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NIHR Signal Radiotherapy benefits some men whose prostate cancer has spread to their bones

Published on 22 January 2019

doi: 10.3310/signal-000715

Adding radiotherapy directed at the prostate to hormone treatment for all men with metastatic prostate cancer makes no difference to overall survival. However, when men with a limited number of metastases confined to the bones of the pelvis and spine are treated with radiotherapy to the prostate, their survival improves.

The standard treatment for men with metastatic prostate cancer is anti-androgen hormone therapy, and this is sometimes combined with chemotherapy. Radiotherapy of the prostate itself is only usually used for symptom relief.

This NIHR part-funded trial compared the effects of standard care with or without radiotherapy to the prostate on overall survival for over 2,000 men. It found that radiotherapy improved three-year survival rate from 73 to 81% in men with a limited number of metastases confined to the spine and pelvis. In this group, it also prevented any disease progression over three years in half of them compared to a third on standard care.

This well-conducted multicentre trial supports the use of radiotherapy for this select group of men with limited metastases.

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Why was this study needed?

Prostate cancer is the most common cancer in UK men, with around 47,200 new cases each year. Around 4 in 10 cases in England and Northern Ireland and 6 in 10 cases in Scotland are diagnosed at a late stage when the disease has already spread. At this point, hormone treatment is currently recommended to prevent androgens in the body promoting tumour growth, alongside other chemotherapy drugs. In this situation, radiotherapy to the prostate is only given to provide symptom relief.

Recently, the results of some studies have suggested that radiotherapy to the original tumour site might have additional benefits. A previous trial of 432 men suggested that those with fewer than five secondary bone tumours had better survival when radiotherapy was added to hormone therapy. This randomised controlled trial set out to provide further evidence for this.

What did this study do?

STAMPEDE was a randomised controlled trial that took place in 117 hospitals in Switzerland and the UK. A total of 2,061 men with newly diagnosed prostate cancer with metastases, confirmed on a bone scan, took part.

Participants were randomised to either standard care (lifelong anti-androgen hormone therapy, with or without chemotherapy using docetaxel) or standard care plus radiotherapy to the prostate.

This was a large study that was well-powered to detect effects on overall survival. There were also adequate numbers of men in each subgroup to determine the effect on men with low and high metastatic burden, defined according to how far the metastases had spread.

What did it find?

After three years:

  • There was no difference in overall survival between men who had radiotherapy with standard care compared with those who just had standard care (hazard ratio [HR] 0.92, 95% confidence interval [CI] 0.80 to 1.06). After an average follow-up of 37 months, 370 men in the radiotherapy group had died (three-year survival 65%) compared to 391 men in the control group (three-year survival 62%).
  • In men with lower metastatic burden (metastases to either the local lymph nodes or the bones in the pelvis or spine) radiotherapy improved three-year survival rate, 81% versus 73% of those on standard care (HR 0.68, 95% CI 0.52 to 0.90).
  • By contrast, in men with a high metastatic burden (four or more bone metastases with one or more outside the spine or pelvis, or metastases to other organs, or both) the addition of radiotherapy had no benefit on survival, 53% versus 54% on standard care (HR 1.07, 95% CI 0.90 to 1.28).
  • Overall failure-free survival (the proportion of people who did not have a rise in PSA or progression of disease) was increased by radiotherapy, with 32% having no progression compared to 22% with standard care (HR 0.76, 95% CI 0.68 to 0.84).
  • The failure-free survival difference was mostly due to people with low metastatic burden, with 50% having no progression on radiotherapy compared to 33% on standard care (HR 0.59, 95% CI 0.49 to 0.72). There was no difference for people with high metastatic burden, 18% versus 17% (HR 0.88, 95% CI 0.77 to 1.01). 

What does current guidance say on this issue?

NICE guidelines from 2014 recommend that all men with metastatic prostate cancer are offered a bilateral orchidectomy (removal of both testicles) as an alternative to androgen-blocking hormonal treatments.

There is no recommendation regarding radiotherapy in men with metastatic prostate cancer.

What are the implications?

This study adds further evidence that radiotherapy could benefit men with newly diagnosed prostate cancer with local metastases. The trial used CT and bone scans to define low and high metastatic burden. PET scans, which can detect smaller cancer deposits, are becoming widely available and may allocate people differently. However, the researchers did perform further analysis using different definitions of ‘low metastatic burden', with similar positive results. They are now planning to refine the definition to be more clinically useful.

Nevertheless, radiotherapy can now be considered as a potential add-on treatment in men without advanced metastases, but the optimal dose and schedule still needs to be determined.

Citation and Funding

Parker CC, James ND, Brawley CD et al; Systemic Therapy for Advanced or Metastatic Prostate cancer: Evaluation of Drug Efficacy (STAMPEDE) investigators. Radiotherapy to the primary tumour for newly diagnosed, metastatic prostate cancer (STAMPEDE): a randomised controlled phase 3 trial. Lancet. 2018;392:2353-66.

Funded by Cancer Research UK, UK Medical Research Council, Swiss Group for Clinical Cancer Research, Astellas, Clovis Oncology, Janssen, Novartis, Pfizer and Sanofi-Aventis. This project was part-funded by the National Institute for Health Research (NIHR) Biomedical Research Centre at the Royal Marsden NHS Foundation Trust.

Bibliography

Boeri L, Sharma, V, Karnes, RJ. Radiotherapy for newly diagnosed oligometastatic prostate cancer. Lancet. 2018;392:2327-28.

Boevé LMS, Hulshof MCCM, Vis AN et al. Effect on survival of androgen deprivation therapy alone compared to androgen deprivation therapy combined with concurrent radiation therapy to the prostate in patients with primary bone metastatic prostate cancer in a prospective randomised clinical trial: data from the HORRAD Trial. Eur Urol. 2018; Sep 25. doi: 10.1016/j.eururo.2018.09.008. [Epub ahead of print].

Cancer Research UK. Prostate cancer statistics. London: Cancer Research UK; accessed January 2019.

NICE. Prostate cancer: diagnosis and management. CG175. London: National Institute for Health and Care Excellence. 2014.

Why was this study needed?

Prostate cancer is the most common cancer in UK men, with around 47,200 new cases each year. Around 4 in 10 cases in England and Northern Ireland and 6 in 10 cases in Scotland are diagnosed at a late stage when the disease has already spread. At this point, hormone treatment is currently recommended to prevent androgens in the body promoting tumour growth, alongside other chemotherapy drugs. In this situation, radiotherapy to the prostate is only given to provide symptom relief.

Recently, the results of some studies have suggested that radiotherapy to the original tumour site might have additional benefits. A previous trial of 432 men suggested that those with fewer than five secondary bone tumours had better survival when radiotherapy was added to hormone therapy. This randomised controlled trial set out to provide further evidence for this.

What did this study do?

STAMPEDE was a randomised controlled trial that took place in 117 hospitals in Switzerland and the UK. A total of 2,061 men with newly diagnosed prostate cancer with metastases, confirmed on a bone scan, took part.

Participants were randomised to either standard care (lifelong anti-androgen hormone therapy, with or without chemotherapy using docetaxel) or standard care plus radiotherapy to the prostate.

This was a large study that was well-powered to detect effects on overall survival. There were also adequate numbers of men in each subgroup to determine the effect on men with low and high metastatic burden, defined according to how far the metastases had spread.

What did it find?

After three years:

  • There was no difference in overall survival between men who had radiotherapy with standard care compared with those who just had standard care (hazard ratio [HR] 0.92, 95% confidence interval [CI] 0.80 to 1.06). After an average follow-up of 37 months, 370 men in the radiotherapy group had died (three-year survival 65%) compared to 391 men in the control group (three-year survival 62%).
  • In men with lower metastatic burden (metastases to either the local lymph nodes or the bones in the pelvis or spine) radiotherapy improved three-year survival rate, 81% versus 73% of those on standard care (HR 0.68, 95% CI 0.52 to 0.90).
  • By contrast, in men with a high metastatic burden (four or more bone metastases with one or more outside the spine or pelvis, or metastases to other organs, or both) the addition of radiotherapy had no benefit on survival, 53% versus 54% on standard care (HR 1.07, 95% CI 0.90 to 1.28).
  • Overall failure-free survival (the proportion of people who did not have a rise in PSA or progression of disease) was increased by radiotherapy, with 32% having no progression compared to 22% with standard care (HR 0.76, 95% CI 0.68 to 0.84).
  • The failure-free survival difference was mostly due to people with low metastatic burden, with 50% having no progression on radiotherapy compared to 33% on standard care (HR 0.59, 95% CI 0.49 to 0.72). There was no difference for people with high metastatic burden, 18% versus 17% (HR 0.88, 95% CI 0.77 to 1.01). 

What does current guidance say on this issue?

NICE guidelines from 2014 recommend that all men with metastatic prostate cancer are offered a bilateral orchidectomy (removal of both testicles) as an alternative to androgen-blocking hormonal treatments.

There is no recommendation regarding radiotherapy in men with metastatic prostate cancer.

What are the implications?

This study adds further evidence that radiotherapy could benefit men with newly diagnosed prostate cancer with local metastases. The trial used CT and bone scans to define low and high metastatic burden. PET scans, which can detect smaller cancer deposits, are becoming widely available and may allocate people differently. However, the researchers did perform further analysis using different definitions of ‘low metastatic burden', with similar positive results. They are now planning to refine the definition to be more clinically useful.

Nevertheless, radiotherapy can now be considered as a potential add-on treatment in men without advanced metastases, but the optimal dose and schedule still needs to be determined.

Citation and Funding

Parker CC, James ND, Brawley CD et al; Systemic Therapy for Advanced or Metastatic Prostate cancer: Evaluation of Drug Efficacy (STAMPEDE) investigators. Radiotherapy to the primary tumour for newly diagnosed, metastatic prostate cancer (STAMPEDE): a randomised controlled phase 3 trial. Lancet. 2018;392:2353-66.

Funded by Cancer Research UK, UK Medical Research Council, Swiss Group for Clinical Cancer Research, Astellas, Clovis Oncology, Janssen, Novartis, Pfizer and Sanofi-Aventis. This project was part-funded by the National Institute for Health Research (NIHR) Biomedical Research Centre at the Royal Marsden NHS Foundation Trust.

Bibliography

Boeri L, Sharma, V, Karnes, RJ. Radiotherapy for newly diagnosed oligometastatic prostate cancer. Lancet. 2018;392:2327-28.

Boevé LMS, Hulshof MCCM, Vis AN et al. Effect on survival of androgen deprivation therapy alone compared to androgen deprivation therapy combined with concurrent radiation therapy to the prostate in patients with primary bone metastatic prostate cancer in a prospective randomised clinical trial: data from the HORRAD Trial. Eur Urol. 2018; Sep 25. doi: 10.1016/j.eururo.2018.09.008. [Epub ahead of print].

Cancer Research UK. Prostate cancer statistics. London: Cancer Research UK; accessed January 2019.

NICE. Prostate cancer: diagnosis and management. CG175. London: National Institute for Health and Care Excellence. 2014.

Radiotherapy to the primary tumour for newly diagnosed, metastatic prostate cancer (STAMPEDE): a randomised controlled phase 3 trial

Published on 21 October 2018

C Parker, N James, C Brawley, N Clarke, A Hoyle, A Ali, A Ritchie, G Attard, S howdhury, W Cross, D Dearnaley, S Gillessen, C Gilson, R Jones, R Langley, Z Malik, M Mason, D Matheson, R Millman, M Russell, G Thalmann, C Amos, R Alonzi, A Bahl, A Birtle, O Din, H Douis, C Eswar, J Gale, M Gannon, S Jonnada, S Khaksar, J Lester, J O'Sullivan, O Parikh, I Pedley, D Pudney, D Sheehan, N Srihari, A Tran, M Parmar, M Sydes

The Lancet , 2018

Background Based on previous findings, we hypothesised that radiotherapy to the prostate would improve overall survival in men with metastatic prostate cancer, and that the benefit would be greatest in patients with a low metastatic burden. We aimed to compare standard of care for metastatic prostate cancer, with and without radiotherapy. Methods We did a randomised controlled phase 3 trial at 117 hospitals in Switzerland and the UK. Eligible patients had newly diagnosed metastatic prostate cancer. We randomly allocated patients open-label in a 1:1 ratio to standard of care (control group) or standard of care and radiotherapy (radiotherapy group). Randomisation was stratified by hospital, age at randomisation, nodal involvement, WHO performance status, planned androgen deprivation therapy, planned docetaxel use (from December, 2015), and regular aspirin or non-steroidal anti-inflammatory drug use. Standard of care was lifelong androgen deprivation therapy, with up-front docetaxel permitted from December, 2015. Men allocated radiotherapy received either a daily (55 Gy in 20 fractions over 4 weeks) or weekly (36 Gy in six fractions over 6 weeks) schedule that was nominated before randomisation. The primary outcome was overall survival, measured as the number of deaths; this analysis had 90% power with a one-sided α of 2·5% for a hazard ratio (HR) of 0·75. Secondary outcomes were failure-free survival, progression-free survival, metastatic progression-free survival, prostate cancer-specific survival, and symptomatic local event-free survival. Analyses used Cox proportional hazards and flexible parametric models, adjusted for stratification factors. The primary outcome analysis was by intention to treat. Two prespecified subgroup analyses tested the effects of prostate radiotherapy by baseline metastatic burden and radiotherapy schedule. Findings Between Jan 22, 2013, and Sept 2, 2016, 2061 men underwent randomisation, 1029 were allocated the control and 1032 radiotherapy. Allocated groups were balanced, with a median age of 68 years (IQR 63–73) and median amount of prostate-specific antigen of 97 ng/mL (33–315). 367 (18%) patients received early docetaxel. 1082 (52%) participants nominated the daily radiotherapy schedule before randomisation and 979 (48%) the weekly schedule. 819 (40%) men had a low metastatic burden, 1120 (54%) had a high metastatic burden, and the metastatic burden was unknown for 122 (6%). Radiotherapy improved failure-free survival (HR 0·76, 95% CI 0·68–0·84; p<0·0001) but not overall survival (0·92, 0·80–1·06; p=0·266). Radiotherapy was well tolerated, with 48 (5%) adverse events (Radiation Therapy Oncology Group grade 3–4) reported during radiotherapy and 37 (4%) after radiotherapy. The proportion reporting at least one severe adverse event (Common Terminology Criteria for Adverse Events grade 3 or worse) was similar by treatment group in the safety population (398 [38%] with control and 380 [39%] with radiotherapy). Interpretation Radiotherapy to the prostate did not improve overall survival for unselected patients with newly diagnosed metastatic prostate cancer. Funding Cancer Research UK, UK Medical Research Council, Swiss Group for Clinical Cancer Research, Astellas, Clovis Oncology, Janssen, Novartis, Pfizer, and Sanofi-Aventis.

Patients receiving radiotherapy chose between two treatment schedules before randomisation: either 36 Gray (Gy) given in six consecutive weekly fractions of 6 Gy, or 55 Gy given in 20 daily fractions of 2.75 Gy over four weeks.

Expert commentary

There is some evidence to suggest that treatment of the primary tumour can reduce tumour progression elsewhere (metastatic disease). This was tested in prostate cancer in the STAMPEDE trial. Over 2,000 men were recruited, which is exceptional. Prostate radiotherapy did not improve overall survival in men with newly diagnosed metastatic disease. However, radiotherapy did improve survival in men with low metastatic burden. This is prostate cancer that has spread either to lymph glands or to the bones in the pelvis and spine but has not spread to other organs.

Given the survival advantage, prostate radiotherapy in men with low metastatic burden should now be the new standard of care. 

Mr Trevor Dorkin, Consultant Urologist, The Newcastle upon Tyne Hospitals NHS Foundation Trust

The commentator declares no conflicting interests

Expert commentary

Treating the primary once the cancer has metastasised has conventionally thought to be futile. This has been challenged by finding that in low metastatic burden prostate cancer, radiotherapy to the primary significantly improves survival and should become standard of care.

This study raises the issue whether this would apply to other cancers and interesting biological questions as to the mechanism. Is it an effect of debulking the primary?  Is it immunological?  Is it due to reducing secondary spread of aggressive clones?

It seems we have underestimated in prostate cancer, the impact of local control in the setting of metastatic disease

Professor Robert Huddart, Reader and Honorary Consultant, Royal Marsden NHS Foundation Trust

Professor Huddart works in the same department as the study chief investigator and has been a local investigator on the study.

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