Portal de Periódicos da CAPES

Prostate Radiotherapy for Men with Metastatic Disease: A New Comparison in the STAMPEDE Trial

2013; Elsevier BV; Volume: 25; Issue: 5 Linguagem: Inglês

10.1016/j.clon.2013.01.005

1433-2981

Chris Parker, Matthew R. Sydes, M.D. Mason, Noel W. Clarke, Daniel M. Aebersold, Johann S. de Bono, David P. Dearnaley, A.W.S. Ritchie, John M. Russell, George N. Thalmann, Mahesh Parmar, Nicholas D. James,

Bladder and Urothelial Cancer Treatments

Many patients presenting with metastatic prostate cancer ask whether they should have treatment to the prostate itself in addition to their hormone therapy. This question is increasingly common and there is a growing sense that these inquiring patients may be on to something, as international randomised controlled trials have now proven a survival benefit to adding radiotherapy to hormone therapy for men with locally advanced disease [1Warde P. Mason M. Ding K. et al.Combined androgen deprivation therapy and radiation therapy for locally advanced prostate cancer: a randomised, phase 3 trial.Lancet. 2011; 378: 2104-2111Abstract Full Text Full Text PDF PubMed Scopus (451) Google Scholar, 2Widmark A. Klepp O. Solberg A. et al.Endocrine treatment, with or without radiotherapy, in locally advanced prostate cancer (SPCG-7/SFUO-3): an open randomised phase III trial.Lancet. 2009; 373: 301-308Abstract Full Text Full Text PDF PubMed Scopus (679) Google Scholar]. From early in 2013, the STAMPEDE trial will investigate whether treatment directed against the primary tumour might indeed retard metastatic progression and thereby prolong survival by testing the role of radiotherapy to the prostate in men presenting with metastatic disease.RationaleThere are several lines of evidence to support the testing of prostate radiotherapy in men with metastatic disease.The Primary Tumour may Prepare the ‘Soil’ for MetastasisWe now know that, far from being merely the source of the ‘seed’, the primary tumour also helps to prepare the ‘soil’. Kaplan et al. [[3]Kaplan R.N. Riba R.D. Zacharoulis S. et al.VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche.Nature. 2005; 438: 820-827Crossref PubMed Scopus (2427) Google Scholar] were the first to show that the initial event at a metastatic site is not the arrival of tumour cells, but rather the clustering of bone marrow-derived cells. These bone marrow-derived cells make the local microenvironment of the secondary organ more receptive to tumour cell colonisation. It has since been found that recruitment of these bone marrow-derived cells from the marrow is stimulated by endocrine factors released by the primary tumour [[4]Psaila B. Lyden D. The metastatic niche: adapting the foreign soil.Nat Rev Cancer. 2008; 9: 285-293Crossref Scopus (915) Google Scholar]. An implication of this work is that therapy directed at the primary tumour, by abrogating this endocrine signalling, could retard the formation and the growth of distant metastases.Cytoreductive Nephrectomy Provides Proof of PrincipleTherapy directed against the primary tumour in the presence of metastatic disease has been evaluated rigorously in only one malignancy: renal carcinoma. Two co-operative groups ran randomised trials of radical nephrectomy in this setting [5Flanigan R.C. Salmon S.E. Blumenstein B.A. et al.Nephrectomy followed by interferon alfa-2b compared with interferon alfa-2b alone for metastatic renal-cell cancer.N Engl J Med. 2001; 345: 1655-1659Crossref PubMed Scopus (1395) Google Scholar, 6Mickisch G.H. Garin A. van Poppel H. de Prijck L. Sylvester R. Radical nephrectomy plus interferon-alfa-based immunotherapy compared with interferon alfa alone in metastatic renal-cell carcinoma: a randomised trial.Lancet. 2001; 358: 966-970Abstract Full Text Full Text PDF PubMed Scopus (1163) Google Scholar]. The trials enrolled patients with previously untreated metastatic renal carcinoma whose primary tumours were amenable to surgical resection. Patients were randomised to receive the standard systemic therapy of the day, interferon-alpha, either alone or with radical nephrectomy. Adding nephrectomy was shown to significantly improve median survival from 7 to 17 months in one trial, and from 8 to 11 months in the other. The mechanism by which nephrectomy improves survival remains uncertain, but is compatible with the theory that factors secreted by the primary tumour promote metastatic progression.Supporting Prostate Cancer DataWeckermann et al. [[7]Weckermann D. Polzer B. Ragg T. et al.Perioperative activation of disseminated tumor cells in bone marrow of patients with prostate cancer.J Clin Oncol. 2009; 27: 1549-1556Crossref PubMed Scopus (128) Google Scholar] collected bone marrow aspirates from a large cohort of patients with clinically localised prostate cancer treated by radical prostatectomy. Detection of disseminated tumour cells (DTCs) in bone marrow before prostatectomy conferred a five-fold increased risk of developing metastases. Conversely, DTCs detected after surgery were not associated with any excess risk. Thus, the risk of metastatic dissemination posed by DTCs was restricted to men with an intact primary tumour. This observation is consistent with the theory that factors derived from the primary tumour are required to stimulate DTCs to colonise and grow into overt metastases.New STAMPEDE Research Arm: Prostate Radiotherapy for Men with Metastatic DiseaseWe hypothesise that local therapy to the primary site may retard distant disease progression and prolong survival in patients who first present with metastatic prostate cancer. This proposal will be tested in the STAMPEDE trial (registered as NCT00268476) by including a new comparison: prostate radiotherapy for patients with metastatic disease.Design ConsiderationsFollowing the same processes used for the addition of an abiraterone comparison to STAMPEDE from November 2011 [[8]Sydes M.R. James N.D. Mason M.D. et al.Flexible trial design in practice – dropping and adding arms in STAMPEDE: a multi-arm multi-stage randomised controlled trial.Trials. 2011; 12: A3Crossref PubMed Google Scholar], a new research arm is being included in the trial's randomisation by protocol amendment. This new arm (which will be referred to as arm H) will be hormone therapy plus radiotherapy to the prostate.The STAMPEDE trial recruits a broad spectrum of men, including high-risk non-metastatic patients and patients who have failed previous local therapy. These patients cannot, of course, be allocated to arm H. Only patients with newly diagnosed metastatic disease and no contraindication to radiotherapy can be allocated to the new arm. As with all the existing arms, these patients will be compared only against the same subset of patients who are contemporaneously allocated to the control arm, hormone therapy alone (arm A). Figure 1 depicts the flow of future patients joining the trial. Adding new questions by protocol amendment is much quicker and much cheaper than setting up a new (and competing) trial and is hence an efficient use of scarce research resources.A relative improvement of 25% in overall survival (hazard ratio 0.75) is the target, as for the other arms. There will be an equal allocation ratio, and the same intermediate lack of sufficient activity guidelines will be used as for the other ongoing comparisons. Accounting for co-recruitment to the trial's other comparisons, around 1200 metastatic patients will be included in this comparison, with 600 of them allocated to radiotherapy to the prostate. Important secondary outcome measures will be radiotherapy toxicity and the complications of uncontrolled pelvic disease (such as the need for ureteric stents, trans-urethral resection of the prostate (TURP) or colostomy).Radiotherapy TechniqueThe radiotherapy treatment aims to deliver a high dose for local tumour control using a simple technique in a convenient, patient friendly schedule. The clinical target volume will consist of the prostate gland alone, while the base of the seminal vesicles should also be included if they are involved by the primary tumour. The planning target volume will have an 8 mm margin posteriorly and a 10 mm margin in other directions around the clinical target volume to account for prostate gland motion and uncertainty in daily treatment set-up. These treatment volume definitions are recommended guidelines, but may be altered at the investigator's discretion in particular circumstances. For example, the posterior planning target volume margin may be adjusted according to the rectal diameter. Two dose-fractionation schedules are permitted according to patient and clinician choice: either 36 Gy in six fractions, administered weekly over 5 consecutive weeks or 55 Gy in 20 fractions, administered daily, 5 days per week, over 4 weeks. Radiotherapy will start promptly after randomisation, sooner than the standard of care radiotherapy used for M0 patients in the trial, who have at least 6 months of hormone therapy before their radiotherapy. The rationale for this is that the median time to progression in metastatic patients is relatively short and delayed radiotherapy could result in significant numbers of arm H patients not receiving their allocated treatment before progression.TimelinesBased on the current excellent rate of recruitment to STAMPEDE, we anticipate that accrual to the new arm should be complete within 4 years of activation (i.e. before the end of 2016), with overall survival data available around 2018. A positive result could spur on the evaluation of primary tumour-directed therapy in the face of metastatic disease in other cancers.The STAMPEDE trial may now be effectively regarded as a programmatic collection of studies in advanced prostate cancer within one protocol rather than a single trial in the conventional sense. The STAMPEDE Trial Management Group is actively considering, and seeking suggestions for, further comparisons that could be addressed, either across the whole trial or in defined subsets as in this case.The original trial arms included three regimens (docetaxel, zoledronate and the two drugs combined) that have now successfully completed all interim analyses and will close to recruitment spring 2013 with survival data expected in 2015. We are therefore also seeking suggestions for studies of relapsing patients, both for these arms and the more recent abiraterone arm. The first such trial with which the STAMPEDE Trial Management Group is engaging, CANTATA, will compare docetaxel rechallenge with cabazitaxel treatment in patients relapsing in the docetaxel arms. We welcome proposals from active researchers.If you would like any further details about the STAMPEDE trial, please contact [email protected] . Many patients presenting with metastatic prostate cancer ask whether they should have treatment to the prostate itself in addition to their hormone therapy. This question is increasingly common and there is a growing sense that these inquiring patients may be on to something, as international randomised controlled trials have now proven a survival benefit to adding radiotherapy to hormone therapy for men with locally advanced disease [1Warde P. Mason M. Ding K. et al.Combined androgen deprivation therapy and radiation therapy for locally advanced prostate cancer: a randomised, phase 3 trial.Lancet. 2011; 378: 2104-2111Abstract Full Text Full Text PDF PubMed Scopus (451) Google Scholar, 2Widmark A. Klepp O. Solberg A. et al.Endocrine treatment, with or without radiotherapy, in locally advanced prostate cancer (SPCG-7/SFUO-3): an open randomised phase III trial.Lancet. 2009; 373: 301-308Abstract Full Text Full Text PDF PubMed Scopus (679) Google Scholar]. From early in 2013, the STAMPEDE trial will investigate whether treatment directed against the primary tumour might indeed retard metastatic progression and thereby prolong survival by testing the role of radiotherapy to the prostate in men presenting with metastatic disease. RationaleThere are several lines of evidence to support the testing of prostate radiotherapy in men with metastatic disease.The Primary Tumour may Prepare the ‘Soil’ for MetastasisWe now know that, far from being merely the source of the ‘seed’, the primary tumour also helps to prepare the ‘soil’. Kaplan et al. [[3]Kaplan R.N. Riba R.D. Zacharoulis S. et al.VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche.Nature. 2005; 438: 820-827Crossref PubMed Scopus (2427) Google Scholar] were the first to show that the initial event at a metastatic site is not the arrival of tumour cells, but rather the clustering of bone marrow-derived cells. These bone marrow-derived cells make the local microenvironment of the secondary organ more receptive to tumour cell colonisation. It has since been found that recruitment of these bone marrow-derived cells from the marrow is stimulated by endocrine factors released by the primary tumour [[4]Psaila B. Lyden D. The metastatic niche: adapting the foreign soil.Nat Rev Cancer. 2008; 9: 285-293Crossref Scopus (915) Google Scholar]. An implication of this work is that therapy directed at the primary tumour, by abrogating this endocrine signalling, could retard the formation and the growth of distant metastases.Cytoreductive Nephrectomy Provides Proof of PrincipleTherapy directed against the primary tumour in the presence of metastatic disease has been evaluated rigorously in only one malignancy: renal carcinoma. Two co-operative groups ran randomised trials of radical nephrectomy in this setting [5Flanigan R.C. Salmon S.E. Blumenstein B.A. et al.Nephrectomy followed by interferon alfa-2b compared with interferon alfa-2b alone for metastatic renal-cell cancer.N Engl J Med. 2001; 345: 1655-1659Crossref PubMed Scopus (1395) Google Scholar, 6Mickisch G.H. Garin A. van Poppel H. de Prijck L. Sylvester R. Radical nephrectomy plus interferon-alfa-based immunotherapy compared with interferon alfa alone in metastatic renal-cell carcinoma: a randomised trial.Lancet. 2001; 358: 966-970Abstract Full Text Full Text PDF PubMed Scopus (1163) Google Scholar]. The trials enrolled patients with previously untreated metastatic renal carcinoma whose primary tumours were amenable to surgical resection. Patients were randomised to receive the standard systemic therapy of the day, interferon-alpha, either alone or with radical nephrectomy. Adding nephrectomy was shown to significantly improve median survival from 7 to 17 months in one trial, and from 8 to 11 months in the other. The mechanism by which nephrectomy improves survival remains uncertain, but is compatible with the theory that factors secreted by the primary tumour promote metastatic progression.Supporting Prostate Cancer DataWeckermann et al. [[7]Weckermann D. Polzer B. Ragg T. et al.Perioperative activation of disseminated tumor cells in bone marrow of patients with prostate cancer.J Clin Oncol. 2009; 27: 1549-1556Crossref PubMed Scopus (128) Google Scholar] collected bone marrow aspirates from a large cohort of patients with clinically localised prostate cancer treated by radical prostatectomy. Detection of disseminated tumour cells (DTCs) in bone marrow before prostatectomy conferred a five-fold increased risk of developing metastases. Conversely, DTCs detected after surgery were not associated with any excess risk. Thus, the risk of metastatic dissemination posed by DTCs was restricted to men with an intact primary tumour. This observation is consistent with the theory that factors derived from the primary tumour are required to stimulate DTCs to colonise and grow into overt metastases. There are several lines of evidence to support the testing of prostate radiotherapy in men with metastatic disease. The Primary Tumour may Prepare the ‘Soil’ for MetastasisWe now know that, far from being merely the source of the ‘seed’, the primary tumour also helps to prepare the ‘soil’. Kaplan et al. [[3]Kaplan R.N. Riba R.D. Zacharoulis S. et al.VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche.Nature. 2005; 438: 820-827Crossref PubMed Scopus (2427) Google Scholar] were the first to show that the initial event at a metastatic site is not the arrival of tumour cells, but rather the clustering of bone marrow-derived cells. These bone marrow-derived cells make the local microenvironment of the secondary organ more receptive to tumour cell colonisation. It has since been found that recruitment of these bone marrow-derived cells from the marrow is stimulated by endocrine factors released by the primary tumour [[4]Psaila B. Lyden D. The metastatic niche: adapting the foreign soil.Nat Rev Cancer. 2008; 9: 285-293Crossref Scopus (915) Google Scholar]. An implication of this work is that therapy directed at the primary tumour, by abrogating this endocrine signalling, could retard the formation and the growth of distant metastases. We now know that, far from being merely the source of the ‘seed’, the primary tumour also helps to prepare the ‘soil’. Kaplan et al. [[3]Kaplan R.N. Riba R.D. Zacharoulis S. et al.VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche.Nature. 2005; 438: 820-827Crossref PubMed Scopus (2427) Google Scholar] were the first to show that the initial event at a metastatic site is not the arrival of tumour cells, but rather the clustering of bone marrow-derived cells. These bone marrow-derived cells make the local microenvironment of the secondary organ more receptive to tumour cell colonisation. It has since been found that recruitment of these bone marrow-derived cells from the marrow is stimulated by endocrine factors released by the primary tumour [[4]Psaila B. Lyden D. The metastatic niche: adapting the foreign soil.Nat Rev Cancer. 2008; 9: 285-293Crossref Scopus (915) Google Scholar]. An implication of this work is that therapy directed at the primary tumour, by abrogating this endocrine signalling, could retard the formation and the growth of distant metastases. Cytoreductive Nephrectomy Provides Proof of PrincipleTherapy directed against the primary tumour in the presence of metastatic disease has been evaluated rigorously in only one malignancy: renal carcinoma. Two co-operative groups ran randomised trials of radical nephrectomy in this setting [5Flanigan R.C. Salmon S.E. Blumenstein B.A. et al.Nephrectomy followed by interferon alfa-2b compared with interferon alfa-2b alone for metastatic renal-cell cancer.N Engl J Med. 2001; 345: 1655-1659Crossref PubMed Scopus (1395) Google Scholar, 6Mickisch G.H. Garin A. van Poppel H. de Prijck L. Sylvester R. Radical nephrectomy plus interferon-alfa-based immunotherapy compared with interferon alfa alone in metastatic renal-cell carcinoma: a randomised trial.Lancet. 2001; 358: 966-970Abstract Full Text Full Text PDF PubMed Scopus (1163) Google Scholar]. The trials enrolled patients with previously untreated metastatic renal carcinoma whose primary tumours were amenable to surgical resection. Patients were randomised to receive the standard systemic therapy of the day, interferon-alpha, either alone or with radical nephrectomy. Adding nephrectomy was shown to significantly improve median survival from 7 to 17 months in one trial, and from 8 to 11 months in the other. The mechanism by which nephrectomy improves survival remains uncertain, but is compatible with the theory that factors secreted by the primary tumour promote metastatic progression. Therapy directed against the primary tumour in the presence of metastatic disease has been evaluated rigorously in only one malignancy: renal carcinoma. Two co-operative groups ran randomised trials of radical nephrectomy in this setting [5Flanigan R.C. Salmon S.E. Blumenstein B.A. et al.Nephrectomy followed by interferon alfa-2b compared with interferon alfa-2b alone for metastatic renal-cell cancer.N Engl J Med. 2001; 345: 1655-1659Crossref PubMed Scopus (1395) Google Scholar, 6Mickisch G.H. Garin A. van Poppel H. de Prijck L. Sylvester R. Radical nephrectomy plus interferon-alfa-based immunotherapy compared with interferon alfa alone in metastatic renal-cell carcinoma: a randomised trial.Lancet. 2001; 358: 966-970Abstract Full Text Full Text PDF PubMed Scopus (1163) Google Scholar]. The trials enrolled patients with previously untreated metastatic renal carcinoma whose primary tumours were amenable to surgical resection. Patients were randomised to receive the standard systemic therapy of the day, interferon-alpha, either alone or with radical nephrectomy. Adding nephrectomy was shown to significantly improve median survival from 7 to 17 months in one trial, and from 8 to 11 months in the other. The mechanism by which nephrectomy improves survival remains uncertain, but is compatible with the theory that factors secreted by the primary tumour promote metastatic progression. Supporting Prostate Cancer DataWeckermann et al. [[7]Weckermann D. Polzer B. Ragg T. et al.Perioperative activation of disseminated tumor cells in bone marrow of patients with prostate cancer.J Clin Oncol. 2009; 27: 1549-1556Crossref PubMed Scopus (128) Google Scholar] collected bone marrow aspirates from a large cohort of patients with clinically localised prostate cancer treated by radical prostatectomy. Detection of disseminated tumour cells (DTCs) in bone marrow before prostatectomy conferred a five-fold increased risk of developing metastases. Conversely, DTCs detected after surgery were not associated with any excess risk. Thus, the risk of metastatic dissemination posed by DTCs was restricted to men with an intact primary tumour. This observation is consistent with the theory that factors derived from the primary tumour are required to stimulate DTCs to colonise and grow into overt metastases. Weckermann et al. [[7]Weckermann D. Polzer B. Ragg T. et al.Perioperative activation of disseminated tumor cells in bone marrow of patients with prostate cancer.J Clin Oncol. 2009; 27: 1549-1556Crossref PubMed Scopus (128) Google Scholar] collected bone marrow aspirates from a large cohort of patients with clinically localised prostate cancer treated by radical prostatectomy. Detection of disseminated tumour cells (DTCs) in bone marrow before prostatectomy conferred a five-fold increased risk of developing metastases. Conversely, DTCs detected after surgery were not associated with any excess risk. Thus, the risk of metastatic dissemination posed by DTCs was restricted to men with an intact primary tumour. This observation is consistent with the theory that factors derived from the primary tumour are required to stimulate DTCs to colonise and grow into overt metastases. New STAMPEDE Research Arm: Prostate Radiotherapy for Men with Metastatic DiseaseWe hypothesise that local therapy to the primary site may retard distant disease progression and prolong survival in patients who first present with metastatic prostate cancer. This proposal will be tested in the STAMPEDE trial (registered as NCT00268476) by including a new comparison: prostate radiotherapy for patients with metastatic disease.Design ConsiderationsFollowing the same processes used for the addition of an abiraterone comparison to STAMPEDE from November 2011 [[8]Sydes M.R. James N.D. Mason M.D. et al.Flexible trial design in practice – dropping and adding arms in STAMPEDE: a multi-arm multi-stage randomised controlled trial.Trials. 2011; 12: A3Crossref PubMed Google Scholar], a new research arm is being included in the trial's randomisation by protocol amendment. This new arm (which will be referred to as arm H) will be hormone therapy plus radiotherapy to the prostate.The STAMPEDE trial recruits a broad spectrum of men, including high-risk non-metastatic patients and patients who have failed previous local therapy. These patients cannot, of course, be allocated to arm H. Only patients with newly diagnosed metastatic disease and no contraindication to radiotherapy can be allocated to the new arm. As with all the existing arms, these patients will be compared only against the same subset of patients who are contemporaneously allocated to the control arm, hormone therapy alone (arm A). Figure 1 depicts the flow of future patients joining the trial. Adding new questions by protocol amendment is much quicker and much cheaper than setting up a new (and competing) trial and is hence an efficient use of scarce research resources.A relative improvement of 25% in overall survival (hazard ratio 0.75) is the target, as for the other arms. There will be an equal allocation ratio, and the same intermediate lack of sufficient activity guidelines will be used as for the other ongoing comparisons. Accounting for co-recruitment to the trial's other comparisons, around 1200 metastatic patients will be included in this comparison, with 600 of them allocated to radiotherapy to the prostate. Important secondary outcome measures will be radiotherapy toxicity and the complications of uncontrolled pelvic disease (such as the need for ureteric stents, trans-urethral resection of the prostate (TURP) or colostomy).Radiotherapy TechniqueThe radiotherapy treatment aims to deliver a high dose for local tumour control using a simple technique in a convenient, patient friendly schedule. The clinical target volume will consist of the prostate gland alone, while the base of the seminal vesicles should also be included if they are involved by the primary tumour. The planning target volume will have an 8 mm margin posteriorly and a 10 mm margin in other directions around the clinical target volume to account for prostate gland motion and uncertainty in daily treatment set-up. These treatment volume definitions are recommended guidelines, but may be altered at the investigator's discretion in particular circumstances. For example, the posterior planning target volume margin may be adjusted according to the rectal diameter. Two dose-fractionation schedules are permitted according to patient and clinician choice: either 36 Gy in six fractions, administered weekly over 5 consecutive weeks or 55 Gy in 20 fractions, administered daily, 5 days per week, over 4 weeks. Radiotherapy will start promptly after randomisation, sooner than the standard of care radiotherapy used for M0 patients in the trial, who have at least 6 months of hormone therapy before their radiotherapy. The rationale for this is that the median time to progression in metastatic patients is relatively short and delayed radiotherapy could result in significant numbers of arm H patients not receiving their allocated treatment before progression.TimelinesBased on the current excellent rate of recruitment to STAMPEDE, we anticipate that accrual to the new arm should be complete within 4 years of activation (i.e. before the end of 2016), with overall survival data available around 2018. A positive result could spur on the evaluation of primary tumour-directed therapy in the face of metastatic disease in other cancers.The STAMPEDE trial may now be effectively regarded as a programmatic collection of studies in advanced prostate cancer within one protocol rather than a single trial in the conventional sense. The STAMPEDE Trial Management Group is actively considering, and seeking suggestions for, further comparisons that could be addressed, either across the whole trial or in defined subsets as in this case.The original trial arms included three regimens (docetaxel, zoledronate and the two drugs combined) that have now successfully completed all interim analyses and will close to recruitment spring 2013 with survival data expected in 2015. We are therefore also seeking suggestions for studies of relapsing patients, both for these arms and the more recent abiraterone arm. The first such trial with which the STAMPEDE Trial Management Group is engaging, CANTATA, will compare docetaxel rechallenge with cabazitaxel treatment in patients relapsing in the docetaxel arms. We welcome proposals from active researchers.If you would like any further details about the STAMPEDE trial, please contact [email protected] . We hypothesise that local therapy to the primary site may retard distant disease progression and prolong survival in patients who first present with metastatic prostate cancer. This proposal will be tested in the STAMPEDE trial (registered as NCT00268476) by including a new comparison: prostate radiotherapy for patients with metastatic disease. Design ConsiderationsFollowing the same processes used for the addition of an abiraterone comparison to STAMPEDE from November 2011 [[8]Sydes M.R. James N.D. Mason M.D. et al.Flexible trial design in practice – dropping and adding arms in STAMPEDE: a multi-arm multi-stage randomised controlled trial.Trials. 2011; 12: A3Crossref PubMed Google Scholar], a new research arm is being included in the trial's randomisation by protocol amendment. This new arm (which will be referred to as arm H) will be hormone therapy plus radiotherapy to the prostate.The STAMPEDE trial recruits a broad spectrum of men, including high-risk non-metastatic patients and patients who have failed previous local therapy. These patients cannot, of course, be allocated to arm H. Only patients with newly diagnosed metastatic disease and no contraindication to radiotherapy can be allocated to the new arm. As with all the existing arms, these patients will be compared only against the same subset of patients who are contemporaneously allocated to the control arm, hormone therapy alone (arm A). Figure 1 depicts the flow of future patients joining the trial. Adding new questions by protocol amendment is much quicker and much cheaper than setting up a new (and competing) trial and is hence an efficient use of scarce research resources.A relative improvement of 25% in overall survival (hazard ratio 0.75) is the target, as for the other arms. There will be an equal allocation ratio, and the same intermediate lack of sufficient activity guidelines will be used as for the other ongoing comparisons. Accounting for co-recruitment to the trial's other comparisons, around 1200 metastatic patients will be included in this comparison, with 600 of them allocated to radiotherapy to the prostate. Important secondary outcome measures will be radiotherapy toxicity and the complications of uncontrolled pelvic disease (such as the need for ureteric stents, trans-urethral resection of the prostate (TURP) or colostomy). Following the same processes used for the addition of an abiraterone comparison to STAMPEDE from November 2011 [[8]Sydes M.R. James N.D. Mason M.D. et al.Flexible trial design in practice – dropping and adding arms in STAMPEDE: a multi-arm multi-stage randomised controlled trial.Trials. 2011; 12: A3Crossref PubMed Google Scholar], a new research arm is being included in the trial's randomisation by protocol amendment. This new arm (which will be referred to as arm H) will be hormone therapy plus radiotherapy to the prostate. The STAMPEDE trial recruits a broad spectrum of men, including high-risk non-metastatic patients and patients who have failed previous local therapy. These patients cannot, of course, be allocated to arm H. Only patients with newly diagnosed metastatic disease and no contraindication to radiotherapy can be allocated to the new arm. As with all the existing arms, these patients will be compared only against the same subset of patients who are contemporaneously allocated to the control arm, hormone therapy alone (arm A). Figure 1 depicts the flow of future patients joining the trial. Adding new questions by protocol amendment is much quicker and much cheaper than setting up a new (and competing) trial and is hence an efficient use of scarce research resources. A relative improvement of 25% in overall survival (hazard ratio 0.75) is the target, as for the other arms. There will be an equal allocation ratio, and the same intermediate lack of sufficient activity guidelines will be used as for the other ongoing comparisons. Accounting for co-recruitment to the trial's other comparisons, around 1200 metastatic patients will be included in this comparison, with 600 of them allocated to radiotherapy to the prostate. Important secondary outcome measures will be radiotherapy toxicity and the complications of uncontrolled pelvic disease (such as the need for ureteric stents, trans-urethral resection of the prostate (TURP) or colostomy). Radiotherapy TechniqueThe radiotherapy treatment aims to deliver a high dose for local tumour control using a simple technique in a convenient, patient friendly schedule. The clinical target volume will consist of the prostate gland alone, while the base of the seminal vesicles should also be included if they are involved by the primary tumour. The planning target volume will have an 8 mm margin posteriorly and a 10 mm margin in other directions around the clinical target volume to account for prostate gland motion and uncertainty in daily treatment set-up. These treatment volume definitions are recommended guidelines, but may be altered at the investigator's discretion in particular circumstances. For example, the posterior planning target volume margin may be adjusted according to the rectal diameter. Two dose-fractionation schedules are permitted according to patient and clinician choice: either 36 Gy in six fractions, administered weekly over 5 consecutive weeks or 55 Gy in 20 fractions, administered daily, 5 days per week, over 4 weeks. Radiotherapy will start promptly after randomisation, sooner than the standard of care radiotherapy used for M0 patients in the trial, who have at least 6 months of hormone therapy before their radiotherapy. The rationale for this is that the median time to progression in metastatic patients is relatively short and delayed radiotherapy could result in significant numbers of arm H patients not receiving their allocated treatment before progression. The radiotherapy treatment aims to deliver a high dose for local tumour control using a simple technique in a convenient, patient friendly schedule. The clinical target volume will consist of the prostate gland alone, while the base of the seminal vesicles should also be included if they are involved by the primary tumour. The planning target volume will have an 8 mm margin posteriorly and a 10 mm margin in other directions around the clinical target volume to account for prostate gland motion and uncertainty in daily treatment set-up. These treatment volume definitions are recommended guidelines, but may be altered at the investigator's discretion in particular circumstances. For example, the posterior planning target volume margin may be adjusted according to the rectal diameter. Two dose-fractionation schedules are permitted according to patient and clinician choice: either 36 Gy in six fractions, administered weekly over 5 consecutive weeks or 55 Gy in 20 fractions, administered daily, 5 days per week, over 4 weeks. Radiotherapy will start promptly after randomisation, sooner than the standard of care radiotherapy used for M0 patients in the trial, who have at least 6 months of hormone therapy before their radiotherapy. The rationale for this is that the median time to progression in metastatic patients is relatively short and delayed radiotherapy could result in significant numbers of arm H patients not receiving their allocated treatment before progression. TimelinesBased on the current excellent rate of recruitment to STAMPEDE, we anticipate that accrual to the new arm should be complete within 4 years of activation (i.e. before the end of 2016), with overall survival data available around 2018. A positive result could spur on the evaluation of primary tumour-directed therapy in the face of metastatic disease in other cancers.The STAMPEDE trial may now be effectively regarded as a programmatic collection of studies in advanced prostate cancer within one protocol rather than a single trial in the conventional sense. The STAMPEDE Trial Management Group is actively considering, and seeking suggestions for, further comparisons that could be addressed, either across the whole trial or in defined subsets as in this case.The original trial arms included three regimens (docetaxel, zoledronate and the two drugs combined) that have now successfully completed all interim analyses and will close to recruitment spring 2013 with survival data expected in 2015. We are therefore also seeking suggestions for studies of relapsing patients, both for these arms and the more recent abiraterone arm. The first such trial with which the STAMPEDE Trial Management Group is engaging, CANTATA, will compare docetaxel rechallenge with cabazitaxel treatment in patients relapsing in the docetaxel arms. We welcome proposals from active researchers.If you would like any further details about the STAMPEDE trial, please contact [email protected] . Based on the current excellent rate of recruitment to STAMPEDE, we anticipate that accrual to the new arm should be complete within 4 years of activation (i.e. before the end of 2016), with overall survival data available around 2018. A positive result could spur on the evaluation of primary tumour-directed therapy in the face of metastatic disease in other cancers. The STAMPEDE trial may now be effectively regarded as a programmatic collection of studies in advanced prostate cancer within one protocol rather than a single trial in the conventional sense. The STAMPEDE Trial Management Group is actively considering, and seeking suggestions for, further comparisons that could be addressed, either across the whole trial or in defined subsets as in this case. The original trial arms included three regimens (docetaxel, zoledronate and the two drugs combined) that have now successfully completed all interim analyses and will close to recruitment spring 2013 with survival data expected in 2015. We are therefore also seeking suggestions for studies of relapsing patients, both for these arms and the more recent abiraterone arm. The first such trial with which the STAMPEDE Trial Management Group is engaging, CANTATA, will compare docetaxel rechallenge with cabazitaxel treatment in patients relapsing in the docetaxel arms. We welcome proposals from active researchers. If you would like any further details about the STAMPEDE trial, please contact [email protected] . The authors would like to thank Cancer Research UK (grant funding; CRUK/06/019 ), Novartis (educational grant, free drug), Pfizer (educational grant, free drug), Sanofi Aventis (educational grant, free and discounted drug), Janssen Pharma NV (educational grant, free drug), Medical Research Council (core funding), National Cancer Research Network (on-site support). MRS and MKBP are employed by the Medical Research Council.