We conducted this randomized controlled study aiming to evaluate the survival and clinical benefits of adding cytoreductive prostate radiotherapy to the standard of care in metastatic prostate cancer patients. First, regarding patients’ characteristics, our study population had a median age of 70 years old. Most patients had concurrent comorbidities (65.1%).
Most patients were also presented with T3 + disease (67.1%), N0 (61.9%) and M1b (77.8%). Bone metastases were detected in 69.8% whereas visceral metastases were detected in 14.3% of patients. Most patients had a high Gleason score of 8–10 (74.6%) and performance score of 1 (65.1%). Additionally, high metastatic volume disease was stratified in 63.5% whereas low metastatic volume was classified in 36.5% of patients. Docetaxel was received by 25% of patients and second line anti-androgens were received by 27% of patients. Palliative bone-directed radiotherapy was received by 54% of patients.
In comparison, arm H of the STAMPEDE randomized controlled phase III trial conducted by Parker et al. treated 1032 metastatic hormone-naïve prostate cancer patients with prostate radiotherapy at 117 hospitals across Switzerland and the UK (16). Despite the large sample size difference (2061 versus 63 patients), most of their patients' characteristics were similar to ours, with a median population age of 68 years and 56.5% of their patients having comorbidities. However, their patients were presented with more T3 + disease (90%) and M1b (89%) but with more N1 disease (64%) and fewer N0 disease (36%). Bone metastases were found in 89% of their patients, while visceral metastases were detected in 9.5%. Most patients had a Gleason score of 8–10 (82.5%), and a performance score of 0 in 71%. Low metastatic burden was stratified in 42.5% whereas high metastatic burden in 57.5% of their patients. Docetaxel was received by 18% of their population. However, there was no data regarding any second line anti-androgen received. Palliative metastases-directed radiotherapy was not yet received by their patients.
The HORRAD study by Boevé et al. randomized 432 metastatic prostate cancer patients with slightly different inclusion criteria (PSA > 20 ng/ml and bone metastases) and included a larger sample size to determine if there was a survival benefit from EBRT to the primary prostate in patients diagnosed with metastatic prostate cancer. Their patients' characteristics were comparable to ours, with a median age of 67 years and most of their patients similarly having T3 + disease (84%). However, they had a better performance score than our patients, PS 0 (84.5%), and a higher proportion of their patients received docetaxel (44%). Second-line anti-androgens were received by only 8% of their patients, and palliative metastases-directed radiotherapy was not yet received by their patients (20).
Regarding patient stratification, our study stratified metastatic prostate cancer patients according to their metastatic disease volume into high-volume and low-volume metastatic disease. Boevé et al. differently subdivided their patients into < 5, 5–15, or more bone lesions based on skeletal scintigraphy. Similar to our study, Boevé et al. underwent no stratification at the time of randomization (17). In contrast, Parker et al. stratified patients at randomization based on their metastatic burden into low and high burden disease. Additionally, they stratified patients based on their age, nodal involvement, performance score, planned hormonal treatment, analgesic use, and docetaxel administration (19).
Regarding the radiation dose, we prescribed the same conventional regimen 70Gy in 35 fractions over 7 weeks which was prescribed by Boevé et al. (17). In this study, we used the same hypofractionated regimen (55Gy in 20 daily fractions over 4 weeks) prescribed by Parker et al. (16). This regimen offered several advantages, including shorter overall treatment duration, cost-effectiveness, and patient convenience. The radiation dose used in our study was lower than the current doses used in clinical practice for localized prostate cancer. Higher radiation doses have been studied in dose-escalating studies, but the benefits for patient survival were doubtful (24). Moreover, escalated doses come with a risk of increased gastrointestinal (GI) and genitourinary (GU) toxicities in metastatic patients (20). Therefore, the two more convenient schedules (70Gy/35fx and 55Gy/20fx) were permitted in this study.
The regression analysis for biochemical and survival outcomes has demonstrated the significant impact of cytoreductive prostate-directed radiotherapy on biochemical progression-free survival in metastatic prostate cancer patients. Parallel to our findings, Boevé et al. reported that the median biochemical progression-free survival was better in the prostate radiotherapy group compared to the control group (p = 0.02) (11). Our prespecified subgroup analysis revealed that prostate radiotherapy improved biochemical progression-free survival in low metastatic volume (HR: 0.031, p = 0.001), high metastatic volume (HR: 0.270, p = 0.002), and metastatic castration sensitive disease (HR: 0.043, p < 0.001). Meanwhile, Burdett et al. showed that there was an improvement in biochemical progression-free survival with prostate radiotherapy (HR: 0.74, p = 0.009) (19).
In addition, our study found an overall survival benefit resulting from adding prostate radiotherapy to standard ADT in metastatic prostate cancer patients (median OS = 16.33 vs 11.33, p = 0.003). Conversely, Boevé et al. found no significant overall survival difference between the prostate radiotherapy group and the control group. However, they reported better overall survival, particularly in patients with five or fewer bone metastases treated with prostate radiotherapy (HR: 0.68) (11).
Contrary to our findings, Parker et al. prostate radiotherapy did not significantly impact overall survival in the total cohort at a median follow-up of 61.3 months (HR: 1.00, p = 0.974) (27). However, Parker et al. conducted a subgroup analysis by metastatic burden and found that prostate radiotherapy improved overall survival (HR: 0.68, p = 0.007) in the low metastatic burden subgroup after a median follow-up of 37 months (19). Parker et al. consistently found, through subgroup analysis, that prostate radiotherapy continued to offer a significant overall survival benefit in the low metastatic burden subgroup after a median follow-up of 61.3 months (HR: 0.64, p < 0.001). However, their exploratory subgroup analysis, corresponding to our data, indicated that prostate radiotherapy did not significantly improve overall survival for patients in the high metastatic burden subgroup (HR: 1.11, p = 0.164) (25).
Sooriakumaran et al. discovered that patients who received radiotherapy in addition to ADT had a three times lower mortality rate than patients who received ADT alone (21). Culp et al. published that metastatic prostate cancer patients who received prostate brachytherapy had a better 5-year overall survival compared to patients who underwent no local therapy (5-year OS: 52.6% versus 22.5%; p < 0.001) (22). Antwi and Everson suggested that local therapy for primary disease in metastatic prostate cancer, including brachytherapy, improved survival outcomes with a 57% lower mortality risk. They also found that the mortality risk was higher for visceral disease (M1c) and bone-restricted disease (M1b) as compared to node-positive disease (M1a) (23).
Satkunasivam et al. concluded that metastatic prostate cancer patients who received prostate IMRT had a 62% reduction in mortality risk compared to the control group (24). Rusthoven et al. concluded that metastatic prostate cancer patients who received prostate radiotherapy in addition to ADT had a statistically significant absolute 5-year overall survival benefit of 16% compared to ADT alone (HR: 0.62, P < 0.0001) (25). Contrary to our findings, Satkunasivam et al. and Parikh et al. found that conformal radiation therapy was not associated with improved overall survival (24, 26).
Leyh-Bannurah et al. concluded that prostate-directed radiotherapy, when combined with ADT, resulted in better overall survival in metastatic prostate cancer compared to ADT alone (27). Löppenberg et al. found that the 3-year overall survival was higher in patients who received local therapy, including prostate radiotherapy, compared to those who received no local therapy (69% versus 54%). Similar to our findings, Löppenberg et al. concluded that patients with a low tumor volume tend to benefit greatly from radiotherapy (28). Parikh et al. also found that patients who received local therapy, including prostate IMRT, had improved 5-year overall survival (45.7% versus 17.1%) compared to those who did not receive local therapy. They concluded that prostate radiotherapy remained significantly associated with overall survival (HR: 0.35, P < 0.01) (26).
Morgan et al. found that prostate radiotherapy was associated with improved overall survival (HR: 0.59, p = 0.0001). The 2-year and 5-year overall survival rates were 74.5% and 41.1%, respectively, for those receiving prostate RT and 53.1% and 25.0%, respectively, for those not receiving radiotherapy. Morgan et al. reported a median overall survival of 47.4 months for patients who received prostate radiotherapy compared to 26.3 months for those who did not (15). Thereafter, Burdett et al. conducted the STOPCAP M1 meta-analysis and reported opposite findings to ours, showing no improvement in overall survival with prostate radiotherapy (HR: 0.92, p = 0.195). However, they did report a 7% improvement in 3-year overall survival for patients with low volume disease (19).
There were some limitations in our study. Firstly, the small sample size may affect the generalizability of our results. Secondly, the short duration of follow-up may have underestimated the potential benefits of prostate radiotherapy and could have failed to detect late effects that may take years to develop. The lack of experience with IMRT in our center was another limitation. Additionally, the precise correlation between the volume of disease and the degree of benefit from local radiotherapy remains unclear. Finally, we did not require the use of PSMA-PET due to resource limitations, even though PSMA-PET has shown higher sensitivity for the detection of metastatic deposits than conventional imaging (29, 30).