Κυριακή 3 Νοεμβρίου 2013

MR/PET: current status in clinical routine and market

Description of technology


Positron Emission Tomography combined with Magnetic Resonance Imaging (PET-MRI) is an emerging technology recently proposed to be used in oncology, neurology and cardiology for diagnostic purposes. The market offers three different PET-MRI systems, developed by three manufacturers (GE, Philips and Siemens). The GE system - "Trimodality PET-CT + MR" – is able to capture and correlate PET, CT and MR images based on two separate devices, a PET-CT and a MRI. The Philips system – “Ingenuity TF” - has PET and MR gantries arranged in the direction of the main scanner axis with a patient handling system mounted between the gantries. Siemens has developed a fully integrated PET-MRI system – Biograph mMR - with simultaneous acquisition with a single gantry. This is the only system capable of simultaneously acquiring the image PET-CT and  MR, instead the other two systems use special software to merge the two types of images. In oncology the expected benefits include the improvement of diagnostic accuracy compared to PET-CT, especially for soft tissue cancers, with a lower radiation exposure.




Clinical relevance and burden disease

We can hypothesize the diagnostic application for some cancers, such as primary brain tumours, carcinoid tumours, prostate and uterine cancer, because they were objects of few feasibility studies in the first half of 2000 years where PET and MR images were combined through fusion of computerized records after separate data acquisition (Cuerva Carvajal 2007). Outside the oncologic field post acquisition PET and MR imaging fusion has been applied in one small study for pre-operative assessment of children with tuberous sclerosis in order to better identify epileptogenous tuberosities for selection of surgical treatment (Cuerva Carvajal 2007). In synthesis, thus far no precise disease emerges to profit by the application of combined PET-MRI images, and so it is impossible to identify any target disease and any clinical need to be covered with the application of this new technology.



Various sectors of diagnosis are sure to benefit from a hybrid system MR / PET in neurology cardiology, oncology and functional imaging.

Manufacturers and traders trust company


The market offers three different PET-MRI systems, developed by GE, Philips and Siemens.

GE has "Trimodality PET-CT + MR", a system able to capture and correlate PET, CT and MR images. The system proposed by GE is made up of two separate machines, a PET-CT (Discovery PET-CT 690) and a 3 Tesla MRI (Discovery MR 750), placed in two separate rooms and connected together via a mobile patient table on rails (Patient Transfer Discovery table) which allows the patient to transfer from one modality to the other without moving from the table. The system is therefore based on the acquisition of separate PETCT and MRI images, then processed together through a fusion software managed by the operator through the “Advantage” workstation. The error as a result of this transfer is about 5mm.



The serial non-hybrid MR / PET of GE Trimodality PET-CT + MR.

Philips system is composed by a 3 Tesla MR and a PET Time of Flight based. It has PET and MRI gantries arranged in the direction of the main scanner axis with a patient handling system mounted between the gantries. The PET was placed coaxially at a distance of 4.2 m from the MRI (distance between centers of FOV); magnet type is Superconducting 3T; maximum FOV (cm) 50 × 50 × 45 (MRI) and Axial FOV 18 cm (PET). The Time of Flight technology allows to make fast acquisitions (5 minutes examination) and to infuse the patient with a very low dose of radiopharmaceutical.


The serial hybrid modality MR / PET of Philips Ingenuity TF.


Siemens has developed a fully integrated PET-MRI system with simultaneous acquisition with a single gantry: PET detectors integrated into the bore of the MRI. It enables the precise alignment of MRI and PET by performing both scans at the same time. The magnet type is Superconducting 3 Tesla. This integrated system uses a non-magnetic detection technology based on Avalanche PhotoDiode (APD). Such technology is not optimal for a PET tomograph and prevents the use of Time of Flight. Further solid state technologies are being studied that will allow to develop PET/MRI tomographs without sacrifice the performance of individual tools.



The single hybrid modality MR / PET of the Siemens Biograph mMR.



Current regulatory status


Product name 
Manufacturer 
FDA 
CE mark
Biograph™ mMR
Siemens S.p.A.
N.K103429 released on 2011-06-08
N.10433372 released on 2011-
05-24
Ingenuity TF PET-MR
Philips S.p.A. 
yes
N.2251362 released on 2010-12-22
Tri-modality PET-CT+MR
GE Healthcare
yes
yes


Context of use analysis

Currently the technology is used in hospitals and advanced research centers where clinical research is accompanied by the development of the technology itself.

GE's technology is installed in:
1. “University Hospital” -  Zurich;
     2.“University Hospital” - Korea and it's in progress in:
other five sistems worldwide.
 
Siemens's technology is installed in:
1.IMP Erlangen;
2.Klinikum rechts der Isar – Munich;
3.University Hospital – Tubingen;
4.University Hospital – Leipzig;
5.CEMODI – Bremen;
6.University Hospital – Essen;
7.MGH – Boston;
8.NIH – Bethesda;
     9.Washington University – St. Louis;
and it's in progress in:
University College London Hospitals;
SDN, Naples;
DKFZ – Heidelberg;
Rigshospitalet – Copenhagen;
University of Noth Carolina – Chapel Hill;
Mt. Sinai Medical Center – New York;
Indiana University – Indianapolis;
Lawson Health Research Institute – London, Ontario;
PLA 301 – Beijing;
Parkway Novena Hospital – Singapore; Biopolis/CIRC – Singapore.


Philips's technology is installed in:
1.Mt. Sinai – New York;
2.University Hospital – Geneva;
3.FZD – Dresden;
4.CNIC – Madrid
5.Pusan National University – Korea


Comparators

Due to the absence of any clear target disease it is impossible to define any comparator. Manufacturers propose the following comparators: MRI (Philips), PET-CT (GE), MRI or PET or PET-CT (Siemens)



Effectiveness and safety

Methods for systematic review of evidence profile, diagnostic accuracy, effectiveness and safety

Literature search
Search strategy
The following electronic databases have been searched:
-       National Library of Medicine’s Medline database (PubMed);
The key words used were related only to the index test [(biograph AND mMR) OR (ingenuity AND PET) OR "PET-MR" OR "PET-MRI" OR "PET-MR" OR "PET-MRI")]. Period restriction: from January 2006 (date of the literature search update of a previous HTA document (Cuerva Carvajal 2007) till present. Language restrictions: documents in English, Italian, French, Spanish, Portuguese, German. Reference lists of identified articles have been checked for additional references.
Inclusion criteria
-       Types of studies: systematic reviews and primary studies assessing the feasibility, diagnostic accuracy, effectiveness and safety of the index test. Among primary literature, we have included only full report with any study design with the exception of case reports and case series with less than 10 patients.
-       Participants: any type of medical condition. We have excluded studies considering phantoms, animals, healthy people.
-       Index test: We have assessed studies considering any hybrid PET-MRI system integrating Positron Emission Tomography (PET) with Magnetic Resonance (MR) imaging and enabling the delivery in a single test session of anatomical-functional fusion imaging. We have included studies using any radioactive tracer for PET. We have excluded studies analyzing fusion of images obtained during different test sessions.
-       Outcomes of interest: any kind of outcomes reported in studies, subdividing them in the following three subgroups: feasibility outcomes, diagnostic accuracy outcomes (sensitivity, specificity, likelihood ratios, diagnostic odds ratios, ROC curves), clinical effectiveness and safety outcomes (i.e. quality of life, adverse events, time to recurrence, disease free survival, overall survival).
-       Comparator: any kind of potential diagnostic imaging test used in the standard practice.
-       Reference standard (for diagnostic accuracy studies): any reference standard considered.

Study selection
We have used Reference Manager software (version 10) to manage the references. The selection of the studies to be included have followed these steps:
1.  exclusion on the basis of title and abstract;
2.  full text retrieving of the potentially interesting studies;
3.  reading of the selected articles and application of the inclusion criteria.
Selection have be performed by two independent reviewers. The results have been compared and differences discussed. Differences in the selection have been resolved by mutual agreement.

Data extraction
Data have been extracted related to study design, study population, index test, reference standard, comparator, outcomes, and pre-test probabilities. Data extraction from included studies have been carried out using single study tables of evidence.

Methodological quality assessment
The following criteria have been used for the quality assessment of different study designs:
-  Systematic reviews criteria drawn from the AMSTAR checklist [Shea B, 2007];
-  Diagnostic cross-sectional studies criteria drawn from the QUADAS checklist [Whiting P, 2003];
-  Randomized controlled trials criteria suggested by the Cochrane Handbook [Higgins JPT, 2009];
-  Case control studies and cohort studies criteria drawn from the New Castle-Ottawa checklist.
The quality of evidence have been summarized by disease and by outcome according to GRADE method when possible.


Analysis and synthesis
Studies have been analyzed and synthesized using a tabulation constructed on the basis of the data extraction form and classified according to the following descriptors: medical disorder, study design, number of included patients, outcomes assessed. Studies results have been reported only descriptively.

Interpretation of results
Interpretation of the studies’ results have been carried out in terms of numerosity, quality and consistency of results.

Results
From the 256 eligible references we analyzed in full text 48 studies. After application of inclusion criteria 1 case series was included (Boss 2010). We excluded 4 case reports (Garibotto 2011, Miese 2011, Thorwarth 2011, Wissmeyer 2011) and 1 case series of 8 patients (Boss 2011).
The only study included (Boss 2010) analyzed the feasibility of PET-MRI in a series of brain tumour patients (10 subjects). There are no data about diagnostic accuracy or clinical effectiveness.
 The safety aspects of the technology should be further developed with specific studies of the effects of radiation and electromagnetic fields on patients and operators. 

 

Potential benefits for patients

PET-MRI may be useful in early diagnosis of cancers and degenerative diseases and also allow for better monitoring of the patient's condition. However, at present, the technology is still experimental, and no evidence of scientific evidence in support of these considerations.

Manufacters indicate the following potential benefits: 
1.educing exposure to radiation; improving 2.pediatric imaging;
3.visualization of the tumors that existing systems do not allow  to view; 4.reduction in the time of the examinations; execution of a single test for both 5.MR and PET results; reduction in the time of reporting; decreasing doses of the contrast medium.

Investments for the acquisition of PET/MRI are substantial and related to the construction of suitable premises and facilities. Although operating costs are substantial and relate to the maintenance and specialist staff involved. The manufacturers usually provide the technology framework of agreements and specific research projects, investments.

Costs


Methods for costs and impact
Technical and cost data are important to forecast structural, organizational and economic impact of PETMR on the Italian NHS. Moreover - due to the experimental phase of the technology - the definition of present marketing status and worldwide clinical and research utilization is important to programme and refine future processes on PET-MRI.
Two surveys were planned with the aim at collecting and defining the above reported contextual issues. In the first survey each of the three manufacturers were formally contacted by AGENAS on behalf of RIHTA and underwent a structured interview on the technical, organizational and cost issues of each specific PET/MR machines. An ad hoc questionnaire – with close and open-ended answers - was devised and will sent to each manufacturer before the meeting between manufacturers’ and RIHTA’s representatives. Data from the interview were analysed and reported qualitatively. The second survey aimed at collecting data on the worldwide diffusion of PET/MR and the clinical and research activities at present. We identified researchers in the field through a preliminary literature search. A structured questionnaire was devised and sent by post to the researchers identified as responsible of the PET/MR centers. The questionnaire gathered information on two topic areas: information about routine clinical activity and research activity using PET/MRI.

The costs of the technology depend on the Manufacturers: 

1. GE: The cost of the PET-MRI system (including shuttle) varies from € 3.750.000,00 to € 4.250.000,00, depending on the system CT-PET provided (number slice of the TAC) and the MRI system (1.5T or 3T). Maintenance cost by year is about 10% of the cost of the entire system (PETCT, MRI and Shuttle).

 2. Philips: The cost of the PET/MR system is about €4.000.000,00. Maintenance cost by year is about 8% of the cost of the system.

 3. Siemens: The cost of a PET-MR Siemens is around € 5.000.000,00. Maintenance cost by year amounts to € 300,000.00.

  

Potential structural and organizational impact:


STRUCTURAL IMPACT
The structural impact of the new technology is very important. The complexity of technology is linked to the management and technical issues generated from the magnetic field, which require huge resources related to the costs of technology investment, structural and operational. The PET-MRI systems must be housed in specially designed and built for this technology as well as provide suitable locations for the safety of staff and patients.
The installation of a PET-MRI system requires standard equipment and construction works for individual PET and MRI systems: Faraday cage, leaded and magnetic shielding.

ORGANIZATIONAL IMPACT
Because of the current use of PET-MRI is mainly experimental we have to consider the involvement of new and highly qualified professionals (researchers, physical and engineers). 

Conclusions:

Due to the lack of any evidence on the diagnostic accuracy, clinical effectiveness and safety of PET-MRI for any kind of patients we cannot recommend the PET-MRI for any clinical indication.
Further information about the fields of application and the expected benefits by the application of the technology are needed.

References:

1. Boss A, Bisdas S, Kolb A, Hofmann M, Ernemann U, Claussen CD et al. Hybrid PET/MRI of intracranial masses: initial experiences and comparison to PET/CT. J Nucl Med. 2010;51:1198-205.
2.   Boss A, Stegger L, Bisdas S, Kolb A, Schwenzer N, Pfister M et al. Feasibility of simultaneous PET/MR imaging in the head and upper neck area. Eur Radiol. 2011;21:1439-46.
3. Cuerva Carvajal A, Villegas Portero R. Tomografía por emisión de positrones combinada con resonancia magnética (PET/RM). Positron Emisión Tomography combined with Magnetic Resonance (PET/RM). Sevilla: Agencia de Evaluación de Tecnologías Sanitarias de Andalucía; Madrid: Ministerio de Sanidad y Consumo, 2007.
4. Garibotto V, Vargas MI, Lovblad KO, Ratib O. A PET-MRI case of corticocerebellar diaschisis after stroke. Clin Nucl Med. 2011;36:821-25.
5. Miese F, Scherer A, Ostendorf B, Heinzel A, Lanzman RS, Kropil P et al. Hybrid (18)F-FDG PET-MRI of the hand in rheumatoid arthritis: initial results. Clin Rheumatol. 2011;30:1247-50.
6. Thorwarth D, Henke G, Muller AC, Reimold M, Beyer T, Boss A et al. Simultaneous 68Ga-DOTATOCPET/MRI for IMRT treatment planning for meningioma: first experience. Int J Radiat Oncol Biol Phys. 2011;81:277-83.
7. Wissmeyer M, Heinzer S, Majno P, Buchegger F, Zaidi H, Garibotto V et al. Y Time-of-flight PET/MR on a hybrid scanner following liver radioembolisation (SIRT). Eur J Nucl Med Mol Imaging. 2011;38:1744-45.

MR/PET: current status in clinical routine and market

Description of technology Positron Emission Tomography combined with Magnetic Resonance Imaging (PET-MRI) is an emerging technology rec...