Authors:

Deep Chakrabarti

,

David Dearnaley

Date of publication: 27 August 2025
Last update: 27 August 2025

Abstract

External beam radiotherapy for prostate cancer came of age with the introduction of high energy linear accelerators in the 1960-80’s. Usage increased dramatically after the introduction of PSA testing in the 1980’s. The dose delivered was limited by side-effects on particularly the rectum, which limited prostate cancer control. A series of physics, engineering, computing, and imaging innovations has led to ever more precise treatment which has substantially reduced side-effects and permitted dose-escalation with increased treatment effectiveness. In parallel we have learnt that hypofractionation is effective and safe leading to reduced costs and treatment burden for patients. Radiotherapy can be more effective when combined with hormone therapy. Many of the technical advances, assessments of different fractionation schedules and combinations of radiotherapy with androgen deprivation therapy have been rigorously assessed in randomised controlled trials. The evolution, rather than revolution, of radiotherapy for prostate cancer has happened because of meticulous research and development by many teams of clinicians and scientists. Much of this work has been done in Europe. The result is more effective, convenient and kinder treatment for patients who have contributed through their considerable support for the many clinical trials that have been done.

Introduction

Radiotherapy technology has developed rapidly over the last 50 years with considerable input from European researchers and clinicians. Improved imaging with CT and MR permits more accurate localisation of the prostate and the dominant prostate cancer lesion(s). Considerably faster computing speeds have revolutionised treatment planning using intensity modulated radiotherapy (IMRT) and fast treatment delivery techniques such as volumetrically modified arc therapy (VMAT) are widely available. Image guidance with cone-beam CT or fiducial markers are part of routine practice and improve treatment accuracy which allows for reduced treatment “safety margins” and reduces side effects. Adaptive radiotherapy modifying treatments in real time to track the prostate for example using the MR-Linac technology or stereotactic body radiotherapy (SBRT) are increasingly used. These technology advances have paralleled the development of hypofractionated radiotherapy (HFRT) and are important components to the success of reduced fractionation. The success of modest HFRT has encouraged the development and clinical trial evaluation of more extreme forms of hypofractionation. Additionally clinical trials have shown the benefit of using adjuvant hormonal therapy with RT in intermediate or high risk localised prostate cancer. Randomised trials are defining the role of radiotherapy post-prostatectomy and also in limited metastatic disease. In combination these advances have improved patient outcomes, disease control, and survival with reduced treatment related side-effects.

A) RADIOTHERAPY PROGRESS: PHYSICS, IMAGING, COMPUTING AND ENGINEERING

X-rays were discovered in 1895 by Wilhelm Roentgen working in Wurzburg, Germany. Just six years later he was awarded the first Nobel Prize for Physics. (J. Jones & Nadrljanski, 2010) The door was open to develop the modern radiotherapy that we see today. But before the discovery of the linear accelerator (linac), external beam radiotherapy was delivered using low energy x-ray tubes and radioisotopes, like Caesium-137 and Cobalt-60. Cobalt-60, an artificial radioisotope saw its origins in the nuclear reactor of the Manhattan Project of the World War II. Throughout the second world war, military radar devices required an MW-output microwave, which led to the development of two tubes. Boot and Randall designed the Magnetron in 1939 (England), while the Varian brothers (USA) developed the Klystron. The basic difference between these is that Magnetron is a self-generator in response to DC input, while the Klystron is an amplifier that amplifies low power microwave input. These particle accelerator tubes were central to the design of the linacs which followed.

The first two telecobalt units were installed in Canada, and the first in Europe was in the Hospital San Lorenzo, in Borgo Valsugana, Italy in 1953. The first particle accelerators were described by the Swedish physicist Gustaf Ising in 1924, and Norwegian physicist Rolf Widerøe in 1927. The first linac-based treatment for cancer was in the Hammersmith Hospital in London in 1953 (Bewley 1985) using an accelerator tube length of about 3 metres and a 2 MW magnetron (Photo 1).

Photo 1: A model of the 1953 8 MeV Linac installation at the Hammersmith Hospital, London, UK. (from Back to the future: the history and development of the clinical linear accelerator David I Thwaites and John B Tuohy Phys. Med. Biol. 51 (2006) R343–R362 doi:10.1088/0031-9155/51/13/R20)

 

While telecobalt units could deliver only mono-energetic beams (1.17 MV gamma rays), modern linacs can deliver a range of higher energies (6-25 MeV) with reliability and accuracy. The increased tissue penetration from high energy modern linacs makes it possible to treat deep-seated cancers more effectively and safely. The history of the technical and engineering advances culminating in the modern iso-centric linac have been well reviewed.(Thwaites & Tuohy, 2006).

For a long period of time, simulation (the term used to describe the process of checking the accuracy of treatment) of radiation therapy used fluoroscopy and kilovolt X ray images of the patient. These were taken in the treatment position before radiotherapy began. Bony landmarks could be identified. However, the position of tumours and normal tissue had to be estimated from clinical examination, anatomical knowledge and diagnostic radiological images. The radiation portals or treatment fields used had to be generous to ensure adequate tumour coverage which often meant that considerable amounts of normal tissue were included. The arrival of computerised tomography (CT) revolutionised radiotherapy. It became possible for the first time to directly visualise the tumour and organs to be spared from radiation. Sir Godfrey Hounsfield developed the CT scanner in the UK in the 1970s (Photo 2).

Photo 2: Sir Godfrey Hounsfield was a British electrical engineer who shared the 1979 Nobel Prize for Physiology or Medicine with Allan MacLeod Cormack for his part in developing the diagnostic technique of CT. His name is immortalised in the radiodensity measure in Hounsfield units. Godfrey Hounsfield stands beside the EMI-Scanner in 1972

 

The first use in medical practice was at the Atkinson Morley Hospital in Wimbledon, London in 1971 to scan a patient with a brain cyst. Whole body scanners were developed later around 1975. Diagnostic CT and subsequently CT-simulation rapidly developed as the standard of care in radiotherapy planning. The era between 1980 and 2000 witnessed the evolution of radiotherapy from conventional to three-dimensional conformal radiotherapy (CFRT) (Figure 1a).

Figure 1: a) Conventional radiotherapy using rectangular treatment beams to treat the prostate b) 3D conformal (CFRT) using fixed beams shaped by a c) multileaf collimator (MLC) d) Intensity modulated radiotherapy (IMRT) using dynamic movement of MLC leaves to produce the complex shape of pelvic lymph node chains e) IMRT with Image guided radiotherapy (IGRT) using gold grains implanted in the prostate f) Stereotactic body radiotherapy (SBRT) using Cyberknife® g) Elekta MR Linac installed at Royal Marsden Hospital, Sutton, UK.

 

Conformal Radiotherapy (CFRT)

Historically, the delivery of external beam radiotherapy (EBRT) was in the form of conventional square or rectangular fields using metal blocks to shield normal tissues (Figure 1a). The introduction of multi-leaf collimators (MLC) made it possible to contour radiation beams to follow the shape of the tumour (CFRT) and spare more normal tissue (Figure 1b/c). Increased doses of RT could then be given. The more complex RT planning was enabled by more powerful and faster RT planning computers. While this represented a significant improvement over conventional radiotherapy, it had its limitations. The shapes produced had concave borders (eg spheres or ovoids) but could not follow the convex shapes of the target volumes, eg. to cover pelvic lymph nodes (Figure 1d) or to sculpt around normal tissues such as the rectum. IMRT was developed to treat these more complex tumour targets.

Intensity Modulated radiotherapy (IMRT)

Two interrelated problems needed to be solved. Firstly, the physics and engineering technology needed to be understood and developed to produce radiotherapy beams of variable intensity or fluence. Secondly novel computer planning methods were required to rapidly calculate how best to position and change the fluence from multiple RT beams. Together these innovations are known as intensity modulated radiotherapy (IMRT Figure 1d).(Cho, 2018, p. 201) Andreas Brahme, the Swedish physicist was one of the pioneers of IMRT physics. He solved one of the earliest problems in modern IMRT in 1982 of an inverse problem of rotational beam fluence to deliver a uniform dose to a doughnut shaped target (Figure 2).(A Brahme et al., 1982) In 1984, the first commercial MLCs were patented by Brahme, and commercialised by Scanditronix.(Anders Brahme, 1987) In IMRT, the radiation beam is broken up into smaller “beamlets”, which can be further adjusted individually to vary the intensity or fluence. There are numerous possibilities of how to sculpt the radiotherapy dose. The modulation is accomplished by moving the leaves of the multileaf collimator. This can be done while the leaves are stationary while the RT beam is on (step-and-shoot), while the leaves are in motion while the beam is on (dynamic), or while both the leaves and the linac gantry move with the beam on - volumetric modulated arc therapy (VMAT).

Figure 2 Prostate target, rectum and bladder. The fluence should be the greatest where the length of intersection between a beam and the target volume (prostate) was the greatest. Conversely, if the beam intersects the rectum or bladder it should have a lower fluence. To have a doughnut shaped distribution, the centre of the beam could be blocked at each step of the arc and by a complete rotation, a doughnut-shaped distribution is obtained.

 

The second key development was of inverse planning. Previously a physicist tried a permutation and combination of beam directions and intensities to achieve tumour coverage and normal tissue avoidance (forward planning). Inverse planning is computer-led. The planning algorithm is given details of the required tumour dose and acceptable dose levels to normal tissues. The computer then generates a solution by minimising or maximising an objective problem or ‘cost function’ for tumour and normal tissues. By the late 1980s and early 1990s, a handful of physicists were working on IMRT in Europe and USA including teams at the German Cancer Research Centre (DKFZ), Heidelberg led by Wolfgang Schlegel with Thomas Bortfeld (subsequenty Memorial Sloane Kettering, New York), Steve Webb, (The Institute of Cancer Research and Royal Marsden Hospital (ICR/RMH, London, UK), Andreas Brahme (Karolinska Institute, Sweden), and Charles Boyer (Stanford University ,California) (Table 1).(T. Bortfeld, 2006; Cho, 2018) (Photo 3) Novel systems were developed, such as the NOMOS MIMiC with the Peacock planning system, in the USA in 1992.

Photo 3: Some early inventors of IMRT a) Andreas Brahme (Sweden) b) from the left - Jorg Stein, Thomas Bortfeld, Dick Fraass, Wolfgang Schlegel and Steve Webb (Germany and UK at ESTRO Edinburgh 1998)

 

This used a mini-MLC array and slice by slice rotational paradigm. The MIMiC fixed as an accessory to the head of a linac.(M. P. Carol, 1995) The first patient was treated in 1994 with commercialisation in 1995. The concept of tomotherapy, which used IMRT to treat slice by slice on a CT was proposed by Mackie in 1993. The first prototype was developed in 2001 in Wisconsin, with a patient treated in 2002. Further developments followed in a period of intense activity. Multiple static field MLC in 1994, dynamic field MLC in 1994, optimal and analytic solutions for the sliding-window leaf trajectory problem by three research groups (Karolinska group in Stockholm, MSKCC group in New York, and DKFZ group in Heidelberg) in 1994, and intensity modulated arc therapy in 1995. Subsequently Karl Otto (Vancouver Cancer Centre, British Columbia, Canada) and James Bedford (ICR, United Kingdom) were instrumental in the development of volumetric modulated arc therapy (VMAT), or IMRT in a single gantry arc. By late 1990s, most manufacturers offered some form of embryonic IMRT (Figure 1d). Worldwide, the first patient treated with dynamic MLC was at the Memorial Sloan Kettering Hospital in New York in 1996. The first prostate IMRT in the UK was at the RMH/ICR in 2000. The RMH/ICR was also the first hospital worldwide to treat a patient with VMAT in 2008. There was rapid uptake of the new techniques internationally despite a glaring lack of gold-standard phase 3 trials. The only exceptions were in studies of normal tissue sparing in head and neck cancers performed at ICR/RMH.(Nutting et al., 2011) However, the technology has proven irresistible. Treatment “beam-on” times have reduced dramatically from about 45 minutes in the early days of IMRT to 2-3 minutes with VMAT and now inverse planned IMRT is routine for prostate cancer and many other malignancies. (Photo 3)

Image-guided radiotherapy

A high degree of treatment accuracy is needed for these more precise and sculpted modern forms of radiotherapy. Image guided radiotherapy (IGRT) can be achieved ideally using implanted gold grain fiducial markers in the prostate (Figure 1e) or cone-beam CT (CBCT) which was widely introduced in the 2000’s. Initial CBCT “proof of principle”, using the linacs megavoltage Xrays, was by Robb and colleagues in 1974 (USA) who imaged the thorax. Feldkamp and colleagues described the mathematical algorithm in 1984 (USA).(Robb et al., 1974) In the 1980s, Zonarc® (Palomex Oy, Helsinki, Finland) and Scanora® (Soredex Oy, Helsinki Finland, Tammisalo and colleagues) were developed as multifunction imaging methods for structures of the head and neck. Mozzo et al. developed a practical method for CBCT in 1998 in Verona, Italy.(Mozzo et al., 1998) Although widely used, CBCT images are difficult to interpret in the pelvis as the definition of bowel, rectum, prostate and bladder can be indistinct.

Anders Widmark and his Swedish colleagues from Umeå University, described a specialised urethral catheter containing radio-opaque markers.(Bergström et al., 1998) This is visualised during radiotherapy to ensure accurate treatment delivery. Robert Smeenk (2010) and Dutch colleagues from Nijmegen developed and tested an endorectal balloon to improve accuracy and reduce anorectal doses.(Smeenk et al., 2012) At present, neither is widely used, and IMRT with cone-beam guidance with fiducial markers is widely practiced. Detailed analysis of the accuracy of IGRT using gold grains (Figure 1e) has shown how planning safety margins can be substantially reduced.(McNair et al., 2008) The Calypso TM system, now available from Varian, using implantable electromagnetic transponders(Kupelian et al., 2007) gives information on the prostates position at 10Hz. Prostate motion can be monitored throughout treatment with the potential for adaptive therapy. Radiopaque peri-rectal spacer hydrogels are also being developed and assessed.(Icht et al., 2024) The “proof of the pudding” is whether patient outcomes are meaningfully improved without risking rare but serious complications from such minimally invasive procedures.(Hall et al., 2021)

Stereotactic radiotherapy

Stereotactic body radiotherapy (SBRT) or stereotactic ablative body radiotherapy (SABR) was initial developed by Lax and Blomgren in the early 1990’s at the Karolinska Institute in Sweden.(Blomgren et al., 1995) Prostate SBRT was initially performed with CyberKnifeTM (Figure 1f) but can now be delivered using a linac with image guidance with fiducial markers. In the United Kingdom, the first patients were treated with CyberknifeTM at the Mount Vernon Cancer Centre in Middlesex, and RMH/ICR in spring/summer 2011.

MR-Linac

The MR-Linac combines magnetic resonance imaging with a linac and was first described by Lagendijk and Bakker from Utrecht (2000).(Lagendijk et al., 2016) It is particularly useful in prostate radiotherapy, since pelvic anatomy is better visualised on MR than conventional CT. Of the various MR-linacs in use, the one with the highest-intensity electromagnetic field is Elekta’s Unity, designed in The Netherlands/Utrecht and based on a 1.5 T magnet (Philips, Ingenia, The Netherlands, Eindhoven). The first MR-Linacs in Europe were introduced to treat patients in 2017 at UMC Utrecht and in 2018 at Odense University Hospital, The Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, University Hospital Tübingen, and ICR/RMH, London (Figure 1g). MR images can be repeated during radiotherapy with the possibility of re-planning treatment in real-time to account for any changes in position or shape of the prostate. The MR-Linac gives the most precise adaptive IGRT/IMRT presently available. The potential to reduce treatment margins and safely deliver ultra-hypofractionated radiotherapy (see below) is being explored in the Hermes trial at RMH/ICR London. This phase 2 randomised trial treats men with intermediate or lower high risk prostate cancer. Daily adaptive RT to 36.25 Gy/5f over 2 weeks is compared with 24 Gy/2f over 8 days with an integrated boost to the MRI visible tumour of 27 Gy in 2 fractions using the Elekta Unity MR-Linac. In a pre-planned interim analysis, the acute GU toxicities were below the pre-specified threshold. Further studies include the use of MRI-guided radiotherapy for de-escalation or reduction of margins to improve toxicities (DESTINATION NCT05709496, DESTINATION2 NCT05709496), and prostate re-irradiation.

 

B) EUROPEAN CLINICAL TRIALS OF PROSTATE RADIOTHERAPY

Background

Curative radiotherapy for prostate cancer became possible after the introduction of linear accelerators. Led by Bagshaw and Del Regato in the USA, initial reports were published in the late 1950s and 1960s.(Bagshaw et al., 1965; Del Regato, 1967) It was realised that there was a limit to the dose that could be given to the prostate to avoid serious side effects to the bowel or bladder. In Europe, initial reports on small patient series were from Spain, Germany, and Russia. The use of curative radiotherapy increased rapidly in localised prostate cancer from 12% to 27% in the USA between 1974-83 and for example from 13% to 31% between 1975-89 in the Netherlands. The surge in diagnoses caused by the widespread introduction of prostate specific antigen (PSA) testing in the 1980’s was in part responsible for dramatic increases in RT usage in for example in Detroit with a 355% rise and RMH, London 387% rise. It was appreciated that PSA testing after RT was a reliable indicator of disease control, and a consensus conference determined the level of nadir +2ng/ml post treatment.(Roach et al., 2006) This definition has been extensively used in the phase 3 randomised controlled trials which have tested radiotherapy techniques, dose, fractionation and the additional use of adjuvant systemic treatment. Testing novel radiotherapy technologies has been done in a piecemeal way driven by varying cultures in different health care systems. For example, in the UK there is generally a need to produce robust evidence from phase 3 trials before new technologies are accepted as the standard of care in the NHS.

CFRT and dose escalation

The only trial testing CFRT was done at RMH/ICR. We compared conventional and conformal radiotherapy (Figure 1a, b) publishing results in 1999. 225 men with localised PCa were treated between 1988 and 1995 to a dose of 64 Gy in 32 fractions(f) with 3 to 6 months of androgen deprivation (ADT). Radiation proctitis was reduced from 15% to 5% There was no difference in local control. CFRT became the standard of care. (Supplementary Table 1).(D. P. Dearnaley et al., 1999) A pilot study of dose escalation using CFRT followed immediately (1995-7) which randomised 126 patients to either 64Gy in 32f or 74Gy in 37f as well as a standard (1.5cm) or reduced (1.0cm) planning safety margin. There was a 12% increase in PSA control but increased side effects in both the dose-escalated and larger margin groups (Supplementary Table 1 ).(D. P. Dearnaley et al., 2005) The study design was rapidly adopted and funded by the UK Medical Research Council (MRC) but dropping the safety margin randomisation. Between 1998 and 2002 843 men with localized PCa from the UK, Australia and New Zealand were randomised to receive either 64Gy or 74Gy using additionally 3-6 months ADT, as in the pilot study. Recruitment was rapid and the original target of 450 men was increased to allow analysis of low, moderate or high-risk prostate cancer sub-groups. A 12% improvement in PSA control was found with dose escalation but there was similar overall survival (OS) in the randomised groups. The increased disease control came at the cost of increased late bowel toxicities.(D. P. Dearnaley et al., 2014) Similar results were found in 2 other European Trials in France and the Netherlands and 2 studies performed in the USA.(Kishan, Wang, et al., 2022) The American RTOG 0126 trial with 1522 patients is the largest dose-escalation study reported. 79.2Gy in 44f was compared with 70.2Gy in 39f. PSA control improved by 15% at 8 years with a reduced need for salvage therapy. No OS benefit was found with increased dose but late gastrointestinal (GI) and genitourinary (GU) toxicities increased by 6%(GI) and 5%(GU) (Supplementary Table 1).(Michalski et al., 2018)

Intensity-modulated (IMRT) and image guided (IGRT) radiotherapy

There have been no phase 3 trials comparing CFRT and IMRT in prostate cancer. A retrospective comparison between the 74Gy dose groups in RT01 and CHHiP (see below) suggested a reduction in RTOG GI ≥ grade 2 side effects from 33% to 14% supported by a more than halving of patient reported bowel “bother and distress”. The improvement probably related to the use of IMRT rather than CFRT (Figure 1b/c) as well as the strict dose-constraints applied in CHHiP.(D. Dearnaley et al., 2016) The impact of IGRT has also been under-researched. A French collaborative group compared daily with weekly IGRT using cone-beam CT and fiducial markers. 470 patients were randomised and there was a reduction in acute GI (6% vs11%), late GI (HR 0.71 p=0.027) as well as reduced PSA-failure 9% vs 21%. A decrease of OS in the daily IGRT group due to second cancers and cardiovascular disease was unexplained.(De Crevoisier et al., 2018) A modest sub-study in CHHiP additionally randomised groups to IMRT with or without IGRT using fiducial gold-grain markers. GI and GU side effects reduced from 8.3% to 5.8% and 8.4% to 3.9% respectively.(Murray et al., 2020) NICE Guidance in the UK now mandates the use of IMRT and also recommends IGRT.(NICE, n.d.) Both IMRT and IGRT are recommended in European Guidelines.(Cornford et al., 2024)

Hypofractionation in Prostate cancer (HFRT)

There was growing interest in the late1990’s in the radiation sensitivity of breast and prostate cancer to changes in radiotherapy fraction size. Historically, conventional radiotherapy had been delivered in 1.8-2.0 Gy fractions. This was based on the assumption that tumours behaved like early-reacting rather than late-reacting normal tissues. The fraction sensitivity of cancers and normal tissue is usually described by the α/β ratio. A high ratio is seen for acute reactions and a low ratio for late reactions.

The α/β ratio for most cancers and acute normal tissue reactions is about 10 Gy. But for prostate cancer, a low value of 1.5-3.0 Gy was suggested by European and American radiobiologists similar to the α/β ratio of 3Gy for late-reacting normal tissues.(Bentzen & Ritter, 2005; Fowler et al., 2001; Vogelius & Bentzen, 2013) The theory was tested in the CHHiP trial which randomised 3216 men with mostly intermediate or high-risk cancers to conventional radiotherapy (74 Gy in 37 fractions), or one of two hypofractionated (HFRT) regimens (60 Gy in 20 fractions, or 57 Gy in 19 fractions) along with 3-6 months of androgen deprivation (ADT). The HFRT regimen of 60 Gy in 20 daily fractions was found to be non-inferior for biochemical control with similar overall survival and late side effects for both the HFRT arms.(D. Dearnaley et al., 2016) For men aged 75 years or more, the regimen of 57 Gy in 19 daily fractions achieved similar biochemical failure rates with lower gastrointestinal toxicity. Similar effects have been maintained on long-term follow-up. Importantly, for the first time, dose constraints have been defined for HFRT using detailed dosimetry and both clinician and patient-reported outcomes.(Wilkins et al., 2020) Translational research used prostate biopsies from 1875 patients collected from 109 hospitals. A range of tissue biomarkers using a range of immunochemical markers, for example of proliferation and DNA repair pathways, has failed to identify fractionation-dependent patient sub-groups suggesting that the trial results should be generally applicable to localised prostate cancer.(Wilkins et al., 2023) (Photo 4) A substantial Canadian trial, PROFIT led by Charles Catton (2017), used similar fractionation schedules reaching the same conclusions in 1206 men with intermediate-risk disease again using a non-inferiority design.(Catton et al., 2017) In contradistinction the Dutch HYPRO trial, randomised 820 men with intermediate-high risk prostate cancer to a higher hypofractionated dose of 64·6 Gy in 19 fractions over 6.5 weeks or 78 Gy in 39 daily fractions as control. The trial didn’t show an advantage for HFRT but had more long-term side effects.(Incrocci et al., 2016) We have speculated that the failure to improve outcome was because of the prolonged treatment times in the hypofractionated group. Increased side effects were probably due to the increased dose and planning methods.

Moderate HFRT has been established as a standard of care and recommended as an option in the EUA and AUA/ASTRO guidelines as well as being mandated in the UK by NICE.(AUA, n.d.; Cornford et al., 2024; Eastham et al., 2022; NICE, n.d.) HFRT is more convenient for patients and there are considerable cost benefits for health care systems changing from conventional fractionation to HFRT. Savings have been estimated to be £28 million/year in the UK, $360 million/year in the USA and up to $2.55 billion/year globally.(D. Dearnaley & Hall, 2018; Moore et al., 2019) This worldwide saving in resource potentially allows an additional 0.9 million patients to be treated annually.(Abdel-Wahab et al., 2024) In addition it has been reported that HFRT assists decarbonisation strategies in radiation oncology.(Bhatia et al., 2024)

Ultra-hypofractionated radiotherapy (UHRT)

Of historic interest, the first series of patients treated with UHRT (≥6 Gy per day) were at St Thomas’ Hospital, London. Beginning in 1964, apparently satisfactory results were obtained in this pre-PSA era using 36Gy in 6f. The first trial to formally test an UHRT approach was the Scandinavian HYPO-RT-PC trial led by Anders Widmark (Photo 5) from the Nordic Cancer Union, the Swedish Cancer Society, and the Swedish Research Council. 12 centres in Sweden and Denmark randomised 1200 men with intermediate to high-risk disease to conventional radiotherapy (78 Gy in 39 fractions) or UHRT (42.7 Gy in 7 fractions) using IGRT methods without androgen deprivation. The trial showed UHRT was as effective as conventional fractionation (CF) with similar long term side effects although with a short-lasting increase in early side effects.(Widmark et al., 2019) (Photo 5)

Photo 5: Prof Anders Widmark, Department of Radiation Sciences, Oncology Unit, Umea University, Umea, Sweden. He led ground-breaking phase 3 multi-centre studies in Sweden within the framework of the Scandinavian Prostate Cancer Group (SPCG) and the Swedish Association for Urological Oncology (SFOU). Radiotherapy added to hormonal therapy was shown to improve survival (SPCG-7) and the first phase 3 trial of extreme hypofractionation and IGRT (HYPO-RT-PC) has given similar outcomes to much longer courses of conventionally fractionated radiotherapy (Supplementary table 1 and Supplementary tables 2).

 

The PACE (Prostate Advances in Comparative Evidence) group of trials have evaluated UHRT stereotactic ablative body radiotherapy (for intermediate (PACE-B) and high-risk (PACE-C) disease.(A. Tree et al., 2024; Van As, Griffin, et al., 2024) The PACE-B trial is the first randomized phase 3 trial to compare conventional (IMRT+/-IGRT) radiotherapy with stereotactic radiotherapy. The trial randomized 874 men to SBRT/UHRT (36.25 Gy in 5 fractions) or control radiotherapy (78 Gy in 39 fractions, or 62 Gy in 20 fractions). Patients were recruited from 39 Centres in the UK, Ireland and Canada. Tumour control was similar for the five-fraction regimen with freedom from biochemical or clinical failure rates of 94.6% (CF) and 95.8% (HFRT), and acute toxicities were similar to CF/HFRT. Late GU side effects were also similar but UHRT was associated with a small increase in late GU side effects (Supplementary Table 1).(Van As, Griffin, et al., 2024)

Intraprostatic boost

European and US studies have shown that the site of disease recurrence within the prostate after radiotherapy is usually at the site of the dominant intraprostatic lesion (DIL) at diagnosis.(Cellini et al., 2002) The DIL can be identified on multiparametric MR imaging which can be satisfactorily targeted using IMRT.(Alexander et al., 2019) Trials have therefore evaluated boosting DILs. The European FLAME trial, reported by Linda Kerkmeijer in 2021, randomised 571 men in the Netherlands and Belgium with intermediate and high-risk disease between 2009 and 2015. Treatment was either 77 Gy (fractions of 2.2 Gy) to the entire prostate, or an additional simultaneous focal boost up to 95 Gy (fractions up to 2.7 Gy) to the DIL. The focal boost improved biochemical disease-free survival with similar overall and prostate-cancer specific survival, with a slight increase in late gastrointestinal and genitourinary toxicities.(Kerkmeijer et al., 2021) Subsequently, the hypo-FLAME trial from 4 academic centres in the Netherlands and Belgium, reported acceptable GU and GI toxicities treating 100 men with UHFT of 35 Gy in 5 weekly fractions to the whole prostate gland with an integrated boost up to 50 Gy to the DIL. Draulans and colleagues (2024) reported excellent 5-year control rates of 93%.(Draulans et al., 2024) The hypo-FLAME 2.0 trial continued this approach showing it was possible to reduce overall treatment time from 29 to 15 days but there was some increase in acute side effects. Longer term results are awaited.

In the UK, the DELINEATE study (RMH and ICR) evaluated standard and hypofractionated dose escalation to multiparametric MRI defined DILs. In a phase 2 multicohort study 265 men were treated using 2Gy then 3Gy and finally an UHRT cohort. Short course ADT was given. In a group of patients with intermediate and high-risk disease very low 5 years freedom from biochemical/clinical failure rates of 97-98% were shown. Acute and late toxicities were low.(A. C. Tree et al., 2023) The UHRT cohort has now completed recruitment. A phase 3 multicentre trial PIVOTALboost (ISRCTN80146950) led by the UK ICR Clinical Trials and Statistics Unit (CTSU) using the HFRT schedule has now completed recruitment of 2232 patients (August 2024). (Photo 4)

Photo 4: Symposium on Prostate Cancer, The Institute of Cancer Research (ICR) May 2019. David Dearnaley, ICR and Royal Marsden NHS Foundation Trust (RMH) with some of his past clinical research fellows involved in prostate cancer radiotherapy research. They include clinicians, physicists, radiographers and nurse specialists who have who developed successful academic careers. Clockwise from left: Prof Helen McNair, Lead Clinical Academic Radiographer, Radiotherapy, ICR and RMH, - studies of treatment accuracy, IGRT and Health Service Reseach; Prof Joe O’Sullivan, School of Medicine, Dentistry and Biomedical Sciences, Queens’s University, Belfast, N.Ireland - trials of molecular radiotherapy such as Radium-223 in metastatic prostate cancer; Prof David Dearnaley ICR and RMH- trials of radiotherapy, fractionation and systemic treatments; Dr Julia Murray RMH and ICR – trials of pelvic and paraaortic IMRT; Dr Vincent Khoo RMH and ICR – optimisation of prostate radiotherapy including IGRT,IMRT and SABR; Dr Miquel Ferreira, Guy’s and St Thomas’ NHS Foundation Trust and King’s College London – interaction of microbiome and pelvic radiotherapy; Dr Victoria Harris, Guy's and St Thomas' NHS Foundation Trust – Guidelines for pelvic lymph node RT, Frank Ellis Medal for paper on pelvic IMRT 2020; Prof John Staffurth, School of Medicine Cardiff University and Velindre Cancer Centre, Cardiff, Wales – IMRT and SBRT for pelvic cancers; Prof Sara Faithful, School of Health Sciences , University of Surrey, Guildford - cancer survivorship, functional health assessment and lifestyle interventions; Dr Anna Wilkins, ICR and RMH, CHHiP trial translational research, radiation response and the microenvironment; Prof Nick van As, RMH (Medical Director) and ICR, Chief Investigator PACE A and B trials of extreme hypofractionation and SBRT.

Pelvic Radiotherapy (Supplementary Table 1)

Prophylactic pelvic lymph node irradiation has remained controversial because of the inconclusive results of phase 3 trials in Europe and the US.(Pommier et al., 2016; Roach et al., 2018) Various difficulties in interpreting the trials relates to the modest doses of RT delivered to prostate and pelvis, inadequate treatment of some lymph node groups, inclusion of patients with a low risk of lymph node involvement and interaction with scheduling of hormone treatment. A more recent modestly sized trial included 224 patients from Mumbai (Murthy et al 2021) but has addressed many of these concerns. High-risk patients were recruited, staging usually included PSMA PET to exclude early metastatic disease, high-dose IMRT and IGRT was used with comprehensive pelvic lymph node coverage. ADT was given for at least 2 years. Impressive improvements were reported with highly significant gains in biochemical and clinical progression-free survival with reduced metastases but at 5 years no survival advantage was seen yet.(Murthy et al., 2021) (We were particularly pleased to see this trial as Vedang Murthy had been our clinical fellow in the past). At ICR/RMH we developed both conventionally fractionated and HFRT pelvic lymph node IMRT showing that doses of up to 60Gy in 37f or 47Gy in 20f could be safely delivered (Ferreira 2017).(Reis Ferreira et al., 2017) We took forward the conventional fractionation schedule in the muticentre randomised phase 2 PIVOTAL trial showing that the IMRT techniques were generalisable to other UK Centres and that side effects were little different from prostate only RT.(D. Dearnaley et al., 2019) Following the results of the CHHiP trial, the HFRT schedule was chosen for further evaluation in the PIVOTALboost trial which randomised treatments between 4 options, Prostate IMRT with or without pelvic RT and with or without DIL boost (see above). Recruitment of 2232 patients completed in August 2024. In parallel an innovative intergroup collaboration, trial EORTC 1331- RTOG 0924 completed randomisation of over 2500 patients in 2019. Men with unfavourable intermediate risk or favourable high-risk disease had short course ADT with either prostate alone or prostate and pelvic RT. The results of these large trials will finally determine the value of lymph node RT in future practice but will need to accommodate newer imaging modalities to define lymph nodes such as PSMA PET and any advances in hormonal adjuvant treatment. The PEARLS phase 2/3 international multicentre trial (ISRCTN36344989) led by the ICR/RMH CTSU (Chief Investigator Julia Murray) is the first study to test the use of IMRT in lymph node positive disease. PSMA PET imaging is used to define lymph node location and trial eligibility. Recruitment of 893 patients started in 2022, randomisation is between pelvic and pelvic and paraaortic lymph node RT. Future developments include SBRT for prostate and nodal irradiation (PACE-NODES trial; NCT05613023)

Radiotherapy and Surgery

Post-prostatectomy adjuvant or salvage radiotherapy

The use of post-prostatectomy adjuvant radiotherapy (ART) has been controversial for many years. Physicians face a difficult set of decisions in attempting to delay the onset of metastatic disease and death whilst avoiding overtreatment of patients whose disease may never affect their overall survival (OS) or quality of life (QoL). A comprehensive review has been made in the EAU Guidelines.(Cornford et al., 2024) In brief although four randomised trials have shown significant 20-23% improvements in biochemical failure-free survival, only the US SWOG 8794 trial has shown a benefit in overall survival with studies from the EORTC, German ARO and FinnProstate groups showing no advantage to ART. A meta-analysis of three phase 3 trials from UK, France and Australia comparing ART with salvage RT (SRT) showed no benefit to ART. The UK Radicals trial clearly showed worse faecal and urinary incontinence using ART. Additionally, the SPPORT study showed an advantage to the addition of pelvic lymph node radiotherapy in failure free progression.(Pollack et al., 2022) EAU Guidelines presently recommends ART only for very high-risk patients post-surgery and SRT without ADT after PSA recurrence. There is a downside to additional ADT for patients because of the well-known andropausal side-effects. It’s tempting to suggest that the use of anti-androgens, including the newer more potent agents, rather than LHRHa may be preferred by patients.

Radiotherapy or Prostatectomy as primary treatment

There are of course polarised views and vested interests at play. Only one adequate randomised trial, ProtecT, has been performed and long term 15-year follow-up is now available from this UK study.(Donovan et al., 2023; Hamdy et al., 2023) Radical prostatectomy, radiotherapy with short course ADT and active monitoring were compared. No differences in overall or prostate cancer related survival were seen and RP and RT had similarly low rates of metastases development, long term use of ADT and clinical progression. In the active monitoring group rates of metastases development, use of ADT and progression were about doubled. Generic quality-of-life scores were similar. Urinary continence and erectile dysfunction were worst in the RP group and faeccal leakage in the RT group. The small PACE-A trial compared RP with SBRT in 123 men recruited from 8 UK centres. It showed similar results to ProtecT using the Expanded Prostate Index Composite (EPIC-26), SBRT having less urinary and sexual side-effects but slightly more bowel bother compared with prostatectomy.(Van As, Yasar, et al., 2024) Long-term efficacy outcomes are awaited. The very low progression rates in the ProtecT trial emphasises the value of the technical and clinical efforts described above to minimise side effects and make treatment more convenient and acceptable to patients. A multidisciplinary approach is needed to help each patient make the most appropriate management decision. Clinicians’ egos are best left at home.

Prostate radiotherapy in metastatic disease

There have been clues from observational data and animal models to suggest that radiotherapy to the primary prostate cancer in metastatic disease might improve outcomes. This phenomenon could relate to an abscopal effect mediated by the immune system being stimulated by radiation induced killing in the primary tumour or perhaps a more direct effect reducing metastases promoting growth factors produced by the primary. Three practice-changing European studies have been completed. In the Dutch HORRAD study, time to PSA progression was prolonged but there was no difference in survival. In the larger STAMPEDE Trial (UK, Switzerland) and metanalysis including both studies (Burdett 2019) there was a 7% survival advantage for men who had less than 5 bone metastases but not for men with more extensive disease.(Burdett et al., 2019; Parker et al., 2022) The addition of prostate RT is now included in European Guidelines (Cornford et al., 2021) and has become the standard of care in the UK, being mandated for further patients recruited into the STAMPEDE 1 and 2 trials. But is there an interaction with additional treatment with androgen receptor pathway inhibitors (ARPI) ? The PEACE-1 trial done in Europe and led by the Institut Gustav Roussy in France, has just reported results.(Bossi et al., 2024) The trial examined standard of care (SOC) alone, SOC with abiraterone, SOC with prostate radiotherapy and SOC with abiraterone and RT. There was an interaction between RT and abiraterone with RT producing benefit in radiographic progression-free survival when given with abiraterone in patients with low volume metastatic disease but not when combined with SOC only. Time to castration resistance was increased in both the low volume and overall trial populations. Radiotherapy reduced serious genitourinary events in all groups. The authors suggest RT be used in both low and high-volume metastatic disease. It would, perhaps, be reasonable to use 20 or 6 fractions (or less) to increase patient convenience and reduce treatment costs.

European studies of side-effects

This article has appropriately highlighted randomised controlled trials many of which have included detailed recording of both clinician as well as patient reported outcomes (Supplementary Table 1). But prospective collection of patient characteristics and long-term outcomes with detailed accurate collation of dosimetry data can give valuable insights into the constellation of features causing treatment related side effects. The Italian group, including Claudio Fiorino, Tiziana Rancati and Ricardo Valdagni (Photo 6), have made major contributions over a period of more than 20 years (eg Fiorino 2003, Rancatti 2004, Valdagni 2012, Spampinato 2023).(Fiorino et al., 2003; Valdagni, Kattan, et al., 2012; Valdagni, Vavassori, et al., 2012).

Photo 6: From left to right, Claudio Fiorino, San Raffaele Scientific Institute, Milan, Italy, Tiziana Rancati and Ricardo Valdagni, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. They established the Italian National AIRO PROS01-02 collaboration to study and model factors related to the development of radiation side effects making major contributions over a period of more than 20 years (eg Fiorino etal 2003, Rancatti etal 2004, Valdagni etal 2012, Spampinato etal 2023). Dr Rancati (central image on right) receiving the Best Physics Award from Marianne Aznar, Chair of the ESTRO 2023 Physics track, for her paper on “Genetically-based Cox-NTCP models for late toxicity after prostate cancer RT”.

They set-up the Italian national AIRO PROS01-02 collaborations which now has more than 60 peer reviewed publications listed in “pubmed”. These have included the detailed recording of side effects, developing both physician and patient related tools, modelling of dosimetry and the relationship of DVH to outcomes, establishing safe dose constraints, deriving nomograms and defining target volumes. This has been a major European contribution to the safe development of modern prostate radiotherapy.

European educational initiatives

The rapidity of change over the decades has challenged the radiotherapy community to keep up with evolving technology as well as new understandings of prostate cancer biology, diagnosis and treatment. Europe has been at the forefront of educational initiatives. The physics community led the way with the European School of Medical Physics annual courses 1998-2013 and the IMRT Schools in Heidelberg 1999-2010. ESTRO introduced a Multidisciplinary Management of Prostate Cancer Course back in 2006 and now in its 18th year. This brings together a teaching faculty (Photo 7) including not only radiotherapy and physics but diagnostic radiology, medical oncology, surgery, and pathology experts.

Photo 7: Multidisciplinary Management of Prostate Cancer Course Faculty: Florence from left to right, W. Oosterlinck, Lorenzo Livi (local organiser), Gert De Meerleer (Course Director), G. Villeirs, Chiara Gasparotto (Course OPrganiser) J. Battermann, B. Tombal and Theo de Reijke (missing F.Algaba, D.Dearnaley)

 

On the 4-day course, attendees are guided how to integrate technical and clinical considerations to improve care for patients with prostate cancer. ESTRO educational programs now include courses on Brachytherapy, IGRT, SBRT, and the on-line treatment planning initiative FALCON ((Eriksen et al., 2014)) as well as collaborations with Indian, Thai and South-East Asia Oncology Educational Groups. Encouraging, mentoring and funding oncology trainees, radiographers, physicists and specialist nurses to do radiation related research is also key for the future of radiotherapy development.

 

C) EUROPEAN TRIALS OF RADIOTHERAPY AND HORMONE THERAPY

The introduction of luteinising hormone-releasing analogues (LHRHa) in the late 1980s made it possible for the first time to consider shorter or longer courses of reversible androgen deprivation therapy (ADT) but falling short of the permanent effects of orchidectomy. Numerous phase 3 trials of combined RT and ADT have been conducted over many years using a variety of RT techniques and doses and durations of ADT. Presently EAU Guidelines for patients with intermediate-risk disease treated with radiotherapy strongly recommend high-dose conventional or HFRT using IMRT/IGRT with 4-6 months ADT, and 24-36 months ADT for patients with high-risk presentations.(Cornford et al., 2024) Abiraterone is additionally recommended for clinically node-positive disease.(Attard et al., 2022) European trialists have made very substantial contributions to clarify the value of ADT with radiotherapy. Questions addressed can be considered in several groups. (Photo 8)

Photo 8: Michel Bolla, Professor of Radiation Oncology and Head of Radiation Oncology in the Grenoble University Hospital. He led key EORTC trials, 22863, 22911, 22961 and 22991 over a period of 30 years (table 3) combining radiation and hormonal treatments. Professor Bolla was well known for his expressive and charismatic lectures and talks, and was an enthusiastic opera singer, here performing "L'air de la calomnie" from Rossini's "La Cenerentola" at Tours, 1993.

Does radiotherapy add to the benefit of long-term hormonal treatment?

The answer is a conclusive yes. Until the turn of the century and beyond many clinicians considered ADT alone to be a very reasonable standard of care. Long term follow-up from The Scandinavian trial led by Anders Widmark (SPCG7/SFUO-3) showed a 9.8% overall survival benefit at 10 years with a 17% reduction in prostate cancer deaths at 15 years (Widmark et al., 2009) and the UK MRC PR07/Canadian PR3 Intergroup study reported by Malcom Mason in 2016 showed a 6% survival improvement with a halving of prostate cancer deaths in the RT group.(Mason et al., 2015)

Does long term hormonal treatment improve radiotherapy alone results in high-risk disease?

A small study from the Swedish Umea group showed a long-term benefit of about 20 % in both CSM and OS using orchidectomy in addition to radiotherapy compared with ADT as salvage after RT.(Granfors et al., 2006) EORTC trial 22863 led by Michel Bolla (Photo 8) (Bolla et al., 2010) and RTOG trial 85-31 unequivocally showed overall survival advantages for combined treatment with 18% and 10% OS benefits, with large reductions in prostate cancer deaths and reduction of distant metastases.(Bolla et al., 2010; Pilepich et al., 2005)

Does short-term hormonal treatment improve radiotherapy alone results in intermediate risk disease?

The earlier studies from Australian TROG (Denham et al., 2011) and US groups (Roach et al., 2008; D’Amico et al., 2008; C. U. Jones et al., 2011, 2022) were in patients with quite unfavourable localised presentations.(D’Amico et al., 2008; Denham et al., 2011; C. U. Jones et al., 2022; Roach et al., 2008) All showed advantages in survival using 6 months of ADT compared with RT alone as well as improvement in intermediate endpoints such as PSA and event-free failure. But in the TROG study 3 months LHRHa only improved the intermediate endpoints which did not translate into an OS benefit. The largest trial, RTOG 94-08 showed a 5% survival advantage at 10 years but estimated mean survival time at 18 years differed by only 6 months although disease specific mortality was improved by 6%. More recent trials from Europe (EORTC 22991), US (RTOG 0815) and Canada (PCSIII) have been in mainly intermediate risk patients and the results are more nuanced.(Bolla et al., 2021; Krauss et al., 2023; Nabid et al., 2021a) Failure-free survival and DMFS can be improved by giving 6 months of ADT but any OS benefits are not statistically significant. We think this may be due to the small number of prostate cancer deaths in comparison to other causes of death in these favourable patient populations. Of importance, in a secondary exploratory analysis of the Canadian PCSIII trial, Nabid suggested that intermediate risk patients with unfavourable features had improvements in both DMFS ((HR 1.6 p=0.026) and OS (HR 1.5 p=0.05). But patients with only one unfavourable feature did not benefit form ADT.(Nabid et al., 2021b)

What is the optimal duration of ADT?

European investigators particularly including EORTC Trial 22961 led by Michel Bolla (2009) as well as Irish (Armstong 2011) and Spanish groups (Zapatero 2015) have made major contributions to our understanding of how to use neodjuvant and adjuvant hormone therapy. Meta-analysis (Kishan, Sun, et al., 2022) of these and North American trials clearly shows that 24-36 months of ADT is superior to 6 months or less ADT in locally advanced and high-risk disease. For intermediate risk disease prolonging ADT for more than 6 months is not beneficial.(Kishan, Sun, et al., 2022)

Is short term hormonal treatment needed in intermediate risk disease treated by dose escalation?

The clinical trials of dose escalation performed in Europe and North America have shown no benefit in metastases-free or overall survival although biochemical and failure free survival are improved. In contradistinction use of short course ADT may improve metastases free survival. In EORTC Trial 22991 comparison of patients treated to doses of 70Gy,74Gy and 78 Gy showed similar benefits from the addition of ADT but no apparent benefit of using the higher RT doses.(Bolla et al., 2021) There is only one relatively small Canadian trial PCS111 (Nabid 2021) directly addressing the question and in a three-way randomisation 76Gy alone gave less favourable results than both 76Gy and 70 Gy combined with ADT.(Nabid et al., 2021a) The available evidence points to dose escalation and ADT working via different mechanisms. In addition to ADT giving an additive effect to RT and improving local control (particularly if lower RT doses are given) there is “spatial co-operation” i.e an improvement in treating disease missed by RT leading to control of micro-metastases. In favourable risk intermediate disease this interaction is probably unnecessary and dose escalation alone a very adequate strategy avoiding the side effects of ADT. However, if ADT is used in less favourable intermediate-risk disease doses above 74-76 Gy are unlikely to have a useful effect on outcome and higher doses may impact on RT related side-effects.

Is additional hormonal therapy of value with radiotherapy after prostatectomy?

Three trials from France, the UK and the US have compared SRT with or without adjuvant ADT. All have shown convincing evidence of benefit from ADT in PSA led progression free survival. Although the GETUG-AFU study showed an advantage in metastases-free survival using 6 months ADT,(Carrie et al., 2019) the recent reports from the RADICALS trial showed no benefit to 6 months ADT although the use of subsequent salvage ADT reduced from 28% to 18% at 10 years follow-up.(Parker, Clarke, et al., 2024) But the addition of 2 years LHRHa compared with 6 months significantly improved metastases-free survival by 6% (Parker, Kynaston, et al., 2024) and in RTOG 6901, 2 years of adjuvant bicalutamide significantly improved both disease specific mortality by 6% and overall survival by 5%.(Shipley et al., 2017)

Do new hormonal treatments improve the efficacy of radiotherapy?

Androgen receptor pathway inhibitors (ARPI) such as abiraterone, enzalutamide, apalutamide and darolutamide have transformed the management of metastatic prostate cancer. But can they impact on the management of localised disease with radiotherapy? The answer is an unequivocal yes. In the STAMPEDE trial (UK and Switzerland, Attard 2022) there were highly significant improvements in metastases-free, overall and prostate cancer-specific survival.(Attard et al., 2022) The number of prostate cancer deaths was more than halved. Abiraterone and prednisolone should now be a new standard treatment in addition to ADT and radiotherapy in this very high-risk population. Sadly, it has not yet been made available in the UK despite the availability of generic abiraterone. Ongoing studies will define the roles of other ARPIs and the populations of patients who benefit. (Photo 9).

Photo 9: Meeting of the STAMPEDE Trial Steering Committee in London, 2021. STAMPEDE is the largest phase 3 treatment trial internationally. Using a multi-arm multi-stage (MAMS) design nearly 12,000 patients have been recruited between 2005 and 2023 from the UK and Switzerland. Abiraterone has been shown to improve survival when added to standard hormonal therapy and prostate RT in localised disease, and prostate RT improves survival when added to standard treatment in limited metastatic disease. Presently SBRT to oligometastases is being assessed. Founding members of the Trial Management Group, from left to right: Prof Malcolm Mason, Cardiff University School of Medicine: Prof Matt Sydes Medical Research Council (MRC) Clinical Trials Unit at University College London (UCL), London, UK: Prof Noel Clark, Department of Surgery, The Christie Hospital, and Department of Urology, Salford Royal Hospitals, Manchester, UK: Prof Nick James, Chief Investigator, The Institute of Cancer Research (ICR), and Royal Marsden NHS Foundation Trust (RMH), London, previously Institute of Cancer and Genomic Sciences, University of Birmingham, UK: Professor David Dearnaley, Academic Urology Unit, ICR and RMH: Prof Mahesh Parmar MRC Clinical Trials Unit at UCL; Prof Gert Attard, UCL Cancer Institute, London, far left, second row, led the Abiraterone comparisons and middle of second row Prof Chris Parker, RMH and ICR, lead investigator for prostate RT in metastatic disease and post-operative RT (MRC Radicals Trial) (tables 2 and 3)

Conclusions

Radiotherapy for prostate cancer has been transformed over the last 50 years. We know that local control of disease is better achieved with dose escalation and hypofractionation. The evidence for ultra hypofractionation is looking favourable and will soon mature. DIL boosts are a logical extension driven by improved imaging and IMRT/IGRT or SBRT. Combining these approaches will give extraordinarily high local control rates and with appropriate quality assurance measures very low side effects. There will be considerable benefit for patients and potentially large cost savings to health care systems. The role of ADT is now better understood. The challenge is to more precisely define patients most suitable for dose escalated radiotherapy alone – who will have a very low risk of micrometastatic disease, those who may benefit from short course ADT – who will have a modest risk of disease spread and patients at the highest risk who benefit from longer course ADT possibly with the addition of an ARPI. Translational studies of tissue or blood biomarkers bolted on to historic and future phase 3 trials and linked to long term patient outcomes are likely to be required to individualise treatment. These major advances and successes have been made possible by many collaborations between clinicians, physicists, engineers, therapy radiographers and clinical trial specialists. Thousands of patients have contributed enthusiastically enrolling in clinical studies to benefit, perhaps not themselves, but generations of patients to follow.

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