Stereotactic radiotherapy (Cyberknife®), proton beam therapy and irreversible (electroporation Nanoknife®) for localised prostate cancer (PCa): a systematic review

Research areas: Oncology, High tech medicine

Project team: Louise Schmidt, Pia Lohr
Suggested by: Main Association of the Austrian Social Security Institutions
Duration: February 2018 – June 2018
Language: German (with English summary)
Publication: LBI-HTA Project report No. 107: https://eprints.aihta.at/1165

 

Background:

Prostate cancer is the leading cause of cancer in men in Austria accounting for 23% of all new cancer incidence cases. In 2015 the incidence rate was 131 per 100,000 men and the mortality rate was 37 per 100,000 men. Patients with localized prostate cancer (where cancer is confined to the prostate gland, in the absence of lymph node invasion or metastases, corresponding to stage N0M0) can be defined as low-risk (clinical stage T1-T2a), intermediate-risk (clinical stage T2b) or high risk (clinical stage T2c). The primary goal of treating clinically confined localized prostate cancer is to target men most likely to need intervention to prevent disability or death while minimizing intervention-related complications. Possible treatment options include:

• Surgery: Radical prostatectomy (incl. laparoscopic or robotic-assisted prostatectomy)
• Radiotherapy: External radiotherapy (including conventional radiotherapy, moderately hypofractionated radiotherapy, extremely hypofractionated radiotherapy or stereotactic radiotherapy (SBRT) and proton therapy (PT)), which is used with the support of image guided radiation therapy (IGRT)
• Interstitial brachytherapy (BT): internal radiotherapy
• Cryotherapy
• Observation: Watchful waiting, Active surveillance
• Hormonal therapy 
• High-intensity focused ultrasound (HIFU)
• 43/5000
• Irreversible Electroporation (NanoKnife®)

Radiotherapy:  2 treatment options are the focus of this project

External beam radiation therapy (EBRT) is used as definitive therapy in patients with early and locally advanced disease and intensity-modulated radiation therapy (IMRT) has become the standard method for definitive external radiation to the prostate to treat PCa.

1. Stereotactic radiotherapy (SBRT) involves delivering a high dose of radiation very precisely to a tumor, but with fewer treatments (fractions) than IMRT. Standard EBRT is delivered in 1.8- to 2-Gy fractions per day to a typical dose of 74-80 Gy; In SBRT hypofractionated regimens are given over a shorter period of time (fewer days or weeks) and can deliver daily fractions of 2.5-10 Gy. The Cyberknife® (equivalent of the Gamma Knife®, designed only to treat cancer above the ear and in the cervical spine) is a linear accelerator which delivers the SBRT beams to any part of the body from any direction, using robotic arms. Cyberknife® typically uses photon therapy.
2. Proton (beam) therapy (PT or PBT) is another type of EBRT using ionizing radiation by precisely releasing the high-dosed radiation to the tumor. Proton therapy is delivered in a series of fractions (as with SBRT) via a cyclotron or synchrotron (MedAustron) and it designed to decrease radiation exposure to normal tissues.

Minimally invasive, non-thermal tissue ablation technique

1. Irreversible electroporation (IRE, NanoKnife®) is a relatively new alternative treatment, which involves inserting needles into and around the cancer. It uses short, repetitive, non-thermal high-energy pulses of electricity to destroy the cancer cells. It is performed under general anesthetic and takes 2 to 4 hours.

Project Aim:
The project aims to assess the relative effectiveness and safety of 3 interventions for the therapy of localized prostate cancer: (i) stereotactic body radiation therapy (x-ray or photon based) and (ii) the particle-based proton beam therapy and (iii) irreversible electroporation.

Research Question:
Is stereotactic body radiation therapy (Cyberknife®) or proton beam therapy or irreversible electroporation (e.g., with NanoKnife®) more effective (survival, disease progression, health-related quality of life) and safer (toxicity and other side-effects) than alternative prostate cancer-specific treatment options (e.g. surgery, watchful waiting, internal radiotherapy, other types of external beam radiotherapy) for localized prostate cancer?

Inclusion criteria (PICO):

	Inclusion critera
Population	Patients with low risk, intermediate or high risk localised prostate cancer (cT1a-T2c N0 M0) which refers to the clinical condition where a cancer is confined to the prostate gland, in the absence of lymph node invasion or metastases.
Intervention	1st intervention: Stereotactic body radiation therapy (SBRT) OR stereotactic body radiotherapy OR stereotactic ablative radiotherapy (SABR)  OR stereotactic radiation therapy OR stereotactic body irradiation OR hypofractionat* OR stereotactic radiosurgery OR SRS OR CyberKnife® OR Gammaknife® 2nd intervention: Irreversible electroporation (IRE) OR NanoKnife® 3rd intervention: Proton beam therapy OR particle beam therapy OR proton therapy
Control	Active surveillance, observation (watchful waiting), radical prostatectomy, internal radiotherapy (e.g. brachytherapy), other types of external beam radiotherapy (e.g. intensity modulated radiation therapy), hormonal therapy, high-intensity focused ultrasound
Outcomes	Effectiveness: Survival and disease control: Overall survival Cause-specific survival Metastasis-free survival Biochemical recurrence-free survival Patient-reported health status Urinary incontinence Urinary irritation/obstruction Bowel symptoms Sexual symptoms Hormonal symptoms Safety: Acute complications (within 90 days of treatment) via CTCAE classification
Study design	For Effectiveness: Systematic Reviews & HTAs Randomised controlled trials (RCTs) and controlled trials (CTs) For Safety: All above Non-controlled prospective studies with ? 50 participants[1]

Methods:

Scoping search: To inform this project proposal, an initial scoping search for relevant HTAs or systematic reviews was carried out via the following databases: CRD HTA database, AWMF and National Guidelines Clearing House. In addition a search was made for relevant HTAs or evidence analyses on the websites of the following organisations or agencies: AGENAS/IT; AHRQ/USA; ANZHSN/AU; CVZ/NL; G-BA/DE; GR/NL; KCE/BE; NICE/UK; SIGN/UK; National Comprehensive Cancer Network/USA; American College of Radiology (ACR Appropriateness Criteria) (see table in appendix).

Systematic literature search for project:

• Systematic literature search in the databases: Cochrane Library, Centre for Research and Dissemination (DARE, NHS-EED, HTA), Embase, Medline via Ovid, Clinical Trial Registries. Search limited to studies published in German or English since 2010
• Update of NICE literature search for irreversible electroporation from 06/09/2016 to present day
• Hand search of reference lists.

Screening and data extraction:

First reviewer (LS) will screen all abstracts; second reviewer (PL) will screen excluded studies. The literature selection process will be presented via a PRISMA diagram.

The following data will be extracted: study details (author, country, setting, number of patients, length of follow-up), patient characteristics (tumor stage, risk category, Gleason score, loss to follow-up), intervention characteristics (technique, radiation dose, dose per fraction..), outcomes (as defined in the PICO table above). Data will be extracted by the first reviewer (LS) and checked by the second reviewer (PL).

Risk of bias and strength of evidence:

Risk of bias assessment will be conducted by two researchers (LS und PL) using the Cochrane Risk of Bias Tool (selection bias, performance bias, detection bias, attrition bias, reporting bias, other bias). Strength of evidence will be assessed according to GRADE criteria by two reviewers (LS and PL) and presented in evidence profiles for each endpoint individually.

Time schedule/ milestones:

	Task
Period
February 2018	Systematic literature search, non-systematic hand search of reference lists, abstract screening, PRISMA diagram
March 2018	critical appraisal (risk of bias assessment), data extraction
April 2018	GRADE assessment, report writing
May 2018	1st Draft for internal review
	Revision of 1st draft
	External review
June 2018	Completion of final report

References:

AHRQ (Agency for Healthcare Research and Quality). Comparative effectiveness review number 146. Therapies for clinically localized prostate cancer: Update of a 2008 systematic review. 2014

ACR (American College of Radiology). ACR Appropriateness Criteria. Definitive external-beam irradiation in stage T1 and T2 prostate cancer.  Last review date: 2013.

KCE (Belgian Health Care Knowledge Centre) Report 226. National practice guideline on the treatment of localized prostate cancer- part 2. 2014.

Koontz B. et al. A systematic review of hypofractionation for primary management of prostate cancer. European urology 2015; 68:683-691.

Mottet N. et al. EAU-ESTRO-SIOG Guidelines on prostate cancer. Part 1: screening, diagnosis and local treatment with curative intent. European Urology 2017; 71: 618-629.

NCC-C (National Collaborating Centre for Cancer). Prostate cancer: diagnosis and treatment. January 2014.

NCCN (National Comprehensive cancer network). Prostate Cancer Version 2.2017. 21.02.2017.

NICE (National Institute for Health and Clinical Excellence). Irreversible electroporation for treating prostate cancer. 21.12.2016

NHS England Clinical Commissioning Policy. The use of stereotactic ablative radiotherapy (SABR) in the treatment of prostate cancer. 13.07.2016

Sanda M. et al. Clinically localized prostate cancer: AUA/ASTRO/SUO Guideline. American Urological Association, 2017.

WA-HCA (Washington State Health Care Authority). Health Technology Assessment Proton Beam Therapy. 28.03.2014.