Investigating a novel combination treatment of androgen deprivation therapy, pelvic external beam radiotherapy and radium-223 dichloride in the management of hormone sensitive prostate cancer metastatic to bone

  • Philip Turner

Student thesis: Doctoral ThesisDoctor of Philosophy



Prostate cancer is the commonest malignancy affecting men in the UnitedKingdom; its incidence is set to rise globally. In the UK, approximately 18% ofmen will present with metastatic disease at outset, metastatic hormonesensitive prostate cancer (mHSPC). This is an incurable condition, for whichthe mainstay of treatment consists of androgen deprivation therapy (ADT).Recently a number of treatments added to ADT have been shown to extend survivalin these patients including docetaxel and abiraterone as well as external beamradiotherapy (EBRT) to prostate (in low volume disease). We wished to test thenovel combination of concurrent radium-223 + EBRT to prostate and pelvic lymphnodes in mHSPC.



The combination of ADT + radium-223 + radical prostate and pelvic EBRTin mHSPC would prove feasible, safe, acceptable to patients, leading to a phaseIII randomised trial.



We began by benchmarking our institutional rates of toxicity from EBRTto prostate and pelvic nodes. Informed by that study, we designed a clinicaltrial testing the combination ADT + concurrent radium-223 (at 55 kBq/kg q28days for 6 cycles) + EBRT to prostate and pelvic lymph nodes (74 Gy in 37fractions to prostate + 60 Gy in 37 fractions to pelvic lymph nodes). Primaryendpoints were recruitment, toxicity (CTCAE scoring), and quality of life(patient reported EPIC scoring). Secondary endpoints were radiological responsewith whole body (wb)MRI, PSA/ALP response and time to first symptomaticskeletal event (SSE). We tested a range of potential biomarkers of prognosis,response to treatment and molecular dosimetry.



The trial has successfully completed recruitment. Grade 2 diarrhoeaoccurred in 20% of patients, there was no grade 3 GI toxicity. Grade 3 GUtoxicity occurred in 3.3% of patients, in keeping with prospective trials ofEBRT to prostate and pelvis alone. Grade 3 leucopenia, neutropenia andthrombocytopenia occurred in 6.7%, 3.3% and 3.3% of patients respectively. BothGI and GU domains of quality of life fell during the trial treatments but eachreturned to baseline on completion. wbMRI scans of 26 evaluable patients,between baseline and end of treatment showed complete response in 3 (11.5%),partial response in 14 (53.8%), stable disease in 4 (15.4%) and progressive diseasein 5 (19.2%). There is a significant reduction in ALP between screening andfinal cycle of radium-223 (Median 90 IU/L screening to 55 IU/L p<0.01). Median progression free survival is 21.7 months. Median SSE free survival not reached. 11 of 30 patients developed a fracture on trial, the majority were asymptomatic pathological fractures. Three putative biomarkers have shown interesting initial signal warranting further analysis in larger trials namely: DNA damage repair deficiency assay; rate of complex DNA damage seen on MFISH in leucocytes and rate of gH2AX signal seen on immunofluorescence in leucocytes as markers of bone marrow dosimetry. Circulating tumour cells showed no signal of utility as a biomarker of response.



This treatment combination is safe and feasible with a signal toefficacy and warrants phase III exploration

Date of AwardJul 2020
Original languageEnglish
Awarding Institution
  • Queen's University Belfast
SponsorsBayer PLC, Friends of the Cancer Centre, Prostate Cancer UK & Movember Europe
SupervisorJoe O'Sullivan (Supervisor), Suneil Jain (Supervisor) & Kevin Prise (Supervisor)


  • Prostate Cancer
  • Radionuclide therapy
  • Radiotherapy
  • Radium 223

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