Postop Hypofractionated Radiation Therapy and LHRH in Patients With Prostate Cancer

Official title

Postoperative Hypofractionated Radiation Therapy and Hormonal Therapy in Patients With Prostate Cancer: A Phase II Trial

Overview

Prostate cancer is the second most common cancer among Canadian men of which approximately 20-30% present with high-risk tumour characteristic. Although surgery can be curative in patients evidencing pathological high-risk disease (extracapsular extension, seminal vesicle involvement, positive surgical margins), a large proportion will develop biochemical failure within years from the surgical procedure. The failure rate is even more pronounced in those patients that present with high prostate specific antigen (PSA) levels, pT3 disease, positive margins and Gleason score ≥8 with an estimated 75% failure rate at 10 years. Post-operative radiotherapy (RT) has been shown in three randomized trials to significantly decrease the biochemical failure rate and in one of the trials a survival benefit was also seen with the addition of post-operative RT and is considered by many investigators standard therapy in patients with pathological high-risks factors even in absence of biochemical failure.

Detailed description

Although RT is known to potentially eradicate microscopic disease localized in the prostatic bed, the current dilemma is whether to deliver RT in the adjuvant setting (defined as the use of RT post-prostatectomy to patients at a higher risk of recurrence because of adverse pathological features prior to evidence of disease recurrence (i.e., with an undetectable PSA) or to use it as an early salvage therapy (defined as the use of RT in patients with rising PSA but no evidence of metastatic disease).

There are several institutional retrospective reports on the use of RT as salvage therapy but no randomized trial has ever been completed. The best evidence available, however, supports early salvage RT as the best strategy to be used to maximize results.

Our own group has shown excellent results using this approach in patients with low and intermediate risk disease and is currently exploring this approach in patients with high-risk disease. Hypofractionated RT offers a more convenient shorter course of treatment, reduces health-costs and appears to be as effective and safe as conventionally fractionated regimens.

This Phase 2 trial will study the potential role of hypofractionated in the post-operative setting in patients with high-risk features with the primary objective of assessing toxicity from this approach.

The use of androgen deprivation therapy in combination with RT in the primary treatment for patients with intermediate or high-risk prostate cancer is well established. The use of androgen suppression in the post-operative setting has been less explored and its definitive role has not been fully explored.

This is a phase II clinical trial to assess the feasibility and overall toxicity of adding one injection of neo-adjuvant hormonal therapy starting 12 weeks before plus Hypofractionated Radiotherapy for four weeks concurrently with another injection of luteinizing hormone-releasing hormone (LHRH) analog in patients with post-operative setting in patients with high-risk features.

Interventions

• Drug Eligard
  Eligard dose of 22.5mg given, 50Gy in 20 treatments of radiation therapy to start 12 weeks after first injection concurrent with second injection of Eligard

Primary outcome measures

• Acute Patient Reported Morbidity in genito-urinary and gastrointestinal toxicity [Time frame: Up to 90 days after the end of radiation treatment]

Secondary outcome measures (2)

• Acute Physician-Reported Morbidity in genito-urinary and gastrointestinal toxicity [Time frame: Up to 90 days after the end of radiation treatment]
• Late Patient-Reported Morbidity in genito-urinary and gastrointestinal toxicity [Time frame: from the end of radiotherapy up to five years]

Eligibility criteria

Inclusion criteria

• Histologically proven high risk (any of the following risk factors: surgical positive margins; extra-capsular extension; seminal vesicle involvement, Gleason score >7) adenocarcinoma of the prostate after a radical prostatectomy as primary treatment (adjuvant group), with pathologically negative lymph nodes dissection or clinically negative lymph nodes by imaging \[pelvic and abdominal computed tomography (CT) scan, or magnetic resonance imaging (MRI)\]. Lymphadenectomy is not mandatory. Any type of prostatectomy will be permitted. For this group of patients, the PSA level at time of entry must be below 0.4 ng/ml
• Histologically proven adenocarcinoma after a radical prostatectomy with pathologically negative lymph nodes (lymphadenectomy is not mandatory) or clinically negative lymph nodes by imaging (pelvic and abdominal CT scan, or MRI or) and evidence of biochemical failure (defined as two consecutives rises of the PSA, at any PSA level). PSA upper limit post-prostatectomy must be below 2.0 ng/ml (salvage group). Any type of prostatectomy will be permitted
• Negative bone metastases proven by bone scan. The use of proton emission tomography (PET) fluoride is allowed
• History and physical examination (including digital rectal exam) within 90 days prior of registration
• Adequate marrow reserve defined as: Hemoglobin ≥ 10 g/dl (patients may be transfused in order to achieve this level); Platelets ≥ 100 000 cells/mm3 and a white blood cell count of ≥ 4000 cells/ml3
• AST or ALT <2 x the upper limit of normal
• PSA and testosterone levels within one month of registration Age ≥ 18
• Zubrod Performance Status 0-1
• Patients must sign a study-specific consent form

Exclusion criteria

• Previous exposure to androgen deprivation
• Chemotherapy before or after prostatectomy
• Prior pelvic radiotherapy
• Previous malignancies (except non-melanomatous skin cancer) unless disease-free >5 years
• Severe, active medical condition that makes the use of any of the therapies of the study not recommended

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: Yes

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

Canada · 2 centers

• McGill University Health Centre- Cedars Cancer Centre — Montreal
• McGill University Health Centre-Cedars Cancer Centre — Montreal

Publications

• Punnen S, Cooperberg MR. The epidemiology of high-risk prostate cancer. Curr Opin Urol. 2013 Jul;23(4):331-6. doi: 10.1097/MOU.0b013e328361d48e. PMID 23619582
• Nguyen CT, Reuther AM, Stephenson AJ, Klein EA, Jones JS. The specific definition of high risk prostate cancer has minimal impact on biochemical relapse-free survival. J Urol. 2009 Jan;181(1):75-80. doi: 10.1016/j.juro.2008.09.027. Epub 2008 Nov 13. PMID 19012927
• Wiegel T, Bartkowiak D, Bottke D, Bronner C, Steiner U, Siegmann A, Golz R, Storkel S, Willich N, Semjonow A, Stockle M, Rube C, Rebmann U, Kalble T, Feldmann HJ, Wirth M, Hofmann R, Engenhart-Cabillic R, Hinke A, Hinkelbein W, Miller K. Adjuvant radiotherapy versus wait-and-see after radical prostatectomy: 10-year follow-up of the ARO 96-02/AUO AP 09/95 trial. Eur Urol. 2014 Aug;66(2):243-50. doi PMID 24680359
• Thompson IM Jr, Tangen CM, Paradelo J, Lucia MS, Miller G, Troyer D, Messing E, Forman J, Chin J, Swanson G, Canby-Hagino E, Crawford ED. Adjuvant radiotherapy for pathologically advanced prostate cancer: a randomized clinical trial. JAMA. 2006 Nov 15;296(19):2329-35. doi: 10.1001/jama.296.19.2329. PMID 17105795
• Bolla M, van Poppel H, Tombal B, Vekemans K, Da Pozzo L, de Reijke TM, Verbaeys A, Bosset JF, van Velthoven R, Colombel M, van de Beek C, Verhagen P, van den Bergh A, Sternberg C, Gasser T, van Tienhoven G, Scalliet P, Haustermans K, Collette L; European Organisation for Research and Treatment of Cancer, Radiation Oncology and Genito-Urinary Groups. Postoperative radiotherapy after radical prostat PMID 23084481
• Freedland SJ, Rumble RB, Finelli A, Chen RC, Slovin S, Stein MN, Mendelson DS, Wackett C, Sandler HM; American Society of Clinical Oncology. Adjuvant and salvage radiotherapy after prostatectomy: American Society of Clinical Oncology clinical practice guideline endorsement. J Clin Oncol. 2014 Dec 1;32(34):3892-8. doi: 10.1200/JCO.2014.58.8525. Epub 2014 Nov 3. PMID 25366677
• King CR. Adjuvant versus salvage radiotherapy for high-risk prostate cancer patients. Semin Radiat Oncol. 2013 Jul;23(3):215-21. doi: 10.1016/j.semradonc.2013.01.009. PMID 23763888
• Spiotto MT, Hancock SL, King CR. Radiotherapy after prostatectomy: improved biochemical relapse-free survival with whole pelvic compared with prostate bed only for high-risk patients. Int J Radiat Oncol Biol Phys. 2007 Sep 1;69(1):54-61. doi: 10.1016/j.ijrobp.2007.02.035. Epub 2007 Apr 24. PMID 17459606

Identifiers

NCT: NCT04249154 · 16-126-MUHC

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗