Beyond oncology, new indications for PET also include cardiac assessment and imaging of tumor response therapy

-- by Deborah Dakins

As medical research illuminates the far-flung regions of molecular imaging, tumor immunology, and gene therapy, PET has finally found its place in the sun. While its contributions to cancer staging are well known, the modality is breaking new ground in cardiac assessment and tumor response therapy. On the far horizon lies the potential to use PET to identify coronary artery disease at the endothelial level, and to uncover the mystery of how cancer spreads.

"A lot of what we are working on has to do with understanding the biology of cancer itself," said Dr. Sanjiv Gambhir, associate director of the Crump Institute for Biological Imaging at the University of California, Los Angeles.

Buoyed by favorable FDA reviews for several of its oncologic applications, PET is strengthening its position in new research areas, abetted by the promise of technological advances such as image fusion. These devices, while still in their first-generation stage, hold the promise of combining PET's functional qualities with the anatomic imaging expertise of traditional imaging tools.

"PET is complementary to anatomic imaging methods like CT because size is not a good criterion of whether malignancy is present or absent. But glucose metabolism is a good criterion, and the combination of both studies is superior to either one alone," said Dr. George Segall, director of nuclear medicine at the Palo Alto VA Medical Center in Palo Alto, CA.

ONCOLOGIC IMAGING

Although PET has set its sights beyond the realm of cancer imaging, oncology remains the cornerstone application for the modality.

"PET will replace some studies that are considered conventional nuclear medicine now because of its tremendous capability to image the biochemistry of tumors noninvasively," said Dr. Steven Larson, chief of nuclear medicine at Memorial Sloan-Kettering Medical Center in New York City.

PET has been approved by the FDA for characterization of solitary pulmonary nodules, lung cancer staging, evaluation of colorectal cancer in patients with rising levels of cardioembryonic antigen, and imaging of patients who have lymphoma and melanoma. Researchers at several institutions are focused on establishing PET's comparative accuracy in other cancers.

"One of our primary research goals is to improve the noninvasive staging of tumors for better surgical management, and we're looking at specific circumstances, such as esophageal cancer, to validate PET as a diagnostic tool," Larson said.

Other sites are focusing on advancing PET's applications in brain tumor, which was the first clinical indication for fluorodeoxyglucose (FDG) in tumor imaging. Researchers have found the technique useful in patients with both metastatic and primary brain tumor who have been treated with chemotherapy and whose MRI scans show an increase in the residual abnormality.

"Morphologically, it's impossible to distinguish radiation change from recurrent tumor," Segall said. "PET in this situation is very accurate in distinguishing between those two diagnoses. And it is often used to base treatment decisions without further biopsies, since brain biopsy isn't easy and is very invasive."

In staging cancers of the head and neck, comparative studies report a slight statistical advantage for PET over CT or MRI, with some published reports documenting high sensitivity and specificity for PET. For example, FDG PET is more sensitive in detecting primary tumors (PET sensitivity, 89% to 100%; CT or MRI sensitivity, 68% to 92%), and lymph node involvement (PET sensitivity, 74% to 100%; CT or MRI sensitivity, 36% to 94%).

Other studies, however, document few such differences. But in no study has PET proved inferior to either CT or MRI, according to Dr. Val Lowe, a nuclear medicine specialist at the Mayo Clinic and president-elect of the Institute for Clinical PET.

Detecting the recurrence of disease in head and neck cancer is an area where PET clearly excels. In a prospective study of patients post-therapy, researchers found that PET can detect recurrence when it may be unidentifiable by other clinical methods.1

"PET is very useful in looking for residual disease after primary treatment, usually chemo and radiation, to determine whether salvage surgery is necessary," Segall said. "We also find it's useful in detecting mediastinal disease, which doesn't happen very often, but occasionally can occur with non-enlarged lymph nodes, so it's missed by CT."

Another PET application seeing widespread use is in differentiating recurrent tumor from scar after therapy for colorectal cancer. The technique has also made inroads in assessing thyroid tumor recurrence in postsurgical patients.

"The diagnostic evaluation usually includes another radioiodine scan, but that scan is negative about one-third of the time," Segall said. "So most physicians then order an ultrasound or MRI of the neck, but those studies are negative more than half the time. We find that about two-thirds of these patients can have their recurrent thyroid cancers localized by PET, permitting either follow-up surgery or external beam radiation therapy."

WOMEN'S IMAGING

Other emerging applications for PET in oncologic imaging include staging of breast and gynecologic cancers. At the Palo Alto VA Medical Center, research is focusing on use of PET to stage cervical, uterine, and ovarian cancer prior to laparotomy.

"We're finding that PET is more accurate than CT in detecting tumor recurrence," Segall said. "Having the two together is very helpful, because CT often misses the recurrence or underestimates its extent. But it does offer anatomic detail. So CT provides the anatomic detail necessary for localization and PET actually detects the recurrent tumor."

BREAST CANCER

Studies have demonstrated a number of promising applications for PET in patients with known or suspected breast cancer, including differentiation of benign from malignant masses in select high-risk patients or those with dense breasts or fibrocystic disease. PET's high cost limits its advancement as a competitor to other diagnostic breast imaging modalities or to minimally invasive biopsy, but a new tool, positron emission mammography, could change that. PEM, undergoing clinical trials directed by Dr. Lee Adler, a professor of radiology at Wake Forest University, is designed as a low-cost but highly sensitive system specifically designed for breast imaging.2-4

PET is expected to play a larger role in advanced breast cancer evaluation. Researchers at the Mallinckrodt Institute in St. Louis are evaluating PET's role in advanced breast cancer, using two tracers?FDG and fluoroestradiol (FES)?to predict the response of the cancer to hormonal treatment. Preliminary findings indicate that increased tumor uptake detected by PET soon after initiation of tamoxifen therapy does predict responsiveness to antiestrogen therapy.5 Another study at the same institution is evaluating the accuracy of PET for staging axillary nodal metastases in patients with newly diagnosed breast cancer.

Other researchers are focusing on PET's value in predicting tumor recurrence.

"It's difficult to know how long to treat a woman with recurrent breast cancer with skeletal metastases, because often the bone scan stays positive for months after the tumor has been eradicated," Segall said. "The bone scan basically looks at turnover of healthy bone, and that is an ongoing process for many months after the tumor is gone. So PET is very useful in determining whether chemotherapy has been effective or ineffective."

TUMOR RESPONSE

Indeed, applications for PET in the realm of tumor response therapy represent an area of great future potential, specialists say. Currently, most tumor response information comes from anatomic imaging modalities such as CT, Larson said.

"This is useful, but the disadvantage is that the change in tumor volume lags behind the functional changes at the level of the tumor cell," he said. "So we're using PET both with FDG and other tracers like iodine-124 to monitor response to specific treatments. Tumor response is going to be very important to PET, helping to plan patient treatment, especially systemic treatments."

PET already offers valuable information that aids biological characterization of tumors, so as to differentiate among scar, edema, and tumor, which is important in planning treatment, he said. PET focuses those fields so that one is irradiating the most metabolically active zones.

The next step is evaluating the therapeutic response based on its biological features. For example, determination by PET that a breast tumor expresses estrogen receptors may indicate that it is a target for anti-estrogen treatment, Larson said.

CARDIAC PET

Less well known than its forays into oncology, PET's quiet work in assessing myocardial viability has garnered respect as a reliable preinterventional test in predicting recovery of left-ventricular function after revascularization.

Such assessments are critical, due to the high surgical mortality rate and complication rate for revascularization. Patients with severe coronary artery disease and poor left ventricular function are more likely to benefit from the procedure than those with normal left ventricular function, in whom the risk of surgery may not be warranted.

PET is valuable in making these determinations, and in deciding whether other options such as pharmacologic treatment or cardiac transplant are more appropriate. Typically, these patients suffer from end-stage CAD, with limited physical ability and poor long-term prognosis.

"When you find myocardium (on PET) that is viable, then surgery might markedly change the long-term outcome and quality of life for those patients," said Dr. Heinrich Schelbert, a professor of molecular and medical pharmacology at UCLA. "There are a number of studies that indicate that if you can demonstrate reversibly dysfunctional myocardium, the global function of the left ventricle becomes markedly better. The symptoms related to congestive heart failure improve, and patients can do more physical activity."

In fact, management of patients with poor left ventricular function can be critically affected by a PET study, said Schelbert, a pioneer of this PET application who has performed it at UCLA for the past 12 years.

"In terms of stratifying patients to various treatment possibilities, whether it is revascularization or, if that is no longer possible because there is no evidence of viable myocardium, PET is critical in providing the information with which cardiologists can decide whether a transplant or conservative medical management is the best approach."

PET is also being used for detection of CAD, although it has not significantly outdistanced itself from single-photon emission computed tomography in this regard. Studies have indicated that PET allows more accurate detection of myocardial ischemia than SPECT, offers higher spatial resolution, and allows attenuation correction and quantification of physiological parameters.6

At UCLA, Schelbert and colleagues perform both PET and SPECT for detecting CAD, with SPECT used as the first scan to determine disease extent. PET is reserved for cases in which it is expected that the SPECT study will be suboptimal; for example, if patients are obese or when photo-attenuation is a problem.

The ability to measure blood flow with PET has spawned research focusing on quantitative evaluation of coronary vasomotion and abnormalities associated with coronary risk factors. Studies have shown that patients with risk factors such as diabetes illustrate reduced flow reserve on PET. Conversely, patients considered at risk for CAD who perform lifestyle modifications or participate in a drug-treatment regimen have demonstrated increased flow reserve.7,8

"Because of that, a number of trials are ongoing in which pharmaceutical companies are using flow reserve as the surrogate end point to see how effective these medications are in restoring coronary vasomotion and counteracting the effect of risk factors," Schelbert said. "The assumption is that improvements in vasomotion will indicate that patients will benefit in terms of morbidity and mortality."

Futuristic applications for PET in the heart will focus on identifying heart disease at its earliest stages: in the cell. Techniques are already being explored to use PET to demonstrate abnormalities in endothelial cells and then to evaluate attempts to normalize those cells. Other forward-looking applications include using PET to look at particular peptides or molecules that occur with coronary artery disease, and for detection of unstable plaque.

Other opportunities abound in the realm of gene therapy.

"For gene therapy, PET can monitor the effects of gene expression," Schelbert said. "The other side of that is looking at phenotypic expression or the consequences of gene expression, such as impact on blood flow."

In the long-term, special PET "reporter genes" developed by UCLA researchers to track the effects of gene therapy could also be applied on a broader scale to the study of cancer itself. Today, for example, it is not known how breast cancer cells move from one location to another within the body, said UCLA's Gambhir.

"You can use the same reporter gene technology by marking a person's breast cancer cells with the reporter gene, and watch those cells as they flee from one place to another," he said. "That's called cell trafficking. And it's just one of maybe 100 applications that are down the pipeline."

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(Provided by G. Segall)

References

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2. Thompson CJ, Murthy K, Weinberg IN, et al. Feasibility study for positron emission mammography. Med Phys 1994;21:529-538.
3. Adler LP, Bakale, G, Schnur KC. Innovations in breast cancer: PET for diagnosis and follow-up. Medscape Women's Health 1998;3(6).
4. Weinberg IN, Majewski S, Weisenberger A, et al. Preliminary results for positron emission mammography: Real-time functional breast imaging in a conventional mammography gantry. Eur J Nucl Med 1996;23:804-806.
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