Evidence-based Medicine Across the Globe: The Successes & Challenges of Multinational Imaging Trials

Although evidence-based medicine has been the focus of work by many healthcare researchers, molecular imaging and nuclear medicine has received scant attention in this arena. Clinical colleagues, in fields such as cardiology and oncology, have access to an enormous amount of clinical evidence through existing published, peer-reviewed clinical articles, and are able to routinely participate in multinational trials of the latest interventional devices and pharmaceutical agents. Until recently, molecular and nuclear medicine clinicians had to be content with developing and conducting their own evidence-based studies.

U.S.-based practitioners have just begun to enjoy the fruits of the National Oncologic PET Registry (NOPR) data collection efforts. The prospective trial, which began in 2005, has delivered hard evidence of PET’s capabilities in altering treatment management—leading to expanded reimbursement and greater access to the technology for patients. Outside the U.S., much of the battle to develop a strong evidence basis for molecular imaging and nuclear medicine protocols and procedures is being carried out, seemingly, one facility at a time.

Evidence-based medicine, the practice of healthcare interventions guided by or based on supporting scientific evidence, is a topic of great interest among payors and clinicians. Diagnostic imaging is one of the fastest rising physician service expenditures, according to the American College of Radiology, the Medicare Payment Advisory Commission, the Radiological Society of North America and the U.S. Government Accounting Office. As such, policy makers and payors are increasingly demanding that evidence-based data justify the utilization of imaging procedures.
R. Edward Coleman, MD, professor of radiology and chief of the division of nuclear medicine at Duke University School of Medicine in Durham, N.C., points to a lack of funding from the same governmental and private-payor organizations that are demanding evidence-based data.

“The challenges [to conducting evidence-based medicine research in molecular imaging] are getting the funding to get the studies performed, actually getting the studies performed, getting government approval, and then getting reimbursement from the third-party payors” he says.

Osman Ratib, MD, PhD, professor and chair of radiology and head of the nuclear medicine division at Switzerland’s University Hospital of Geneva, observed that the Balkanization of specialties may play a role in the difficulties faced in gathering evidence-based molecular imaging data.

“Nuclear medicine [and therefore molecular imaging based on radiotracers] suffers from a major strategic mistake that was initiated by the turf battles and defensive position of the nuclear medicine community that actively pursued the goal of isolating these techniques from other imaging modalities, in a way that they can only be performed by certified nuclear medicine physicians,” he says.

“This turf battle is even stronger in many countries in Europe, which has lead to a significant decrease in the number of providers and physicians that can perform those tests. This, added to the strong regulations driven by fear of radioactive substance, has added significant restrictions and costs to perform these tests.”

Metabolic meta data
One of the primary limitations for achieving robust evidence-based medicine studies in molecular imaging has been a lack of prospective studies with a sufficiently randomized cohort. However, meta-analysis of research from single-site and multi-site studies is providing indications for a wider role in the utilization of molecular imaging.

Evidence-based justification for nuclear cardiology procedures has used a literature meta-analysis approach in lieu of instituting a multi-site clinical registry. Myocardial perfusion scintigraphy (MPS) data were presented to the U.K. National Institute of Clinical Excellence by the British Nuclear Cardiology Society and British Nuclear Medicine Society and discussed in Heart (Feb. 2004, Vol. 90 (Suppl V):v37–v40).

“In patients presenting with stable or acute chest pain, strategies of investigation involving MPS are more cost-effective than those not using the technique,” the authors wrote. “MPS also has particular advantages over alternative techniques in the management of a number of patient subgroups, including women, the elderly and those with diabetes, and its use will have a favorable impact on cost-effectiveness in these groups.”

They noted that the technique was being underutilized in the U.K., based on wait time for the procedure (20 weeks), and by comparison, with the numbers of revascularizations and coronary angiograms performed. The researchers found that current number of MPS studies performed in the U.K. was 1,200 per million residents; they estimated that the real need was for 4,000 MPS procedures per million residents.

Rahain Hussain, MD, of the Institute of Nuclear Medicine and Ultrasound in Dhaka, Bangladesh, and John Buscombe, MD, of the department of nuclear medicine, at Royal Free Hospital in London, used an online literature-based approach to the evidence basis for scintimammography.

Their results, published in the journal Nuclear Medicine Communications (July 2006, Vol. 27(7):589-594), reviewed outcomes for 2,424 patients from single-center trials and 3,049 patients from multi-center trials on scintimammography conducted with 99mTC-lablelled isonitriles. They only included studies conducted after 1997, to ensure that the data were from exams conducted after the procedure had become mature.

They found that the procedure had an overall sensitivity of 85 percent and a specificity of 84 percent. They were not able to determine patient outcomes or management changes as a result of the scintimammography procedure, due to the retrospective nature of their analysis. However, they do believe that the multi-national review indicates use of the procedure.

“There is evidence that this is a robust imaging technique delivering high sensitivities and specificities in patients studied in both single-center and multi-center trials and, as such, can be relied on as an adjunctive method for the investigation of primary breast cancer,” they wrote.

Significant innovations
Vincent Gregoire, MD, PhD, professor of radiation oncology in the department of radiation oncology for molecular imaging and experimental radiotherapy at the Université Catholique de Louvain St-Luc University Hospital in Brussels, Belgium, has broken through medical specialty turf barriers in his institution.

He and his colleagues are investigating the use of 18F-FDG PET for target volume selection for three-dimensional radiotherapy and intensity-modulated radiation therapy (IMRT). Their on-going work, originally published in the Journal of Nuclear Medicine (Jan. 2007, Vol. 68: 68S-77S), seeks to validate the utilization of a variety of PET radiotracers for IMRT planning.

“What we did so far was only on head and neck squamous cell carcinoma [HNSCC]. Now I have a new staff member [MD, PhD] extending the work on non-small cell lung cancer [NSCLC], where there is another challenge, i.e. the movement [breathing], which also needs to be taken into account,” he says.

Gregoire’s group is conducting on hypoxic PET tracers. They also have labeled EF3 with 18F and have a clinical study underway that is comparing EF3 with FMiso.
“The use of PET offers a great promise [for target volume selection], but it needs to be validated,” he says. “In HNSCC, what we found is now validated into a multi-center phase II study. People need to share expertise, methodology and need to conduct multi-center studies. This is what my group tries to do. The next step [also under study] is to do ‘radiation dose painting’ based on PET. This requires the development of some tools able to incorporate the PET information on a voxel-by-voxel basis into the treatment planning systems; then we’ll need to do some clinical validation studies.”

A joint Dutch-Spanish study (European Journal of Nuclear Medicine and Molecular Imaging, Jan. 2009, Vol. 36:1-5) recently examined the use of SPECT/CT and portable mini gamma cameras for preoperative lymphatic mapping and real-time intraoperative imaging.

Renato Valdés Olmos, MD, and Lenka Vermeeren, MD, conducted their research at the Netherlands Cancer Institute – Antoni van Leeuwenhoek Hospital, in Amsterdam, The Netherlands. Sergi Vidal-Sicart, MD, from Spain’s Hospital Clinic Barcelona, also participated in the study.

“The value of SPECT/CT for preoperative lymphatic mapping can improve patient care in several ways,” says Olmos. “First of all, SPECT/CT provides clear anatomic location information. It shows the exact location of sentinel nodes which moderates intraoperative sentinel node detection. Especially in regions with complex anatomy or variable drainage patterns, such as the head and neck area or in case of intra-abdominal drainage, this information can help surgeons to accurately plan sentinel node excision.”

“Furthermore, SPECT/CT appears to detect more sentinel nodes than planar images only,” Vermeeren adds. In these patients, SPECT/CT can clearly show the location of the sentinel node. In many cases, the alternative for staging with a sentinel node procedure is a more extensive regional node dissection. Patients can be spared this procedure if SPECT/CT visualizes the sentinel node.”

Multinational breakthroughs
Although multinational, multi-center molecular imaging trials face a variety of challenges—ranging from economics to turf issues—the persistence and perseverance of dedicated clinical researchers can sometimes beat the odds.

“There are, of course, several difficulties in designing and conducting these trials,” says Johannes Czernin, MD, director of the nuclear medicine clinic and a professor of molecular and medical pharmacology at UCLA’s David Geffen School of Medicine and editor of Molecular Imaging Insight. “First, they are expensive; second, investigators don’t have a great personal benefit from participating; third, there are many regulatory issues that render these studies difficult [these then lead to high costs and complicated approval processes].”

A team from India, Austria, Thailand, Italy, Argentina and Belgium were able to conduct a multi-center trial to investigate whether the complementary role of perfusion SPECT, MRI and EEG for pre-surgical localization of temporal lobe epilepsy could be confirmed in a prospective setting. Their results, published in Europeon Journal of Nuclear Medicine Molecular Imaging (Jan. 2008, Vol. 35:107–115), confirmed that perfusion SPECT is an effective diagnostic modality for correctly identifying seizure origin in temporal lobe epilepsy, providing complementary information to ictal EEG and MRI.

The Academy of Molecular Imaging (AMI) recently reported that its randomized, multi-center trial investigating the use of 18F-sodium fluoride PET/CT (18F-NaF) to detect bony metastases has enrolled its first 10 patients. The study compares conventional planar 99mTc-MDP bone imaging with 18F-NaF PET/CT in patients with breast, prostate and non-small cell lung cancers. The protocol was developed in conjunction with the FDA and Centers for Medicare & Medicaid Services (CMS), and calls for data on more than 500 patients. Significantly, the study is being conducted at facilities in both the United States and Europe; Gustav K. von Schulthess MD, PhD, professor and director nuclear medicine will be leading the research at Switzerland’s University of Zurich Hospital.

“This exciting development is the culmination of many months of work and an extraordinary level of collaboration,” says Czernin, principal investigator for the study. “Although AMI is the IND [Investigational New Drug application] holder, this important research is a result of cooperative efforts between 13 clinical sites, AMI and the molecular imaging industry. Siemens Healthcare/PETNET Solutions furnished these initial 18F-NaF doses, and GE Healthcare and IBA Molecular also will provide doses in the future.”

Cancer patients undergo more than 2 million planar 99mTc-MDP scans each year to determine whether the disease has metastasized to their bones. 18F-NaF PET/CT bone scanning may have advantages over this conventional method because it is able to find smaller metastases and differentiate more accurately between cancerous and non-cancerous conditions, according to the AMI.

“We will only succeed in bringing novel imaging probes to the clinic if we design appropriate trials,” says Czernin. “These need to be multicenter trials, they can be randomized; they need solid outcome data/endpoints. Designing and conducting these trials should be among the foremost goals among the imaging community.”