Hypofractionated, Dose Escalation Radiotherapy for High Risk Adenocarcinoma of the Prostate

• ClinicalTrials.gov Identifier: NCT01444820
• Recruitment Status: Unknown
• First Posted: October 3, 2011
• Last Update Posted: October 20, 2020
• Sponsor: Sir Mortimer B. Davis - Jewish General Hospital
• Information provided by (Responsible Party): Dr. Tamim Niazi, Sir Mortimer B. Davis - Jewish General Hospital

Tracking Information

• First Submitted Date: September 29, 2011
• First Posted Date: October 3, 2011
• Last Update Posted Date: October 20, 2020
• Actual Study Start Date: January 2012
• Estimated Primary Completion Date: January 2022 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: September 30, 2011)

Acute and delayed genito-urinary and gastrointestinal toxicity differences [ Time Frame: 6-8 years ]

primary outcome is the acute and delayed genito-urinary and gastrointestinal toxicity differences (at or before 90 days for the acute and 90-180 days and after for the delayed toxicity) in high risk prostate cancer patients treated with the hypofractionation vs standard of care regimen using 3D-CRT or IMRT.

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: August 6, 2014)

• freedom from biochemical failure [ Time Frame: 3 years and 5 years post-treatment ]
  To measure freedom from biochemical failure at 3 and 5 years.
• disease free and overall survival [ Time Frame: at 5 years ]
  To measure disease specific and overall survival at 5 years
• Correlation of rectum and bladder Distribution Volume Histogram (DVH) to toxicities [ Time Frame: at 180 days post treatment ]
  To prospectively correlate dose-volume histograms of the rectum and bladder by studying wall and whole organ volumes to the development of GI and GU toxicity.

Original Secondary Outcome Measures (submitted: September 30, 2011)

• freedom from biochemical failure [ Time Frame: 3 years and 5 years post-treatment ]
  To measure freedom from biochemical failure at 3 and 5 years.
• disease free and overall survival [ Time Frame: at 5 years ]
  To measure disease specific and overall survival at 5 years
• Correlation of rectum and bladder DVH to toxicities [ Time Frame: at 180 days post treatment ]
  To prospectively correlate dose-volume histograms of the rectum and bladder by studying wall and whole organ volumes to the development of GI and GU toxicity.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Hypofractionated, Dose Escalation Radiotherapy for High Risk Adenocarcinoma of the Prostate
• Official Title: Phase III Study of Hypofractionated, Dose Escalation Radiotherapy for High Risk Adenocarcinoma of the Prostate, Using 3D-CRT or Intensity-Modulated Radiotherapy

Brief Summary

In North America, around a quarter a million men are diagnosed with prostate cancer every year, and about 31,000 patients will die of their disease each year. Like other western countries, the incidence in Canada has increased due to an aging population and prostate specific antigen (PSA) screening. This has led to a significant demand on cancer care services for these patients. Prostate cancer patient with high risk features are more often treated with external beam radiation therapy (EBRT) plus two to three years of hormonal manipulation (luteinizing hormone-releasing hormone [LHRH] agonist). The most common radiation dose treatment for these patients is 74-78 Gy in 37-39 daily fractions of 180-200 cGy for a treatment length of 7.5 weeks. This fraction size is believed to offer the best balance between desired tumour kill and unwanted normal tissue injury. Larger fraction sizes of more than 250 cGy (hypofractionation) are usually avoided for curative therapy because late reacting normal tissues. However prostate cancer cells have a unique radiobiology characteristic that suggests that hypofractionated radiotherapy is more efficient at prostate tumour killing than standard fractionation is, and will produce equivalent tumour control with a lower total dose and a shorter overall treatment time. Improved target localization techniques and conformal radiation therapy technology have allowed for dose escalation and hypofractionated radiation delivery in these circumstances with minimal or no increased toxicities.

This trial is designed to determine whether high risk prostate cancer patients can be safely treated with a dose escalation hypofractionated radiation therapy in 5 weeks as opposed to the usual 7-8 weeks. These patients will be randomized to either the usual 76 Gy in 38 fractions or 68 Gy in 25 fractions. 3D-Conformal Radiotherapy (3D-CRT) or Intensity Modulated Radiotherapy (IMRT) will be used to deliver the required radiation dose. Patients will also receive 28 months of androgen deprivation therapy (LHRH agonist). The primary outcome of the study is the acute and delayed toxicity and the secondary outcomes include biochemical failure, prostate specific mortality rate, bone metastases free survival, the prognostic and predictive value of several biological variables: presence of the PTEN deletion; expression of FoxP3 gene variants, topoisomerase 2α and cancer testis antigens; expression of X chromosome-linked micro-RNAs; presence of TMRSS2-ERG gene fusion and quality of life. It is planned to recruit 250 patients to this study.

• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Prostate Cancer

Intervention

• Radiation: hypofractionation
  Centres using IMRT will use the dose painting technique to treat the prostate + proximal 1-cm SV to 6800 cGy in 25 fractions while the pelvic lymph nodes will receive 4500 cGy in 25 fractions. For patients with T3b, the whole SV is to be treated to 6800 cGy. Institutions using 3D-CRT will deliver the required dose to the pelvic volume (including pelvic lymph nodes and boost volume) - 4500 cGy - and a concomitant boost to the prostate and proximal 1-cm (or the whole SV if involved) SV to 6800 cGy.
• Radiation: conventional

  The first phase: whole pelvis including the prostate and regional lymph nodes treated with 4400 cGy in 22 fractions.

  The second phase: prostate + proximal 1-cm SV treated with 3200 cGy in 16 fractions.

  For patients with T3b, the whole SV is to be treated to 7600 cGy.

Study Arms

• Experimental: Hypofractionation
  One phase technique (IMRT or 3D-CRT): radiotherapy to the prostate + pelvic lymphnodes
  Intervention: Radiation: hypofractionation
• Conventional
  two-phase technique (IMRT or 3D-CRT): 1) whole pelvis including the prostate and regional lymph nodes; 2) boost to the prostate
  Intervention: Radiation: conventional

• Publications *: Khriguian J, Tsui JMG, Vaughan R, Kucharczyk MJ, Nabid A, Bettahar R, Vincent L, Martin AG, Jolicoeur M, Yassa M, Barkati M, Igidbashian L, Bahoric B, Archambault R, Villeneuve H, Mohiuddin M, Niazi T. The Clinical Significance of Bone Mineral Density Changes Following Long-Term Androgen Deprivation Therapy in Localized Prostate Cancer Patients. J Urol. 2021 Jun;205(6):1648-1654. doi: 10.1097/JU.0000000000001646. Epub 2021 Feb 12.

Recruitment Information

• Recruitment Status: Unknown status
• Actual Enrollment (submitted: July 13, 2015): 329
• Original Estimated Enrollment (submitted: September 30, 2011): 250
• Estimated Study Completion Date: January 2023
• Estimated Primary Completion Date: January 2022 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

1. Histologically confirmed adenocarcinoma of the prostate diagnosed within 6 months prior to randomization
2. Patient has been classified as high risk defined clinically as: T3 or T4, Gleason Score > 8, and/ or PSA > 20 (ng/mL or μg/L).
3. Pelvic and para-aortic lymph nodes must be negative on computerized tomography (CT scan) or magnetic resonance imaging (MRI) of the abdomen and pelvis performed within 12 weeks prior to randomization.
4. Investigations, including chest X-ray or chest CT scan and bone scan (with radiographs of suspicious areas) have been performed within 12 weeks prior to randomization and are negative for metastases.
5. Patients will have had a PSA test done at the time of diagnosis. This PSA test could be repeated within 28 days prior to randomization.
6. The patient may have received prior androgen suppression therapy provided that androgen suppression therapy commenced no more than 28 days prior to randomization.
7. The patient must not have received any cytotoxic anticancer therapy for prostate cancer prior to randomization.
8. ECOG performance status must be 0 or 1

9. Hematology and biochemistry: should be done within 28 days prior to randomization:

   1. Hemoglobin > 100 g/L
   2. Absolute Neutrophils > 1.5 x 109/L
   3. Platelets > 100 x 109/L
   4. AST and/or ALT < 1.5 x Upper Limit of Normal (ULN)
   5. Alkaline phosphatase < 2.5 x Upper Limit of Normal (ULN)
   6. Total bilirubin < ULN
   7. Serum creatinine < 1.5 x ULN
10. adequate birth control measures should be used by the participant
11. Patient consent must be obtained according to local Institutional and/or University Human Experimentation Committee requirements.
12. Patients must be accessible for treatment and follow-up.

Exclusion Criteria:

1. Patients with a history of other malignancies, except: non-melanoma skin cancer; or other solid tumours curatively treated with no evidence of disease for > 5 years.
2. The presence of small-cell or transitional-cell carcinoma in the biopsy specimen.
3. Patients who had previous chemotherapy for carcinoma of the prostate.
4. Patients who had prior surgical treatment for carcinoma of the prostate apart from trans-urethral resection, including bilateral orchiectomy.
5. Patients with any contraindication to pelvic radiotherapy: including, but not limited to, previous pelvic radiotherapy, inflammatory bowel disease or severe bladder irritability.
6. Patients with serious non malignant disease resulting in a life expectancy less than 3 years.
7. Other serious illness, psychiatric or medical condition that would not permit the patient to be managed according to the protocol
8. Known hypersensitivity to any protocol-indicated study medications.
9. Presence of bilateral hip replacement prostheses.

Sex/Gender

• Sexes Eligible for Study: Male

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Canada

Administrative Information

• NCT Number: NCT01444820
• Other Study ID Numbers: PCS V
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Dr. Tamim Niazi, Sir Mortimer B. Davis - Jewish General Hospital
• Original Responsible Party: Same as current
• Current Study Sponsor: Sir Mortimer B. Davis - Jewish General Hospital
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Principal Investigator: Tamim Niazi, MD; Jewish General Hospital

• PRS Account: Sir Mortimer B. Davis - Jewish General Hospital
• Verification Date: October 2020