Side Effects of Low Dose Rate Brachytherapy and Ultra-hypofractionated Radiotherapy in Low to Intermediate Risk Prostate Cancer

The LDR BURST trial will compare the side effects of two radiotherapy treatments for men with localised prostate cancer. The first treatment is 4D low dose rate brachytherapy where small radioactive seeds are inserted into the prostate gland under ultrasound guidance. A computerised tomography scan is subsequently performed to check seed positioning. Patients usually return home the same day. The seeds emit their radiation over several months before losing their activity. Stereotactic radiotherapy, an alternative treatment, is a form of external radiation using precise high energy x-rays to target the prostate gland. It is delivered in 5 treatment sessions on alternate days; the full treatment course is completed within 2 weeks. Stereotactic radiotherapy has recently been approved by the National Health Service following successful results in international trials demonstrating it is safe and effective to give external radiotherapy in five treatment sessions. Delivering a higher dose in each treatment fraction is known as 'ultra-hypofractionation'. Before the treatment, men will undergo a minor procedure, typically under local anaesthetic, to have metallic markers inserted into the prostate to improve visibility of the prostate gland when planning and delivering the treatment. The side effects of both the radiation treatments are similar. Common side effects include bladder issues, such as needing to urinate more often and having a slower urine flow. Patients might also experience more frequent and looser bowel movements, occasionally with a little blood. Symptoms usually improve over time. Additionally, some men might have trouble achieving or maintaining an erection after radiation treatment, this can often be managed with medications. Both of the treatments use ionising radiation to destroy the prostate cancer cells which may cause cancer many years or decades after exposure. The chances of this happening are the same whether taking part in this trial or not. A protective gel, called Barrigel, will be inserted into the space between the prostate gland and the rectum increasing the distance between them. This significantly reduces the dose of radiation to the rectum. The gel can be inserted at the same time as the brachytherapy seed or fiducial marker insertion. The gel is slowly reabsorbed following treatment over the next 3 to 6 months. The trial will randomly assign 110 men to each radiation treatment to compare their side effects. There is a 50% chance the patient will be assigned to brachytherapy and 50% chance of stereotactic radiotherapy. Patients will be asked to complete four questionnaires prior to starting treatment and at regular time points following treatment. They will be telephoned every 4 weeks for the first 2 months to check on side effects, followed by a face-to-face appointment at 3 months, and a PSA blood test, and then followed up at regular intervals for 5 years.

Sex

Male

Minimum age

18 Years

Inclusion Criteria:

* Men aged ≥18 years at randomisation
* The research subject must have capacity to sign a written informed consent document for the trial
* WHO performance status 0 - 2
* Gleason score 3+3 or 3+4
* PSA ≤ 20 ng/ml (please note if the treating clinician determines androgen deprivation therapy (ADT) is required this is an exclusion criteria). A PSA must be available within 60 days of randomisation.
* Clinical and/or MRI stage T1c -T2c, N0-X, M0-X
* Histological confirmation of prostate adenocarcinoma within the last 18 months (unless on active surveillance). Patients who were on active surveillance should have an up-to-date MRI within 8 weeks of the decision to treat to confirm organ confined disease.

Exclusion Criteria:

* Previous malignancy within the last 2 years (except basal cell carcinoma or squamous cell carcinoma of the skin), or if previous malignancy is expected to significantly compromise 10-year survival.
* Patients under investigation for synchronous primary at time of randomisation
* Prior pelvic radiotherapy.
* Prior treatment with ADT or current need for ADT based on risk features

  * Prostate cancer in greater than 50% of template biopsy cores or a significant maximum core length containing prostate cancer for which the treating clinician deems the patient would benefit from ADT
* Any prior active treatment for prostate cancer (patients previously on active surveillance are eligible if they meet all other eligibility criteria)
* Life expectancy \< 10 years Men with a prostate gland larger than 60 cc, or those with a large median lobe• Hip prostheses or any other implants/hardware that introduce substantial CT artefacts making it challenging to delineate the target or organs at risk. This is to be assessed on a case-by-case basis with the available staging imaging.
* Medical conditions likely to make radiotherapy inadvisable e.g. inflammatory bowel disease, significant urinary symptoms.
* International Prostate Symptom Score (IPSS) \> 15 points
* Anticoagulation with warfarin/ bleeding tendency making fiducial placement, spacer gel insertion or brachytherapy unsafe in the opinion of the clinician
* Contraindications for Barrigel insertion such as previous documented allergic reaction to gel, previous rectal surgery or known rectal fistula.
* Participation in another concurrent treatment protocol for prostate cancer.

• BACKGROUNDVaizey CJ, Carapeti E, Cahill JA, Kamm MA. Prospective comparison of faecal incontinence grading systems. Gut. 1999 Jan;44(1):77-80. doi: 10.1136/gut.44.1.77. PMID 9862829
• BACKGROUNDMariados NF, Orio PF 3rd, Schiffman Z, Van TJ, Engelman A, Nurani R, Kurtzman SM, Lopez E, Chao M, Boike TP, Martinez AA, Gejerman G, Lederer J, Sylvester JE, Bell G, Rivera D, Shore N, Miller K, Sinayuk B, Steinberg ML, Low DA, Kishan AU, King MT. Hyaluronic Acid Spacer for Hypofractionated Prostate Radiation Therapy: A Randomized Clinical Trial. JAMA Oncol. 2023 Apr 1;9(4):511-518. doi: 10.1001/jamaoncol.2022.7592. PMID 36757690
• BACKGROUNDLangley SE, Laing RW. 4D Brachytherapy, a novel real-time prostate brachytherapy technique using stranded and loose seeds. BJU Int. 2012 Feb;109 Suppl 1:1-6. doi: 10.1111/j.1464-410X.2011.10824.x. PMID 22239223
• BACKGROUNDAlexander SE, Kinsella J, McNair HA, Tree AC. National survey of fiducial marker insertion for prostate image guided radiotherapy. Radiography (Lond). 2018 Nov;24(4):275-282. doi: 10.1016/j.radi.2018.06.003. Epub 2018 Jul 7. PMID 30292494
• BACKGROUNDTree AC, Ostler P, van der Voet H, Chu W, Loblaw A, Ford D, Tolan S, Jain S, Martin A, Staffurth J, Armstrong J, Camilleri P, Kancherla K, Frew J, Chan A, Dayes IS, Duffton A, Brand DH, Henderson D, Morrison K, Brown S, Pugh J, Burnett S, Mahmud M, Hinder V, Naismith O, Hall E, van As N; PACE Trial Investigators. Intensity-modulated radiotherapy versus stereotactic body radiotherapy for prostate cancer (PACE-B): 2-year toxicity results from an open-label, randomised, phase 3, non-inferiority trial. Lancet Oncol. 2022 Oct;23(10):1308-1320. doi: 10.1016/S1470-2045(22)00517-4. Epub 2022 Sep 13. PMID 36113498
• BACKGROUNDvan As N, Yasar B, Griffin C, Patel J, Tree AC, Ostler P, van der Voet H, Ford D, Tolan S, Wells P, Mahmood R, Winkler M, Chan A, Thompson A, Ogden C, Naismith O, Pugh J, Manning G, Brown S, Burnett S, Hall E. Radical Prostatectomy Versus Stereotactic Radiotherapy for Clinically Localised Prostate Cancer: Results of the PACE-A Randomised Trial. Eur Urol. 2024 Dec;86(6):566-576. doi: 10.1016/j.eururo.2024.08.030. Epub 2024 Sep 11.