I have read the journal’s policy and the authors of this manuscript have the following competing interests: CCP reports personal fees from Bayer, personal fees from Janssen, personal fees from Clarity Pharmaceuticals, personal fees from Myovant, personal fees from ITM Oncologics, outside the submitted work NDJ received research funding to the institution from Astellas, Astra Zeneca &Janssen; receipt of honoraria/fees on the advisory board for Astra Zenenca, Clovis, Janssen, Merck, Novartis & Sanofi; received fees as a speaker for Bayer & Novartis NWC received honoraria from Astellas & Janssen; took a consulting/advisory role for Astellas, Janssen, Ferring, Bayer & Sanofi; was paid speakers fees b Janssen & Astellas; received funding for the institution from Astra Zeneca; received meeting and travel expenses from Janssen, Astellas, Sanofi, Astra Zeneca, Ferring & Ipsen GA reports personal fees from Sanofi Aventis, during the conduct of the study; personal fees and non-financial support from Astellas, personal fees and non-financial support from Medivation, personal fees from Novartis, personal fees from Millennium Pharmaceuticals, personal fees and non-financial support from Abbott Laboratories, personal fees and non-financial support from Essa Pharmaceuticals, personal fees and non-financial support from Bayer Healthcare Pharmaceuticals, personal fees from Takeda, grants from AstraZeneca, grants from Arno Therapeutics, grants from Innocrin Pharma, grants, personal fees and non-financial support from Janssen, personal fees from Veridex, personal fees and non-financial support from Roche/Ventana, personal fees and non-financial support from Pfizer, personal fees from The Institute of Cancer Research (ICR), outside the submitted work; and The Institute of Cancer Research (ICR) receives royalty income from abiraterone I receive a share of this income through the ICR’s Rewards to Discoverers Scheme SC received consulting fees from Telix, remedy & Huma; received payment for speaker fees and/or manuscript writing and/or educational events from Astra Zeneca, Novartis/AAA, Clovis, Janssen, Bayer, Pfizer, Beigene & Astellas; they were a member of the data safety monitoring/advisory board for Astra Zeneca, Novartis/AAA, Clovis, Janssen, Bayer, Pfizer, Beigene & Astellas DPD received payment to the institution from C33589/A19727 Advances in Physics for Precision Radiotherapy; previous employer, The Institute of Cancer Research receives loyalty income from abiraterone, receives personal share of this income through ICR’s Rewards to Discoverer’s Scheme; honoraria for consultancy from Janssen; EP1933709B1 – Location and Stabilisation Device., European patent issued, Pending in Canada and India SG reports personal fees from Orion, personal fees from Janssen Cilag, personal fees from ProteoMedix, personal fees from Amgen, personal fees from MSD, other from Tolero Pharmaceuticals, other from Astellas Pharma, other from Janssen, other from MSD Merck Sharp&Dome, other from Bayer, other from Roche, other from Pfizer, other from Telixpharma, other from Amgen, other from Bristol-Myers Squibb, other from AAA International SA, other from Orion, other from Silvio Grasso Consulting, from Tolremo, outside the submitted work; In addition, Gillessen has a patent WO2009138392 issued and Menarini Silicon Biosystems (Advisory Board 2019) - not compensated Aranda (Advisory Board 2019) - not compensated RJJ received research funding to the institution from Bayer, Astellas & Pfizer; received honoraria on the advisory board for Janssen, Astellas, Bayer, Pfizer; received speaker fees from Janssen, Astellas, Bayer & Pfizer REL received an institutional grant from the MRC CG received research funding to the institution from Janssen, Clovis Oncology, Sanofi, Astellas, Medical Research Council & Cancer Research UK DF received speaker fees and/or manuscript writing and/or educational events from BMS, IPSEN, EUSA, Pfizer, ESAI; they received travel expenses from Janssen & IPSEN MDM is an advisory board member for Endocyte & Clovis AB received payment for lecture/presentation/speaker bureau/manuscript writing or educational event from Boston Scientific AJB received speaker fees and travel support from Janssen DF received payment for lectures for Janssen, Pfizer & BMS; support for attending conferences/meetings from Genisiscare & BMS AMH received research grants from CRUK and NIHR; support attending meetings from the European Association of Urologists; is a member of the European Association of Urologists & the Prostate Cancer Guidelines Group MK received travel, accommodation and conference fees as expenses from Bayer, travel and accommodation fees for Prostate cancer summits from Janssen AL received expenses for attending meetings and/or travel from Astellas, Bayer, BMS & MSD JMOS received speaker fees from AAA, Astellas, Bayer, Janssen, Novartis, Sanofi and participated as an advisory board member and/or member of the data safety monitoring board for AAA, Astellas, Bayer, Janssen, Novartis & Sanofi NNS received travel/meeting payments from Janssen JT received support for conference attendance from Janssen, Roche & Bayer; participated on the advisory board for Astra Zeneca, Astellas & Bayer MKBP received research funding to the Unit he directs from Acoria Pvt Ltd, Akagera, Amgen, Aspirin Foundation, Astellas, AstraZeneca, Baxter, Bayer, BMS US, Bri-Bio, Cepheid, Cipla, Clovis Inc, CSL Behring, Eli-Lilly, Emergent Biosolutions, Gilead Sciences, GlaxoSmithKline, Grifols, Janssen Products LP, Janssen-Cilag, Johnson & Johnson, Micronoma, Modus Theraputics, Mylan, Novartis, Pfizer, Sanofi, Serum Institute of India, Shionogi, Synteny Biotechnology, Takeda, Tibotec, Transgene, ViiV Healthcare, Virco and Xenothera MRS received research funding to the institution from Astellas, Clovis, Janssen, Novartis, Pfizer, Sanofi-Aventis; received speaker fees from Lilly Oncology & Janssen; independent member of data monitoring committees. All other authors have nothing to declare.
¶ Membership of the STAMPEDE Trial Collaborative Group is listed in
STAMPEDE has previously reported that radiotherapy (RT) to the prostate improved overall survival (OS) for patients with newly diagnosed prostate cancer with low metastatic burden, but not those with high-burden disease. In this final analysis, we report long-term findings on the primary outcome measure of OS and on the secondary outcome measures of symptomatic local events, RT toxicity events, and quality of life (QoL).
Patients were randomised at secondary care sites in the United Kingdom and Switzerland between January 2013 and September 2016, with 1:1 stratified allocation: 1,029 to standard of care (SOC) and 1,032 to SOC+RT. No masking of the treatment allocation was employed. A total of 1,939 had metastatic burden classifiable, with 42% low burden and 58% high burden, balanced by treatment allocation. Intention-to-treat (ITT) analyses used Cox regression and flexible parametric models (FPMs), adjusted for stratification factors age, nodal involvement, the World Health Organization (WHO) performance status, regular aspirin or nonsteroidal anti-inflammatory drug (NSAID) use, and planned docetaxel use. QoL in the first 2 years on trial was assessed using prospectively collected patient responses to QLQ-30 questionnaire.
Patients were followed for a median of 61.3 months. Prostate RT improved OS in patients with low, but not high, metastatic burden (respectively: 202 deaths in SOC versus 156 in SOC+RT, hazard ratio (HR) = 0·64, 95% CI 0.52, 0.79,
Prostate RT improves OS, without detriment in QoL, in men with low-burden, newly diagnosed, metastatic prostate cancer, indicating that it should be recommended as a SOC.
ClinicalTrials.gov
Chris C Parker and colleagues report long-term findings on overall survival and local complications in men with metastatic prostate cancer treated with radiotherapy.
Prostate cancer is the most common cancer in males.
Radiotherapy (RT) to the prostate is widely used as a radical treatment for nonmetastatic prostate cancer.
A comparison was added to the STAMPEDE protocol to assess whether RT to the prostate would also be helpful for males with metastatic prostate cancer. A benefit in survival was targeted.
The trial previously reported a clinically relevant, statistically significant overall survival (OS) benefit for patients with a low metastatic burden but not for men with a high metastatic burden.
This long-term analysis assesses survival with substantially longer follow-up and more events and looked also at complications of local disease.
A randomised controlled trial of adding RT to the prostate to standard of care (SOC) was incorporated into the STAMPEDE protocol.
More than 2,000 patients joined the comparison between 2013 and 2016.
The data set was frozen in 2021 and analysed using standard methods.
There was a clear improvement in survival with prostate RT in the low metastatic burden group.
There was no improvement in survival with prostate RT in the high metastatic burden group.
Symptomatic local progression and the need for later local intervention were improved with RT in the low metastatic burden group.
In the low metastatic burden group, the improvement with RT was similar whether the RT was given with a daily schedule (over 4.5 weeks) or a weekly schedule (over 6 weeks).
The adverse effects of RT were manageable without any impact on long-term quality of life (QoL).
Prostate RT is a relatively cheap, widely accessible, and well-tolerated treatment.
Prostate RT is indicated in patients with newly diagnosed prostate cancer with a low metastatic burden.
RT to the prostate is not routinely indicated for patients with a high metastatic burden.
Prostate radiotherapy (RT) is recommended for men with newly diagnosed, low-burden, metastatic prostate cancer, but not for men with high-burden disease [
We hypothesised that prostate RT would reduce the complications of local disease progression, such as urinary or bowel obstruction. If so, this could benefit men with metastatic disease, regardless of disease burden. Here, we report data on freedom from local interventions (e.g., urinary catheter, ureteric stents, nephrostomies, and colostomy).
Any benefits of prostate RT need to be weighed against the risk of treatment-related adverse events (AEs). We report, for the first time, data from the trial on quality of life (QoL).
The trial was stratified according to the choice of 1 of 2 RT dose-fractionation schedules, nominated prior to randomisation; 36 Gy in 6 fractions over 6 weeks, or 55 Gy in 20 fractions over 4 weeks. The 2 schedules were chosen in the expectation that they would be similarly effective. With the benefit of additional follow-up, and more events in the final analysis, we have tested for any differential impact on OS by choice of RT schedule.
Eligible patients had prostate cancer that was newly diagnosed, with no previous radical treatment, had metastatic disease confirmed on a bone scintigraphic scan and soft tissue imaging, and were within 12 weeks after starting androgen deprivation therapy (ADT). Patients were required to have no contraindications to RT and no clinically significant cardiovascular history. Participants were recruited at secondary care sites in the UK and Switzerland.
The trial was registered as NCT00268476 (
All patients received lifelong hormone therapy as gonadotrophin-releasing hormones (GnRHs) agonists or antagonists or orchidectomy. In addition, docetaxel was permitted after it became available for this setting in the UK. Docetaxel, when used, was given as six 3 weekly cycles of 75mg/m2 with or without prednisolone 10 mg daily.
External beam RT to the prostate was given as 1 of 2 schedules nominated prior to randomisation: 36 Gy in 6 consecutive weekly fractions of 6 Gy or 55 Gy in 20 daily fractions of 2.75 Gy over 4 weeks. Treatment was given with the patient supine, with a full bladder and an empty rectum. The planning target volume consisted of the prostate only with an 8-mm margin posteriorly and a 10-mm margin elsewhere. RT was to commence as soon as practicable after randomisation, and, if the patient was having docetaxel as part of standard of care (SOC), within 3 to 4 weeks after the last docetaxel dose.
Patients were followed up 6 weekly until 6 months after randomisation, 12 weekly to 2 years, 6 monthly to 5 years, and then annually. Toxicities and symptoms were reported at regular follow-up visits or when an AE was categorised as “serious.” These were graded with Common Terminology Criteria for Adverse Events (CTCAE) v4·0. Separately, bowel and bladder adverse effects during RT and long-term possible RT effects were recorded using the RTOG scale [
Metastatic burden at randomisation was evaluated retrospectively through central imaging review of whole body scintigraphy and computerized tomography (CT) or MRI staging scans. Metastatic burden was classified according to the definition used in the CHAARTED trial [
Patients were randomised centrally using a computerised algorithm, developed and maintained by the trials unit. Minimisation with a random element of 20% was used (80% probably of allocation to a minimising treatment), stratifying for hospital, age at randomisation (<70 versus ≥70 years), nodal involvement (negative versus positive versus indeterminate), the World Health Organization (WHO) performance status (0 versus 1 or 2), planned form of ADT (orchidectomy versus LHRH (leuteinising hormone-releasing hormone) agonist versus LHRH antagonist versus dual androgen blockade), and regular aspirin or nonsteroidal anti-inflammatory drug (NSAID) use (yes or no). Planned docetaxel use was added as a stratification factor after use was permitted as part of SOC. Allocation was 1:1 to SOC only or SOC+RT. There was no blinding to treatment allocation.
The primary efficacy outcome measure was OS, defined as time from randomisation to death from any cause. Secondary outcomes for this long-term efficacy analysis included local intervention–free survival (LIFS)—consisting of time from randomisation to the first report on case report forms of TURP, ureteric stent, surgery for bowel obstruction, urinary catheter, nephrostomy, colostomy, death from prostate cancer—and symptomatic local event-free survival (SLEFS), comprising any of these LIFS events or acute kidney injury, urinary tract infection, or urinary tract obstruction. Cause of death was determined by the site investigator, with some cases reclassified as prostate cancer death according to predefined criteria which suggested this to be the likely cause. Patients without the event of interest were censored at the time last known to be event free. QoL analyses focused on Global QoL % and QLQ-30 Summary Score %, as derived from patient reports at scheduled assessment time points in the first 2 years after randomisation (see
The primary outcome measure, OS, was assessed across all patients and separately within patient subgroups characterised by baseline metastatic burden (low versus high) and nominated RT schedule (daily versus weekly).
Standard survival analysis methods were used to analyse time-to-event data in Stata v16.1 (College Station, Texas, United States of America). A nonparametric stratified log-rank test was used to assess any difference in survival between treatment groups; this was stratified across the minimisation factors used at randomisation (except hospital and planned form of hormone therapy) plus protocol-specific time periods defined by other arms recruiting to STAMPEDE or changes to SOC which could affect the population being randomised. Cox proportional hazards (PHs) regression models adjusting for the same stratification factors and stratified by time period were used to estimate relative treatment effect; a HR less than 1·00 favoured the research arm. Unadjusted estimates of treatment effect are also presented. Flexible parametric models (FPMs) were fitted with degrees of freedom (5.5) and adjusted for stratification factors and time periods [
Median follow-up was estimated using the Kaplan–Meier method with reverse censoring on death. All patients were included in the efficacy and QoL analyses according to allocated treatment on an intention-to-treat (ITT) basis; sensitivity analyses exclude patients who did not explicitly fulfill all of the eligibility criteria. AE data are shown for the safety population, in patients with at least 1 follow-up assessment and analysed according to whether RT was received within 1 year of randomisation (SOC+RT) or not (SOC).
Analyses of the QoL outcomes included partly conditional and composite approaches, building on the approaches previously used in the trial [
This trial is reported per the Consolidated Standards of Reporting Trials (CONSORT; see
Between January 22, 2013 and September 2, 2016, 2,061 patients were randomised from 117 hospitals in UK and Switzerland: 1,029 to SOC and 1,032 to SOC+RT. The data set was frozen on March 17, 2021 and included information up to November 30, 2020.
AE, adverse event; CONSORT, Consolidated Standards of Reporting Trials; RT, radiotherapy to the prostate, SOC, standard of care. *Alive, no withdrawal of permission for continued data collection.
Characteristic | SOC ( |
SOC+RT ( |
|
---|---|---|---|
Age at randomisation (years) | Median (IQR) | 68 (63 to 73) | 68 (63 to 73) |
Range | 37 to 86 | 45 to 87 | |
WHO performance status | 0 | 732 (71%) | 734 (71%) |
1 to 2 | 297 (29%) | 298 (29%) | |
Pain from prostate cancer | Absent | 826 (81%) | 855 (83%) |
Present | 198 (19%) | 172 (17%) | |
5 | 5 | ||
Previous notable health issues | Myocardial infarction | 67 (7%) | 58 (6%) |
Cerebrovascular disease | 29 (3%) | 32 (3%) | |
Congestive heart failure | 5 (<1%) | 8 (1%) | |
Angina | 46 (4%) | 52 (5%) | |
Hypertension | 408 (40%) | 444 (43%) | |
T-category at randomisation | T0 | 0 (0%) | 1 (<1%) |
T1 | 12 (1%) | 12 (1%) | |
T2 | 84 (9%) | 89 (9%) | |
T3 | 585 (62%) | 603 (63%) | |
T4 | 260 (28%) | 247 (26%) | |
TX | 88 | 80 | |
N-category at randomisation | N0 | 345 (36%) | 344 (36%) |
N+ | 620 (64%) | 620 (64%) | |
NX | 64 | 68 | |
Metastatic burden | Low metastatic burden* | 409 (42%) | 410 (43%) |
High metastatic burden | 567 (58%) | 553 (57%) | |
Not classified | 53 | 69 | |
Sites of metastases | Bone | 919 (89%) | 917 (89%) |
Liver | 23 (2%) | 19 (2%) | |
Lung | 42 (4%) | 48 (5%) | |
Distant lymph nodes | 295 (29%) | 304 (29%) | |
Other | 35 (3%) | 32 (3%) | |
Gleason sum score | < = 7 | 173 (17%) | 175 (18%) |
8 to 10 | 826 (83%) | 820 (82%) | |
Unknown | 30 | 37 | |
PSA pre-ADT (ng/ml) | Median (IQR) | 98 (30 to 316) | 97 (33 to 313) |
Range | 1 to 20,590 | 1 to 11,156 | |
Time from diagnosis (days) | Median (IQR) | 73 (55 to 94) | 73 (55 to 93) |
1 | 2 | ||
Days from starting hormones | Median (IQR) | 53 (35 to 70) | 55 (34 to 70) |
Range | -3 to 84 | 0 to 86 | |
Planned for SOC docetaxel | No | 845 (82%) | 849 (82%) |
Yes | 184 (18%) | 183 (18%) | |
Nominated RT schedule | 36 Gy/6 f over 6 weeks | 482 (47%) | 498 (48%) |
55 Gy/20 f over 4 weeks | 547 (53%) | 534 (52%) |
*Note: One patient classified with low-burden disease was subsequently restaged as nonmetastatic by the randomising site. They remain in the low metastatic burden subgroup for this analysis.
ADT, androgen deprivation therapy; IQR, interquartile range; PSA, prostate specific antigen; RT, radiotherapy to the prostate; SOC, standard of care; WHO, World Health Organization.
Median duration of follow-up was 61.3 months (interquartile range [IQR] = 53.8 to 73.1) and was similar in both treatment groups: SOC 61.0 (IQR = 53.8 to 72.6) and SOC+RT 61.6 (IQR = 53.8 to 73.1).
A total of 1,183 deaths were reported, 609 in patients allocated to SOC and 574 in those allocated to SOC+RT (
Adjusted HR = 0.90 (95% CI 0.81 to 1.01;
Outcome measure | Patient group | Adjusted HR~ | Unadjusted HR^ | Event free at 5 years+ | RMST+ | ||||
---|---|---|---|---|---|---|---|---|---|
SOC | SOC+RT | SOC | SOC+RT | Difference | |||||
All patients | 0.90 (0.81 to 1.01) | 0.90 (0.81 to 1.01) | 42% | 45% | 52.9 | 55.5 | 2.5 (−0.2 to 5.2) | ||
Low metastatic burden | 0.64 (0.52 to 0.79) | 0.66 (0.54 to 0.82) | 53% | 65% | 60.6 | 69.0 | 8.4 (4.5 to 12.2) | ||
High metastatic burden | 1.11 (0.96 to 1.28) | 1.08 (0.94 to 1.25) | 35% | 30% | 47.7 | 45.5 | −2.2 (−5.7 to 1.2) | ||
Weekly RT (36 Gy/6 f) | 1.00 (0.85 to 1.18) | 1.01 (0.86 to 1.19) | 44% | 42% | 53.9 | 53.6 | −0.3 (−3.4 to 2.8) | ||
− |
|||||||||
Daily RT (55 Gy/20 f) | 0.83 (0.71 to 0.97) | 0.81 (0.69 to 0.95) | 41% | 47% | 52.2 | 57.2 | 5.0 (1.1 to 8.9) | ||
− |
|||||||||
All patients | 0.92 (0.81 to 1.04) | 0.92 (0.81 to 1.04) | 49% | 51% | 57.6 | 59.5 | 1.9 (−1.1 to 5.0) | ||
Low metastatic burden | 0.62 (0.49 to 0.79) | 0.64 (0.50 to 0.81) | 62% | 72% | 65.7 | 73.7 | 8.0 (4.0 to 12.0) | ||
High metastatic burden | 1.12 (0.96 to 1.31) | 1.10 (0.94 to 1.28) | 41% | 35% | 51.8 | 49.0 | −2.8 (−6.6 to 1.0) | ||
All patients | 1.00 (0.90 to 1.13) | 1.00 (0.90 to 1.12) | 39% | 40% | 49.2 | 48.9 | −0.3 (−3.5 to 2.8) | ||
Low metastatic burden | 0.72 (0.59 to 0.88) | 0.73 (0.60 to 0.90) | 46% | 58% | 54.5 | 61.8 | 7.2 (2.5 to 11.9) | ||
High metastatic burden | 1.23 (1.06 to 1.42) | 1.21 (1.05 to 1.40) | 33% | 26% | 45.1 | 39.4 | −5.8 (−9.7 to −1.9) | ||
All patients | 0.94 (0.83 to 1.06) | 0.93 (0.83 to 1.05) | 44% | 47% | 53.5 | 55.1 | 1.6 (−1.5 to 4.7) | ||
Low metastatic burden | 0.62 (0.49 to 0.77) | 0.63 (0.50 to 0.78) | 54% | 67% | 59.7 | 69.1 | 9.5 (5.2 to 13.8) | ||
High metastatic burden | 1.18 (1.01 to 1.37) | 1.16 (1.00 to 1.34) | 38% | 32% | 49.0 | 44.7 | −4.4 (−8.4 to −0.4) |
Note: HR and RMST difference are for SOC+RT relative to SOC.
*Cause-specific treatment × metastatic burden interaction test
#SLEFS: treatment × metastatic burden interaction test
~Estimates from Cox models adjusting for age, nodal involvement, WHO performance status, regular aspirin or NSAID use, and planned SOC docetaxel at randomisation, stratified by randomisation time period.
^Estimates from unadjusted, unstratified Cox models.
+Survival probabilities and RMST estimates are taken from FPMs with t-star = 91 months.
HR, hazard ratio; LIFS, local intervention–free survival; NSAID, nonsteroidal anti-inflammatory drug; RMST, restricted mean event-free (“survival”) time; RT, radiotherapy to the prostate; SLEFS, symptomatic local event–free survival; SOC, standard of care; WHO, World Health Organization.
In the low metastatic burden group, 358 had died: 202/409 SOC and 156/410 SOC+RT. Median survival was 63.6 months for SOC and 85.5 months for SOC+RT (5-year survival 53% versus 65%); adjusted HR = 0.64 (95% CI 0.52 to 0.79;
Adjusted HR = 0.64 (95% CI 0.52 to 0.79;
In the high-burden disease group, 761 had died: 375/567 SOC and 386/553 SOC+RT. Median survival was 41.2 months in SOC and 38.8 months in SOC+RT (5-year survival 35% versus 30%): adjusted HR = 1.11 (95% CI 0.96 to 1.28;
Adjusted HR = 1.11 (95% CI 0.96 to 1.28;
There was clear evidence of differential treatment effect according to metastatic burden: interaction test
Similar results were obtained from cause-specific and competing risk analyses (
In 980 patients nominated prior to randomisation for weekly RT, 575 had died: 282/482 SOC and 293/498 SOC+RT. Median survival was 52.2 months for SOC and 49.9 months for SOC+RT (5-year survival: 44% versus 42%); adjusted HR = 1.00 (95% CI 0.85 to 1.18);
Adjusted HR = 1.00 (95% CI 0.85 to 1.18;
Adjusted HR = 0.83 (95% CI 0.71 to 0.97;
Given that RT improved OS in the low metastatic burden patients, RT schedule was further explored in this subgroup. In 360 patients nominated for weekly RT, 162 had died: 94/190 SOC and 68/170 SOC+RT; adjusted HR = 0.67 (95% CI 0.49 to 0.93;
A total of 1,209 (59%) patients were reported as experiencing at least 1 symptomatic local event: 608 SOC and 601 SOC+RT. In 789 cases (400 SOC and 389 SOC+RT), death from prostate cancer was the only event recorded.
Type of event | SOC ( |
SOC+RT ( |
---|---|---|
Urinary tract infection | 57 (9%) | 80 (13%) |
Urinary catheter | 52 (9%) | 44 (7%) |
Acute kidney injury | 33 (5%) | 34 (6%) |
TURP | 24 (4%) | 24 (4%) |
Urinary tract obstruction | 15 (2%) | 15 (3%) |
Ureteric stent | 19 (3%) | 8 (1%) |
Nephrostomy | 5 (1%) | 2 (<1%) |
Colostomy | 3 (<1%) | 3 (1%) |
Surgery for bowel obstruction | 0 (0%) | 2 (<1%) |
PCa death | 400 (66%) | 389 (65%) |
PCa, prostate cancer; RT, radiotherapy to the prostate; SOC, standard of care; TURP, transurethral resection of the prostate.
A total of 1,086 (53%) patients had 1 or more local intervention events reported, 556 SOC and 530 SOC+RT, of which death from prostate cancer was the only event in 78% and 81% of cases. Median local intervention event–free survival was 51.1 months in SOC and 53.6 months in SOC+RT (5-year survival 44% versus 47%); adjusted HR = 0.94 (95% CI 0.83 to 1.06;
Urinary-related late AEs of grade 3 were reported for 20 (2%) patients who received RT within 1 year after randomisation; 10 (2%) were planned for weekly and 10 (2%) for daily treatment; no grade 4 or 5 urinary-related events were reported. Bowel-related late AEs of grade 3 or 4 were reported for 26 (3%) patients, 15 (3%) planned for weekly and 11 (2%) daily treatment (
Toxicity area | SOC+RT | |
---|---|---|
Weekly, |
Daily, |
|
Hematuria | 4 (1%) | 4 (1%) |
Urethral stricture | 3 (1%) | 4 (1%) |
Cystitis | 3 (1%) | 4 (1%) |
Proctitis | 9 (2%) | 5 (1%) |
Diarrhea | 6 (1%) | 6 (1%) |
Rectal–anal stricture | 0 (0%) | 0 (0%) |
Rectal ulcer | 0 (0%) | 1 (<1%) |
Bowel obstruction | 1 (<1%) | 1 (<1%) |
Note: SOC+RT in safety population (RTOG scale; patients with RT started within 1 year of randomisation). There were no reported grade 5 late RT toxicity events.
RT, radiotherapy to the prostate; SOC, standard of care.
Over the entire reported follow-up period, at least 1 grade 3 to 5 AE was reported for 458 (44%) of SOC and 451 (45%) SOC+RT patients. Areas of focus for this long-term analysis were endocrine disorders: 160/1,052 (15%) SOC versus 155/992 (16%) SOC+RT; musculoskeletal disorders: 112/1,052 (11%) SOC, 104/992 (10%) SOC+RT; blood and bone marrow disorders: 56/1,052 (5%) SOC, 49/992 (5%) SOC+RT; cardiovascular disorders: 46/1,052 (4%) SOC, 56/992 (6%) SOC+RT; renal disorders: 50/1,052 (5%) SOC, 52/992 (5%) SOC+RT; general disorders: 57/1,052 (5%) SOC, 43/992 (4%) SOC+RT; gastrointestinal disorders: 47/1,052 (4%) SOC, 52/992 (5%) SOC+RT; lab abnormalities: 49/1,052 (5%) SOC, 48/992 (5%) SOC+RT (
There was no evidence of a difference in QoL scores over time between the allocated treatment groups. Average Global QoL in the first 2 years after randomisation across all patients was 73.2% SOC and 72.4% SOC+RT; absolute difference −0.8% (95% CI −2.5% to 0.9%),
Outcome measure | Analysis | Average over first 2 years on trial | Difference (95% CI) | |
---|---|---|---|---|
SOC | SOC+RT | |||
Partly conditional | 73.2% | 72.4% | −0.8% (−2.5% to 0.9%) | |
Composite outcome | 60.3% | 61.6% | 1.3% (−1.1% to 3.8%) | |
Cross-sectional: 12 weeks | n/a | n/a | −2.9% (−4.8% to −1.0%) | |
Cross-sectional: 24 weeks | n/a | n/a | −0.9% (−3.1% to 1.3%) | |
Cross-sectional: 60 weeks | n/a | n/a | −1.4% (−4.1% to 1.3%) | |
Cross-sectional: 104 weeks | n/a | n/a | 1.8% (−2.4% to 6.0%) | |
Partly conditional | 85.4% | 84.2% | −1.2% (−2.4% to 0.0%) | |
Composite outcome | 70.6% | 71.7% | 1.2% (−1.3% to 3.6%) | |
Cross-sectional: 12 weeks | n/a | n/a | −2.0% (−3.2% to −0.8%) | |
Cross-sectional: 24 weeks | n/a | n/a | −1.0% (−2.3% to 0.4%) | |
Cross-sectional: 60 weeks | n/a | n/a | −1.0% (−2.8% to 0.7%) | |
Cross-sectional: 104 weeks | n/a | n/a | 0.9% (−1.8% to 3.6%) |
Note: Partly conditional estimates are based on observed and multiply imputed data from patients alive at scheduled assessments within the first 2 years since randomisation. Composite outcome estimates are based on observed data and implied imputation of missing data from scheduled assessments when a patient was alive, and the assumption of a patient’s Global QoL/QLQ-30 Summary Score being 0% at all scheduled assessments after they have died. Cross-sectional analyses estimate the difference in average Global Qol/QLQ-30 Summary Score between SOC+RT and SOC treatment groups at the specified scheduled assessment, controlling for response at baseline, in complete cases only (i.e., in patients with outcome data provided at baseline and who have survived and for who outcome data is available at the specified scheduled assessment).
QoL, quality of life; RT, radiotherapy to the prostate; SOC, standard of care.
Average QLQ-30 Summary Score in the first 2 years across all patients was 85.4% SOC and 84.2% SOC+RT; absolute difference −1.2% (95% CI −2.4% to 0.0%),
Cross-sectional analyses of both Global QoL and QLQ-30 Summary Score indicated evidence of poorer QoL at week 12 after randomisation for patients allocated to SOC+RT—Global QoL absolute difference −2.9% (95% CI −4.8% to −1.0%,
This final analysis has confirmed that prostate RT improves OS in men with newly diagnosed, low-burden metastatic prostate cancer, but not in men with high-burden disease. The magnitude of the survival benefit is substantial and clinically relevant, particularly given that prostate RT is a relatively cheap, widely accessible, and well-tolerated treatment.
These results of the final analysis confirm the findings from the initial analysis. The additional 2 years of follow-up, and the subsequent increase in the number of events for analysis, has reduced the CIs around the point estimate of the HR of the OS benefit for prostate RT. However, the point estimate itself has changed very little, improving from 0.68 to 0.64 for men in the low metastatic disease risk group. This result is consistent with that from the smaller HORRAD trial [
We found no compelling evidence of a difference in efficacy or toxicity between the 2 RT dose-schedules tested. The weekly schedule of 36 Gy in 6 fractions over 6 weeks has an obvious practical advantage in terms of convenience and may be preferred for that reason. A daily schedule might be preferred if pelvic nodal RT were to be used in addition or if RT dose escalation was thought to be appropriate. Prostate RT did not have any long-term impact on QoL either in this trial, or in the HORRAD trial [
The criteria used in the trial to classify cases as low or high burden were taken from those used in the CHAARTED trial [
The trial has several strengths, including the randomised design, the large number of events for analysis, and recruitment from over 100 centres, which adds to the generalisability of the results. The main limitations of the study are the changes in clinical practice since the trial started, particularly with regard to imaging techniques and systemic treatment. The trial recruited between 2013 and 2016 and, while this has the benefit of long follow-up, it also means that newer imaging techniques, such as PSMA (Prostate-specific membrane antigen) PET and whole body MRI, were unavailable. It is important to note that low-burden disease in the trial was defined according to bone scan and CT scan. There is no agreed definition of metastatic disease burden based solely on PSMA PET or on whole body MRI. In patients without visceral disease but who have more than 4 bone metastases on PET or MRI, a bone scan may be required in addition, in order to determine suitability for prostate RT. If this is not practicable, and there remains uncertainty as to whether a patient has high- or low-burden disease, there is a strong argument for using prostate RT.
The systemic treatment of metastatic prostate cancer has changed since the trial recruited. Standard treatment for men with low-burden metastatic disease now includes one of the newer hormone agents (abiraterone or apalutamide or enzalutamide) in addition to ADT. The effect of these agents on the survival benefit of prostate RT is unknown. Similarly, the effect of prostate RT on the survival benefit of the newer hormonal agents is also unknown. Based on current evidence, it is reasonable to assume that both prostate RT and one of the newer hormonal agents should be considered SOC for low-burden metastatic disease, in addition to ADT. The PEACE-1 Trial is testing the use of prostate RT in men receiving ADT + abiraterone.
In summary, this final analysis confirms that prostate RT improves OS in men with low-burden, newly diagnosed, metastatic prostate cancer, indicating that it should be recommended as a SOC.
Adjusted HR = 1.00 (95% CI 0.90 to 1.13;
(TIF)
Adjusted HR = 0.94 (95% CI 0.83 to 1.06;
(TIF)
Difference in weighted average: −0.8% (95% CI −2.5% to 0.9%;
(TIF)
Difference in weighted average: 1.3% (95% CI −1.1% to 3.8%;
(TIF)
Difference in weighted average: −1.2% (95% CI −2.4% to 0.0%;
(TIF)
Difference in weighted average: 1.2% (95% CI −1.3% to 3.6%;
(TIF)
AE, adverse event; CTCAE, Common Terminology Criteria for Adverse Events; RT, radiotherapy to the prostate; SOC, standard of care.
(TIF)
AE, adverse event; CTCAE, Common Terminology Criteria for Adverse Events; RT, radiotherapy to the prostate; SOC, standard of care.
(TIF)
AE, adverse event; CTCAE, Common Terminology Criteria for Adverse Events; RT, radiotherapy to the prostate; SOC, standard of care.
(TIF)
RT, radiotherapy to the prostate; SOC, standard of care.
(TIF)
FFS, failure-free survival; RT, radiotherapy to the prostate; SOC, standard of care.
(TIF)
ADT, androgen deprivation therapy; IQR, interquartile range; PSA, prostate specific antigen; RT, radiotherapy to the prostate; SOC, standard of care; WHO, World Health Organization.
(DOCX)
(PDF)
CONSORT, Consolidated Standards of Reporting Trials.
(PDF)
(PDF)
Large-scale trials do not happen without huge collaborations. Thanks to all central and site staff who have made the STAMPEDE trial happen. See
The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care.
See Credit List included as
androgen deprivation therapy
adverse event
Consolidated Standards of Reporting Trials
Common Terminology Criteria for Adverse Events
flexible parametric model
gonadotrophin-releasing hormone
hazard ratio
interquartile range
intention-to-treat
local intervention–free survival
nonsteroidal anti-inflammatory drug
overall survival
proportional hazard
quality of life
restricted mean event-free (“survival”) time
radiotherapy
symptomatic local event-free survival
standard of care
World Health Organization
Dear Dr Sydes,
Thank you for submitting your manuscript entitled "Radiotherapy to the prostate for men with metastatic prostate cancer: long-term results from the STAMPEDE randomised controlled trial (NCT00268476)" for consideration by PLOS Medicine.
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Dear Dr. Sydes,
Thank you very much for submitting your manuscript "Radiotherapy to the prostate for men with metastatic prostate cancer: long-term results from the STAMPEDE randomised controlled trial (NCT00268476)" (PMEDICINE-D-22-00022R1) for consideration at PLOS Medicine.
Your paper was evaluated by a senior editor and discussed among all the editors here. It was also discussed with an academic editor with relevant expertise, and sent to independent reviewers, including a statistical reviewer. The reviews are appended at the bottom of this email and any accompanying reviewer attachments can be seen via the link below:
[LINK]
In light of these reviews, I am afraid that we will not be able to accept the manuscript for publication in the journal in its current form, but we would like to consider a revised version that addresses the reviewers' and editors' comments. Obviously we cannot make any decision about publication until we have seen the revised manuscript and your response, and we plan to seek re-review by one or more of the reviewers.
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Comments from the reviewers:
Reviewer #1: Parker et al present the updated results of the STAMPEDE trial, arm H. This trial randomized >2000 men with newly diagnosed metastatic prostate cancer in the UK and Switzerland to standard of care (lifelong androgen deprivation therapy) +/- radiation therapy (RT) to the prostate. After the start of enrollment, it was determined that results would be analyzed by the volume of metastatic disease. The authors had previously reported in 2018 that prostate RT improves survival in men with low-volume disease but not high-volume disease, with a significant interaction (Parker et al, Lancet 2018). In this updated analysis, they demonstrate that the survival benefit differences found previously persist with additional follow-up. Furthermore, they present data on local events in the forms of Local Intervention Free Survival and Symptomatic Local Event-Free Survival.
This is an important update of the STAMPEDE trial, arm H, which helped change the treatment paradigm for men with low-volume de novo metastatic prostate cancer. While the updated survival findings, which demonstrated the continued benefit of prostate RT in low-volume disease, are not surprising, the authors do provide additional results in terms of local event analyses, toxicity including from RT, and quality of life (QOL) metrics. The findings of this study are important for the general medical public given the prevalence of prostate cancer. The manuscript is generally well-written and presents appropriate analyses.
Major comments
- Local Intervention Free Survival (LIFS) was defined as "consisting of time from randomisation to the first report on case report forms of TURP, ureteric stent, surgery for bowel obstruction, urinary catheter, nephrostomy, colostomy, death from prostate cancer" (lines 120-122). I am not confident that death from prostate cancer should be considered in the definition of LIFS, since death from prostate cancer is uncommonly a consequence of local progression but rather typically due to an increase in metastatic disease burden. Did the authors consider an analysis of LIFS using a definition which excludes death from prostate cancer, using death from any cause as a competing risk event? Similarly, did the authors consider an analysis of Symptomatic Local Event-Free Survival (SLEFS) using a definition that excludes death from prostate cancer, again using competing risks survival analysis? Understandably, the sample sizes for these analyses are likely to be small since it appears that the majority of patients did not have events besides death from prostate cancer be reported.
- The authors found that when stratified by RT schedule, the hazard ratio (HR) for weekly RT was 1.00 and for daily RT was 0.83 (interaction p=0.088). They then looked at specifically at patients with low-volume status and found a HR of 0.67 for weekly RT and 0.62 for daily RT (interaction p=0.732), demonstrating that RT schedule does not appear to influence outcomes for low-volume patients. As additional exploratory analysis, it may be informative to see a similar analysis of HRs by fractionation schedule for high-volume patients.
- One possible confounder in this study is the receipt of additional therapies not reported here, namely novel androgen receptor signaling inhibitors (ARSI). It is possible that patients in one group were more likely to have received ARSIs which can influence multiple outcomes, including survival, local events, toxicities, and quality of life metrics. Are the authors able to provide data on use of these novel therapies and if not, they should discuss this as a limitation of the study.
Minor comments
- Line 155: There is an extra period after "criteria."
- In Figure 1, it is unclear to me how the n's in the Long-term analysis row were derived from the Follow-up row, e.g. for the first column, 333+74+609=1016, yet the diagram states that n=1029 were analyzed for efficacy. Can the authors clarify this?
- It might be helpful to relabel metastatic disease burden as "low" and "high" in Table 1 to be uniform in the terminology.
- The legend descriptions for Figures 2A and 2B appear flipped (lines 210-218). There is no legend for Figure 2C.
- The authors state that they performed "cause-specific and competing-risk analyses." They should clarify whether this was done using Cox proportional hazard regression vs Fine-Gray regression and define what the competing risks were. Additionally, for prostate cancer-specific mortality, SLEFS, and LIFS, it would be helpful to see interaction p-values as well.
- The authors should clarify the percentage of patients who received 3D conformal RT (3D RT) vs intensity-modulated RT (IMRT). My sense is that the majority of patients likely received 3D RT which, in combination with the generous margins used (8mm posterior and 10mm elsewhere), is expected to increase the level of toxicity from RT compared to more modern, albeit expensive, techniques (i.e. image-guided IMRT with tighter margins, usually around 5mm if not less) used in many other parts of the world. This complicates the interpretation of toxicity and quality of life data presented here and hence should be discussed as a limitation.
Reviewer #2: This paper reports on the long term overall survival, quality of life and local events in patients with primary metastatic prostate cancer, randomised between with radiotherapy to the prostate or standard of care in the SRAMPEDE trial. This is an essential trial since it altered the guidelines into advising radiotherapy to the prostate in patients with low volume metastatic disease. The presented update on the survival data that confirms previous findings is very important. Also reporting on local problems and quality of life is useful, as local radiotherapy of the prostate is known to have a substantial impact on patients' health-related-quality-of-life potentially. The manuscript is well written and has a clear message.
There are a few issues in this report that should be addressed.
1) In the introduction, the authors write that they report on data on freedom from local interventions and mention urinary catheter, ureteric stents, nephrostomies, colostomy. Why did the authors eventually include death in their analysis on symptomatic local event? This is already addressed in their survival analysis. It there a difference in time to local event or proportion of local events when death is not included in this analysis?
2) Table 3 misses in the manuscript.
3) In the introduction, the authors write that the first report on quality of life of this trial. The HORRAD group also published results on the effect on HrQoL of radiotherapy in patients with metastastic prostate cancer. It would be helpful to compare the results of both similar trials in the discussion.
4) In analysing QoL questionnaires, only the global QoL scores were presented. Were there any differences in the different domains of the questionnaires between the two groups?
5) For time-to-event variables, report the number of events but not the proportion. Avoid reporting the percentage of deaths in reporting on survival. Although it is important to report the number of events, patients entered the study at different times and were followed for different periods; hence, the reported proportion is meaningless.
Reviewer #3: This is a useful and well-conducted RCT on the long-term results of radiotherapy on the prostate for men with metastatic prostate cancer. The study design, statistical methods and analyses, and presentation (tables and figures) and interpretation of the results are mostly adequate and of a good standard. However, there are still a few issues needing attention.
1) For the subgroup analyses on low and high burden groups, there are 6% missing data (without disease burden classification). But I haven't seen any sensitivity analysis on the missing data. What is the impact of missing data on the analysis results? Any potential bias? At least we'd like to see the patterns and characteristics of the patients without burden classification as compared to those with burden classification. May need to address the issue as a limitation in the discussion if missing is not at random.
2) In the analysis of the high-burden metastatic disease group (figue 2B), significant interaction was found. However, it is not clear whether the interaction term was dealt with in the analysis, and if yes, how it was dealt with. This question also applies to a few other analyses involving significant interations terms.
3) Sample size calculation was never mentioned in the paper. I am aware this is a follow-up on the previous published paper but at least authors can mention the sample size and direct readers to previous papers or protocol.
4) In statistical analysis section on page 11, it says "The proportional hazards assumption was tested", but with what method?
Any attachments provided with reviews can be seen via the following link:
[LINK]
Submitted filename:
Dear Dr. Sydes,
Thank you very much for re-submitting your manuscript "Radiotherapy to the prostate for men with metastatic prostate cancer: long-term results from the STAMPEDE randomised controlled trial (NCT00268476)" (PMEDICINE-D-22-00022R2) for review by PLOS Medicine.
I have discussed the paper with my colleagues and it was also seen again by three reviewers. I am pleased to say that provided the remaining editorial and production issues are dealt with we are planning to accept the paper for publication in the journal.
The remaining issues that need to be addressed are listed at the end of this email. Any accompanying reviewer attachments can be seen via the link below. Please take these into account before resubmitting your manuscript:
[LINK]
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We look forward to receiving the revised manuscript by Apr 08 2022 11:59PM.
Sincerely,
Callam Davidson,
Associate Editor
PLOS Medicine
------------------------------------------------------------
Requests from Editors:
Please update your title to include the setting (‘Radiotherapy to the prostate for men with metastatic prostate cancer in the UK and Switzerland: long-term results from the STAMPEDE randomised controlled trial’).
As your author list runs to >30 authors, please consider grouping authors under a collaborative group such that the named author list is ≤30 authors.
Data Availability Statement: Thank you for providing a contact email address (
In your abstract ‘Methods and Findings’ please make the following changes:
* Please include the setting.
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* Per our in-house style, please include a single sentence summary of the study’s main limitations at the end of the section (beginning ‘The main limitations of the study were…’, or similar). See previous PLOS Medicine papers for examples.
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There is no need to include the original p values as footnotes.
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The name of the CONSORT checklist file also seems like it does not match the manuscript (‘The Impact of a Community-Oriented Problem-Based Learning Curriculum Reform on the Quality of Primary Care Delivered by Graduates’). Please check.
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Please remove the abbreviations list from the main text and instead define abbreviations on first use/in table and figure legends.
Line 88: Please update the citations here to [2, 3].
When presenting hazard ratios in the Results, please consistently indicate whether these are adjusted or unadjusted ratios (e.g., Section 3.3, paragraph 1 and paragraph 2, HRs are reported differently despite both representing adjusted HRs).
Apologies if I missed it but I couldn’t find an in-text reference for Figure S5?
Comments from Reviewers:
Reviewer #1: I would like to thank the authors for appropriately addressing the comments which I previously raised. I do not have any additional major comments. The authors should be congratulated on this important contribution.
Of note, Table S5 appears to be currently formatted in such a way that the right portion of the table is cut off and not visible in either the PDF or the Word document. I would recommend that the orientation of this page be changed to landscape to allow for the entire table to be viewed.
Reviewer #2: The authors made several improvements to the document based on the reviewers comments, I have no further issues to raise.
Reviewer #3: Thanks authors for their effort to improve the manuscript. I am satisfied with the response and revision. No further issues needing attention.
Any attachments provided with reviews can be seen via the following link:
[LINK]
Submitted filename:
Dear Dr Sydes,
On behalf of my colleagues and the Academic Editor, Dr Brenton, I am pleased to inform you that we have agreed to publish your manuscript "Radiotherapy to the prostate for men with metastatic prostate cancer in the UK and Switzerland: long-term results from the STAMPEDE randomised controlled trial" (PMEDICINE-D-22-00022R3) in PLOS Medicine.
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Please adapt the "Author Summary" so that each of the three subsections consists of no more than 3-4 points. To achieve this, some points can be removed (e.g., "Prostate cancer is the most common cancer ..." and "The dataset was frozen in 2021 ...") and in some cases shorter points could be combined.
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