET is more accurate

and precise in detecting metastatic deposits than conventional imaging (21, 22).

In conclusion, the administration of prostate radiotherapy to metastatic prostate cancer patients is safe, affordable, cost-effective, and available in limited resource settings. When combined with standard androgen deprivation therapy, upfront prostate radiation treatment can improve patient-reported health-related quality of life outcomes, particularly in urinary function with bowel function preservation. Most acute radiation-induced toxicities were transient and manageable without significant long-term effects. We recommend that this study can be replicated with a larger sample size and longer follow-up duration to assess potential late radiation effects in patients who received prostate radiotherapy. Additionally, novel studies are awaited to test the long-term outcomes of combination therapies as part of a treatment intensification plan for metastatic prostate cancer patients.

HRQoL

Health-related quality of life

ADT

Androgen deprivation therapy

EORTC QLQ-PR25

European Organization for Research and Treatment of Cancer Quality of Life Questionnaire

rPFS

Radiographic progression-free survival

PROMs

Patient-reported outcomes measures

ECOG

Eastern Cooperative Oncology Group

Radiotherapy

Grade 2

G3+

Grade 3 or higher

IMRT

Intensity-modulated radiation therapy

Ethics approval and consent to participate

Ethical approval for this study was obtained from the Research Ethics Committee at the Faculty of Medicine, Suez Canal University (approval number: 4492) on 1 March 2020. All participants provided informed consent prior to participation in the study, and the study was conducted in accordance with the principles of the Declaration of Helsinki.

Consent for publication

Not applicable

Availability of data and materials

Data supporting this research findings were collected from registries and medical records at the Department of Clinical Oncology, Suez Canal University Hospital. The study protocol and datasets are attached and included within the article.

Competing interests

The authors declare that they have no affiliations with or involvement in any organization with any financial interest. All authors agree with the contents of the manuscript and there is no financial interest to report. We certify that the submission is original work and is not under review at any other publication.

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Authors’ contributions

All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by H.A, F.E, E.E, I.H and M.Z. The first draft of the manuscript was written by H.A and all authors revised and commented on previous versions of the manuscript. All authors read, critically reviewed, and approved the final manuscript.

Acknowledgements

We thank patients who agreed to participate in this research. We also thank the head of the Department of Clinical Oncology, the medical staff and the radiation physicists’ team at Suez Canal University Hospital for facilitating this work.

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No competing interests reported.

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Quality of Life of Metastatic Prostate Cancer Patients Treated with Prostate Radiotherapy

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