Imaging for Individualized Treatments: Patient Benefits in Oncology, Neurology & Cardiology

As disease treatment becomes more individualized, the spectrum of molecular imaging expands. The role of molecular imaging varies from management of various cancers and differential diagnosis of neurological disorders to identifying patients for cardiac revascularization. Four experts discuss the current and future trends in imaging for individualized treatments in oncology, neurology and cardiology.

Focus on oncology

Clearly, the most explosive growth in oncologic molecular imaging in recent years has been in the realm of 18F-fluorodeoxyglucose (FDG) PET and, more recently, FDG-PET/CT. This modality has become standard of care for planning patient therapy, assessing therapeutic efficacy, and making decisions regarding termination or alteration of therapy in many cancers. And the role of FDG-PET will expand even more rapidly in the next few years, as oncologists become more comfortable in utilizing FDG imaging early during a prescribed therapeutic regimen to assess efficacy and make changes in the therapy where necessary, says Landis K. Griffeth, MD, PhD, director of nuclear medicine at the Baylor University Medical Center in Dallas.

Yet, Griffeth sees these clinical applications of FDG-PET as “midpoints” on the spectrum of molecular imaging. On the most advanced end of the spectrum would be new experimental PET radiopharmaceuticals that may be useful in projecting the response of a tumor to specific types of therapy or may be able to the image precisely the delivery and uptake of a novel therapeutic agent within tumor cells. This latter approach could take a number of forms, ranging from positron-emitter-labeling of a liposomal or nanoparticle vehicle used to deliver a therapeutic agent to a tumor to PET imaging of a reporter gene. On the other end of the spectrum are PET and single-photon techniques that have been utilized for years in the characterization of specific types of tumors, Griffeth explains.

Imaging varies by tumor type

The role of molecular imaging in individualized treatments varies considerably by tumor type. For example, the performance of OctreoScan [Indium-111-DTPA octreotide (pentetreotide)] SPECT/CT for assessment of the somatostatin-receptor-binding status of the patient’s neuroendocrine tumor metastases would be a highly specific arbiter of whether or not the patient would be likely to respond to high-dose octreotide therapy or with pentetreotide therapy labeled with an alternative isotope, says Griffeth.

On the other hand, FDG-PET, while less specific for tumor type, has a much wider applicability in determining whether or not a particular treatment regimen is having the desired effect on a given tumor. For example, there is substantial data to suggest that a dramatic FDG-PET response of a patient’s lymphoma after a few cycles of chemotherapy is a very strong prognostic indicator of the eventual complete clinical response after completion of that prescribed chemotherapy regimen, while a lack of response means that an alternative therapy probably should be considered. Another interesting example Griffeth cites is a gastrointestinal stromal tumor treated with imatinab (Gleevec). In this case, a positive responder can often be identified by a dramatic decrease in FDG uptake after a single dose. Similarly, if that tumor escapes control, as often happens after several years of therapy, recurrent hypermetabolism on simple FDG-PET imaging will typically precede lesion growth on CT.

“Our role in the treatment of specific tumors will expand precipitously if we can identify new tracers that are both sensitive and specific for individual types of tumors and, in particular, do not suffer from some of the limitations of currently available tracers, such as the tendency of FDG to show substantial uptake in inflammatory or granulomatous lesions, ” says Griffeth. Development of agents that will more clearly quantify the delivery of therapeutic agents to a known tumor volume and agents that will most accurately depict early tumor response to therapy will not only lead to more streamlined and individualized therapy for cancer patients, but will greatly simplify the development of new anti-neoplastic agents in future.

Focus on neurology

Fluorine-18 FDG was first administered to study glucose metabolism in the human brain by Abass Alavi in August 1976 at the University of Pennsylvania. “Even though FDG was first used as a brain ligand, in the end it became a huge success in oncology followed by cardiology and ironically found least success in neurology,” says Nicolaas I. Bohnen, MD, associate professor at the departments of radiology and neurology at the University of Michigan in Ann Arbor.

Tissue diagnosis and many years of discontent on dementia treatment are the reasons for the delayed clinical applications in neuroimaging, says Bohnen. He says that it is easy to get FDA approval for a radioligand for oncology, but not for neurology because the approval requires tissue diagnosis. “If you have a tumor and your radioligand is successful in monitoring malignancy, it is easy to put a needle and do tissue diagnosis. In the brain, it is different because patients with dementia would not like to have a brain biopsy [to confirm diagnosis.] That is why a number of studies have been correlated only with autopsy findings.”

FDG-PET is currently is used for the differential diagnosis of Alzheimer’s disease vs. frontal temporal dementia, to localize and focus on seizure disorders and for the diagnosis of residual brain tumor, says Bohnen.

There also are a number of SPECT studies done for individualized diseases in neurology. SPECT imaging with dopamine transporter ligand, GE DaTSCAN (123I-Ioflupane), is used for differential diagnosis of Parkinson’s disease, essential tremor and for patients taking neurologic medication to prevent the development of movement disorders. Typically, changes in Parkinson disease are difficult to see in MR scans, but since the dopamine levels change, DaTSCAN SPECT can determine whether the patient has Parkinson’s disease or not, says Bohnen.

Radioisotopes such as In-111-diethylentriamine penta-acetic acid (DTPA) have been used in radionuclide cisternography SPECT/CT fusion imaging to determine if there is an abnormal accumulation of cerebrospinal fluid in the ventricles of the brain (hydrocephalus) and to identify the location of the cerebrospinal fluid leak, says Bohnen. Another application is the use of Tc-99m exametazime (GE Ceretec) to help confirm brain death.

The biggest excitement in neurology in personalized medicine is amyloid PET imaging, says Bohnen. Amyloid protein is accumulated in patients with Alzheimer’s disease and about 20 to 30 percent of cognitively normal elderly express binding in the amyloid PET scans and it increases with age, he says. He believes the future is bright for molecular imaging and it is possible that we can use molecular imaging for preclinical diagnosis of neurological diseases like Alzheimer’s.

Focus on cardiology

Today’s three major trends in cardiovascular imaging are hybrid imaging, the shift from SPECT to PET and looking at the biology vs. blood flow of the myocardium, says Frank M. Bengel, MD, director of cardiovascular nuclear medicine at Johns Hopkins University in Baltimore.

Compared with oncology, cardiovascular diseases bring several challenges for imaging, such as small size and continuous movement of the structures as well as often small amounts of pathological substrate. State-of-the-art PET/CT hybrid scanners with 64-slice CT are becoming standard of care, offering a comprehensive cardiac examination, including an assessment of anatomic extent of coronary artery disease (CAD) by non-invasive coronary angiography and its functional consequences on myocardial perfusion and metabolism in a single study, says Antti Saraste, MD, PhD, a cardiologist at Turku PET Centre, Turku University Hospital in Finland.

Migrating from SPECT to PET

SPECT imaging with conventional gamma cameras has been the workhorse for nuclear cardiology in the past, says Bengel. Currently, there is limited availability of Tc-99m in the U.S. because of reactor repairs in Canada and the Netherlands. New dedicated camera systems will address this problem because cardiac SPECT studies can be done with smaller doses of tracer, at superior image quality. Moving from SPECT to PET as a superior technique for perfusion imaging is another evolving trend. PET is the most powerful clinical molecular imaging modality due to its high sensitivity and availability of tracers with low risk of toxicity. Fluorine-18-labeled tracers are under development and phase 3 studies will begin within the next few months. Once FDA approved, the 18F labeled tracers will contribute to better availability of myocardial perfusion PET imaging, adds Bengel.

Treatment decisions

Molecular imaging techniques of myocardial metabolism, viability, and innervation have been available for many years and have clearly demonstrated their usefulness in clinical studies, says Saraste. “In addition to diagnosis, molecular imaging could provide surrogate endpoints to evaluate efficacy of therapies in clinical trials and monitor therapy responses.”

Evaluation of myocardial glucose metabolism by FDG-PET is considered the most sensitive tool to detect viability. Many studies have demonstrated the ability of myocardial viability testing to identify patients with ischemic heart disease and left ventricular dysfunction who can potentially benefit from both improved cardiac function and prognosis after revascularization. Evaluation of sympathetic innervation with SPECT and PET may be adopted for wide-spread clinical use provided that ongoing large prospective studies confirm their value in the assessment of prognosis of patients with myocardial infarction or heart failure, Saraste says. In the long run, there will be an even broader variety of tracers directed against other targets, such as angiogenesis and inflammation of myocardium. These new tracers will help us characterize diseases in detail and also will help in directing therapeutic change in an individual patient, says Bengel.

“In the past, the treatment decision in coronary artery disease used to be between interventional therapy and conservative medical therapy,” he says. “This is where myocardial perfusion imaging is established and plays an important role. But the variety of therapeutic options is increasing and today, there are other decisions which are increasingly difficult to make.” For example, when do you implant an implantable cardioverter device (ICD) to protect a patient from life-threatening arrhythmia, or when do you implant a cardiac resynchronization device to improve heart failure, or when should you try novel therapies such as cell transplantation, poses Bengel.

It is here that molecular imaging will play a role in future, providing very specific information about the usefulness of a specific therapy, sums Bengel.