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Device: Radiation Low dose rate prostate brachytherapy is delivered under anaesthesia in a single 1.5-2 hour procedure as an out-patient. The men return 4 weeks later for detailed imaging to assess implant quality.

Device: Radiation High dose rate prostate brachytherapy is delivered in 2 procedures, 2 weeks apart, also under anaesthesia, but no follow-up imaging visit is required.

HDR brachytherapy is also accomplished as an out-patient.

Permanent implantation of radioactive Iodine-125 seeds under anesthesia with ultrasound guidance

Low dose rate prostate brachytherapy

Temporary implantation of radioactive material into the prostate in the form of a stepping source of Iridium 192 that travels through 16-18 needles or catheters strategically placed through the prostate

High Dose Rate prostate brachytherapy

Ross Halperin, MD

This study will offer men with intermediate risk prostate cancer who are suitable for, and interested in, prostate brachytherapy, the opportunity to be randomized between low dose rate (LDR) brachytherapy using permanent implantation of radioactive seeds (the current standard of care in BC) and high dose rate (HDR) or temporary brachytherapy which is also available as a standard of care in BC but only when used as a boost in addition with external beam radiotherapy. In addition, men will be offered the opportunity for testing the aggressiveness of their cancer using Cell Cycle Progression Gene Profile.

Purpose:

To conduct a Phase III randomized trial for favorable tier intermediate risk prostate cancer and selected favorable risk tumors to evaluate the difference in Quality of Life in the urinary domain between LDR and HDR brachytherapy.

Hypothesis:

Because of more rapid dose delivery with HDR compared to LDR brachytherapy (15 minutes vs. 6 months) and more precise control of dose to adjacent critical structures (prostatic and bulbo-membranous urethra and anterior rectal wall), HDR prostate brachytherapy has been associated with more rapid recovery from acute symptoms and a more favorable side effect protocol when used as a boost in combination with external beam radiotherapy. The hypothesis is that this advantage will be maintained when brachytherapy is used as monotherapy without the addition of external beam radiation.

Justification:

In British Columbia, LDR prostate brachytherapy is the current standard for selected men with favorable risk prostate cancer who are not suitable for, or willing to accept active surveillance, and for men with favorable intermediate risk prostate cancer. LDR brachytherapy has been available in BC for over 15 years and is highly effective with 7-year biochemical disease-free rates of \~95%. However, this type of treatment has a prolonged recovery phase with return to baseline urinary function taking 6 to 12 months. This is partly due to the fact that the radiation is delivered over a 6 month period from the implanted seeds, and partly due to uncertainty in final seed placement. HDR brachytherapy has the advantage of delivering treatment very rapidly over 15-20 minutes, and also exploits the radiobiologic nature of prostate cancer which is more responsive to large doses of radiotherapy. Experience with using HDR brachytherapy as a boost has shown a much reduced impact on quality of life.

Objectives:

Primary: To evaluate the difference in QOL in the urinary domain between LDR and HDR brachytherapy using the urinary domain of the EPIC prostate cancer specific QOL questionnaire.

Secondary:

* To assess differences in the bowel and sexual domains of the EPIC prostate cancer specific QOL questionnaire between the 2 treatments
* To asses time to recovery of the IPS Score which is widely used to assess urinary function after prostate cancer treatment. The time to return to baseline +/- 3 points will be determined.
* Acute and long-term toxicity will be graded using the Common Terminology Criteria for Adverse Events (CTCAE V4) at each follow up time point
* TRUS- MRI fusion will be developed within our planning software to facilitate treatment planning
* To assess treatment efficacy, PSA will be recorded every 6 months to 5 years and then annually to 10 years and prostate re-biopsy will be performed at 36 months after radiotherapy.

Optional:

For those patients consenting to targeted biopsies under anaesthesia at the start of their brachytherapy procedure (separate consent)

* Verify MRI-TRUS fusion accuracy
* Correlate Cell Cycle Progression scores with outcome.

Research Method:

Multiparametric MRI (mpMRI)will be performed on all men as a staging procedure to ensure appropriateness for brachytherapy as monotherapy (without the addition of external beam radiotherapy or hormone therapy). The value of mpMRI in staging prostate cancer is widely recognized. Previous studies have shown that over 90% of intermediate risk cancers are visible on mpMRI. The MR images will be fused with the planning trans rectal ultrasound (TRUS) for each patient, ensuring adequate dose coverage of the lesion.

For those patients consenting to optional biopsies under anesthesia, accuracy of the fusion will be verified by obtaining 2 biopsies of the visualized lesion under TRUS guidance at the start of the brachytherapy procedure.

Follow up is as per standard practice to assess urinary, bowel and sexual side effects. In addition to the standard forms, patients will also complete an EPIC questionnaire. The questionnaires are completed every 3 months for 1 year and then every 6 months to 3 years and then annually, as per the standard follow up schedule.

Once the biopsy material has been pathologically confirmed to contain the target lesion, the aggressiveness will be assessed through Cell Cycle Progression (CCP) Gene Profile testing.

Men may be randomized to the type of brachytherapy and decline the biopsies. This initial protocol is a Pilot that will test feasibility of the randomization (patient acceptance). The aim is to accrue 60 men over 18-24 months and if achieved then apply to expand to a total of 200 men.

Comparison of HDR vs. LDR Brachytherapy as Monotherapy for Intermediate Risk Prostate Cancer

A Phase III Randomized Pilot Study of Low Dose Rate Compared to High Dose Rate Prostate Brachytherapy for Favourable Risk and Low Tier Intermediate Risk Prostate Cancer

The urinary domain of the EPIC prostate cancer specific QOL questionnaire will be assessed.

The EPIC score in the bowel and sexual domains will be evaluated at baseline, 1, 3, 6, 12, 24 and 36 months

The IPS Score will be assessed at baseline, 1, 3, 6, 12, 24 and 36 months

Acute and long-term toxicity will be graded using the Common Terminology Criteria for Adverse Events (CTCAE V4) at each follow up time point

TRUS- MRI fusion will be developed within our planning software to facilitate treatment planning

PSA will be recorded every 6 months to 5 years and then annually to 10 years

Prostate re-biopsy will be performed at 36 months to assess the local efficacy of treatment

For those patients consenting to targeted biopsies under anesthesia at the start of their brachytherapy procedure (separate optional consent) MRI-TRUS fusion accuracy will be verified by targeted biopsies and Biopsy material will be sent for genetic testing to determine Cell cycle Progression scores for both arms of the trial to ultimately correlate with outcome.

British Columbia Cancer Agency

Professor of Radiation Oncology

Device: Radiation. Low dose rate prostate brachytherapy is delivered under anesthesia in a single 1.5-2 hour procedure as an out-patient. The men return 4 weeks later for detailed imaging to assess implant quality.

Device: Radiation. High dose rate prostate brachytherapy is delivered in 2 procedures, 2 weeks apart, also under anesthesia, but no follow-up imaging visit is required.

HDR brachytherapy is also accomplished as an out-patient.

High dose rate prostate brachytherapy

Juanita M Crook, MD

Juanita Crook, MD

Deidre Batchelar, PhD

Cynthia Araujo, PhD

David Kim, MD

David Petrik, MD

Michelle Hilts, PhD

Halperin Ross, MD

H17-02904 is a randomized comparison of low dose rate vs. high dose rate prostate brachytherapy for favorable and intermediate risk prostate cancer suitable for brachytherapy as monotherapy. This is a continuation with expanded accrual of the randomized Pilot study H15-02103

Men suitable for prostate brachytherapy as monotherapy will undergo multiparametric Magnetic Resonance Imaging for staging and identification of a dominant lesion and will be randomly selected for either a single low dose rate permanent seed implant or 2 fractions of high dose rate brachytherapy. Using image registration techniques, dominant lesions will be biopsied under anesthesia at the start of the brachytherapy procedure. Biopsies will reviewed for tumor Gleason score and sent for Cell Cycle Progression testing (Prolaris). Patients receiving high dose rate brachytherapy will also have biopsies between the 2 fractions to assess tumor changes induced from the first fraction. Post implant quality assurance will determine the dose to the dominant lesions and compare these between the 2 types of brachytherapy. Post implant symptoms will be tracked for severity and time course.

LDR vs. HDR Brachytherapy for Prostate Cancer

A Phase III Randomized Study of Low Dose Rate Compared to High Dose Rate Prostate Brachytherapy for Favorable Risk and Low Tier Intermediate Risk Prostate Cancer

For patients receiving 2 fractions of high dose rate brachytherapy, biopsy between the 2 fractions will assess radiosensitivity by evaluating changes in oxygenation and cell cycle distribution between the 2 fractions, for ultimate correlation with efficacy

BC Cancer Foundation

Carcinoma

Radiation. High dose rate prostate brachytherapy is delivered under anesthesia in 2 procedures, 1-2 weeks apart.

HDR brachytherapy is also accomplished as an out-patient.

Temporary implantation of radioactive material into the prostate in the form of a stepping source of Iridium 192 that travels through 16-18 needles or catheters strategically placed through the prostate.

Hamid Raziee, MD

Bibi Naghibi Torbati, MD

This is an observational single-center trial for patients with localized prostate cancer suitable for High Dose Rate (HDR) brachytherapy as monotherapy. This study takes a multi-omics approach to study the mechanism of action of HDR brachytherapy through metabolomics, immunological, transcriptomics, and spectroscopic profiling. The results of this study will clarify the optimal dose for HDR prostate brachytherapy by documenting the dose-response relationship seen in the changing tumor metabolites after HDR brachytherapy and investigate the immunogenicity of HDR brachytherapy.

High Dose Rate (HDR) prostate brachytherapy is an effective and highly conformal means of delivering curative radiation to the prostate. Because of the high dose rate, initial studies applied this treatment cautiously in multiple sessions or fractions but this has gradually been reduced from 54 Gy in 9 fractions to 42 Gy in 6, then 36 Gy in 3, then 27 Gy in 2 and finally to one single fraction of 19 Gy. Each change in fractionation was calculated to be equivalent to the previous, and remarkably, efficacy was maintained until the final stage when treatment was reduced to a single fraction. This resulted in a significant drop in cure rates from over 90% to approximately 65%. The investigators assume that the prior fractions served to sensitize the tumor to subsequent radiation; however, this remains an open question.

This observational single-center trial for localized prostate cancer suitable for brachytherapy as monotherapy takes a novel multi-omics approach to study the mechanism of action of High Dose Rate (HDR) brachytherapy through metabolomics, immunological, transcriptomics, and spectroscopic profiling. This is achieved through (1) measurement of changes in metabolites as determined by Raman spectroscopy, (2) analysis of circulating tumor DNA in peripheral blood plasma, (3) evaluation of the changes in immune response by single cell RNA (scRNA)-sequencing, and (4) evaluation of gut microbiome composition before and after treatment. Secondary endpoints of the study include PSA nadir, time to nadir, PSA at 4 years and patterns of failure.

The study will enroll 100 men with localized prostate cancer suitable for brachytherapy as monotherapy. HDR brachytherapy is given in 2 fractions, each one under anesthesia, making it possible to obtain biopsies painlessly at both baseline prior to any treatment, and 1-2 weeks later prior to the second half of treatment. The results of this study will clarify the dose-response relationship for HDR brachytherapy, help to define the optimal dose, clarify the metabolic response to HDR brachytherapy, and investigate the potential immunogenicity of HDR brachytherapy.

Multi-omic Approach to Study HDR Brachytherapy for Favorable Risk and Low Tier Intermediate Risk Prostate Cancer

Multi-omic Approach to Study High Dose Rate (HDR) Brachytherapy for Favorable Risk and Low Tier Intermediate Risk Prostate Cancer

We will report the most important biomolecules altered by radiation (importance determined by the relative change of the score as a component of the Raman spectrum before and after radiation) and whether that observed change corelates with PSA outcome for each individual patient

Number of patients with a (transient) increase in circulating tumor DNA after a single fraction of high-dose rate prostate brachytherapy will be reported

single cell-RNA sequencing of immune cell populations before and after 13.5 Gray of radiation will be used for each individual patient and the number of patients with a change in gene expression (through activation or inactivation) will be reported

To determine microbial composition before brachytherapy and report for the individual patient whether diversity in composition is changed or skewed after treatment with high dose rate prostate brachytherapy. Second assessment is after completion of both fractions of radiation. Number of patients with alteration in microbial composition will be reported.

PSA recorded every 6 months to 5 years and then annually to 10 years

4-year PSA \< 0.2 ng/ml (indicative of cure)

Acute and long-term toxicity will be graded using the Common Terminology Criteria for Adverse Events (CTCAE V5) at each follow up time point

University of British Columbia

Vancouver Prostate Centre

HDR prostate brachytherapy with dose escalation to 1250 cGy to the MRI-defined dominant intraprostatic lesion

2 treatments of 1000 cGy will be delivered to the entire prostate volume while escalating the dose to the visible disease to 1250 cGy

HDR interstitial brachytherapy

Matthew Schmid, MSc

This study will investigate the feasibility of using technology of ultrasound guided HDR brachytherapy to focally increase dose to regions within the prostate that are heavily infiltrated with cancer. Such regions, referred to as dominant intraprostatic lesions (DIL) can be visualized using diffusion contrast enhanced MRI employing an endo-rectal coil. The magnetic resonance (MR) images can be fused with the planning transrectal ultrasound (TRUS) prior to the brachytherapy procedure to design a dose distribution that will encompass the malignant volume with higher than the prescription dose. By its nature, brachytherapy has subvolumes that receive (for example)125% of the prescription dose or 150% of the prescription dose. With TRUS-guided and TRUS-planned HDR these areas can be manipulated to coincide with the DIL. The limit of dose escalation has been reached at whole prostate external beam doses of 81-86 Gy and still failure rates for intermediate and high risk disease are unacceptable. There is much interest in focal dose escalation and TRUS-guided HDR brachytherapy is perfectly suited to achieving this.

Methods: If a dominant nodule is visualized on dynamic contrast enhanced (DCE) MRI, it will be contoured in 3D and the images fused to the planning TRUS study that is done in preparation for brachytherapy (of any type: seeds or HDR). The patient's treatment will consist of the standard combined external beam (4600 centiGray (cGy) in 23 fractions) and HDR brachytherapy boost (2 fractions of 1000 cGy given on days 5 and 15 of the external beam course). During each HDR treatment the plan will be manipulated such that the normally occurring high dose regions (125%, 150%) are positioned at the site of the identified disease. Normally approximately 60% of the prostate volume receives 125% of the dose and 30% receives 150%. By ensuring that the inherent dosimetry favors treatment of the known cancer, no region of the prostate would be "underdosed". HDR treatments are performed under general anesthesia as an out patient procedure.

Statistical Analysis: This is a feasibility study and the data reported will be descriptive including the frequency with which the DIL can be visualized in this population, the DIL volume compared to total prostate volume, and the isodose that can encompass the DIL without violating dose constraints to adjacent organs (urethra and bladder). Toxicity will be monitored and efficacy will be assessed by repeat DCE MRI at 12 months and biopsy at 30 months.

High Dose Rate Prostate Brachytherapy: Dose Escalation to Dominant Intra-prostatic Nodule

High Dose Rate Prostate (HDR) Brachytherapy Dose Escalation to Dominant Intra-prostatic Nodule for Patients With Intermediate and High Risk Prostate Cancer

Feasibility of dose escalation to a minimum dose of 125% of prescription to 90% of the dominant intra-porstatic lesion (DIL) volume as defined on multiparametric endo-rectal magnetic resonance imaging (mpMRI) without exceeding critical organ dose constraints (Urethral volume receiving 115%= 0, Dose to 1cc of rectal wall \< 7 Gy). 2 Fractions were performed and the mean dose to 90% of DIL volume was averaged.

Time to normalize International Prostate Symptom Score (months). Score range 0-35 with 35 being worst outcome. Normalization refers to a return to baseline urinary function prior to treatment.

Efficacy assessed by biochemical PSA response reported at median 5 year follow up.

HDR prostate brachytherapy with dose escalation to 1250 cGy to the MRI-defined dominant intraprostatic lesion

HDR interstitial brachytherapy: 2 treatments of 1000 cGy will be delivered to the entire prostate volume while escalating the dose to the visible disease to 1250 cGy

HDR Interstitial Brachytherapy

Age, Continuous

Sex: Female, Male

Race (NIH/OMB)

Prostate-specific antigen, or PSA, is a protein produced by normal, as well as malignant, cells of the prostate gland. The PSA test measures the level of PSA in a man's blood. For this test, a blood sample is sent to a laboratory for analysis.

Baseline PSA ng/mL

Gleason 7

Gleason 8 or 9

Gleason score is assigned by pathologist on examination of prostate biopsy material and ranges from 2 to 10 with higher score representing more aggressive undifferentiated tumors

Gleason score

Stage T1c

Stage T2a

Stage T2b

Clinical Tumor Stage is assigned from combination of digital rectal exam and imaging. T1 representants tumor that is neither palpable nor visible on imaging. cT2a and cT2b represent palpable/visible disease that is either less than half of one lobe (cT2a) or more than half of one lobe(cT2b).

clinical stage

Dr Juanita Crook

HDR prostate brachytherapy with dose escalation to 1250 centiGray (cGy) to the MRI-defined dominant intraprostatic lesion

HDR interstitial brachytherapy: 2 treatments of 1000 cGy will be delivered to the entire prostate volume while escalating the dose to the visible disease to 1250 cGy

High Dose Rate (HDR) Interstitial Brachytherapy

Average Mean Dose to 90% of DIL Volume

Months to normalization of International Prostate Symptom Score following treatment.

Acute Toxicity

All 25 underwent dose escalation to dominant lesion in prostate to median 132% of prescription dose

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Comparison of HDR vs. LDR Brachytherapy as Monotherapy for Intermediate Risk Prostate Cancer	NCT02692105	Prostate Cancer	Low dose rate p... High Dose Rate ...	40 Years - 80 Years	British Columbia Cancer Agency
Comparison of HDR vs. LDR Brachytherapy as Monotherapy for Intermediate Risk Prostate Cancer	NCT02692105	Prostate Cancer	Low dose rate p... High Dose Rate ...	40 Years - 80 Years	British Columbia Cancer Agency
LDR vs. HDR Brachytherapy for Prostate Cancer	NCT03426748	Prostate Cancer	Low dose rate p... High dose rate ...	40 Years - 80 Years	British Columbia Cancer Agency
Multi-omic Approach to Study HDR Brachytherapy for Favorable Risk and Low Tier Intermediate Risk Prostate Cancer	NCT06200974	Localized Prost...	High dose rate ...	18 Years -	British Columbia Cancer Agency
LDR vs. HDR Brachytherapy for Prostate Cancer	NCT03426748	Prostate Cancer	Low dose rate p... High dose rate ...	40 Years - 80 Years	British Columbia Cancer Agency
Multi-omic Approach to Study HDR Brachytherapy for Favorable Risk and Low Tier Intermediate Risk Prostate Cancer	NCT06200974	Localized Prost...	High dose rate ...	18 Years -	British Columbia Cancer Agency
High Dose Rate Prostate Brachytherapy: Dose Escalation to Dominant Intra-prostatic Nodule	NCT01605097	Prostate Cancer	HDR interstitia...	40 Years - 80 Years	British Columbia Cancer Agency

Spots Global Cancer Trial Database for high dose rate prostate brachytherapy