Chicago in the week after Thanksgiving is a busy place. So you may or may not have found time to hear Richard L. Wahl, M.D.’s talk at the RSNA annual meeting on the future of imaging, "Imaging Cancer in the New Millennium: Form Follows Function." Wahl, who is a professor of internal medicine and radiology at the University of Michigan Medical Center in Ann Arbor, Mich., believes that functional imaging is on the road to overtaking anatomical imaging as a first step in many cancer diagnoses. As director of general nuclear imaging and director of the cancer radio-pharmaceutical program at the University of Michigan cancer center, Wahl has plenty of research under his belt to support his positions.
What exactly do you mean by form following function?
Anatomic imaging has served us well in the last 100 years in the diagnosis of cancer, but it has some limitations. You can look at masses and try to tell if there’s cancer based on size, but not everything that’s enlarged is cancer. A lot of small cancers aren’t detectable because they’re not big enough to be seen with standard equipment like CT, MR or ultrasound.
One of the big problems you face in imaging cancer every day is trying to tell if there’s cancer in lymph nodes. Large lymph nodes are often present that don’t have cancer, and small lymph nodes can harbor cancer. It’s also a problem to detect cancer when patients have had surgery or any kind of anatomic distortion. Once the normal tissue planes are disturbed, it can be very hard to tell if cancer has come back after therapy. And then one of the other issues is following the response to therapy. In other words, if you take an image, and you know there is a cancer there, just scanning it won’t tell you if it’s going to respond to chemotherapy or not. You have to give it a bunch of therapy and then wait a few months and repeat the scan and hope that it shrunk. And even if it’s shrunk, there could still be cancer there. Sometimes there is no shrinkage in size, but the cancer is gone. Scar tissue has replaced the mass. So it can be hard, actually impossible, to tell if a cancer is going to respond. Even if it is being treated, it can sometimes be hard to tell.
So where does functional imaging come in?
There are a bunch of new therapies for cancer coming along that don’t necessarily make tumors shrink but may make them quit growing. It will be hard to tell just using anatomic methods as to whether a patient is responding or not. So there’s a need for better methods to address critical diagnostic issues for diagnosis staging, treatment planning and for assessing treatment response. That’s where the functional imaging comes in. It has the ability to look inside the body, not just at the anatomy, but look at what’s going on metabolically or on a molecular level within masses.
What can functional imaging see that anatomical imaging cannot?
There are a wide range of alterations present in cancers, referred to as functional or molecular alterations, that distinguish cancers from normal tissue. They range from some very basic metabolic things like increased rates of glucose metabolism to increased rates of immunoassay transport in protein synthesis. There also are increased rates of DNA synthesis to other tissues like over-expression of certain receptors or markers on the cell surface compared to normal tissue. Sometimes it’s something as simple as just increased blood flow in the tumor compared to normal tissues. Those functional alterations are targets that can be potentially imaged using several nuclear medicine methods and in particular, positron emission tomography (PET).
What does PET see?
In the last five to 10 years, the greatest progress has been made looking at something really quite simple and fundamental, the increase of metabolism of glucose in cancers compared to normal tissues.
Is it increased in and around the cancer cells or in the bloodstream?
In the cancer cells. Cancer cells have fairly substantial energy demands so the cancer environment often has a low oxygen supply and marginal nutrition from the blood vessels. Cancers tend to use more glucose than normal tissues. Some studies we did over a decade ago, based on some studies originating from the 1930s, showed that if you inject the radio-labeled sugar-analog [F18]-fluoro-2-deoxy-D-glucose (FDG) into a patient, it will accumulate in cancers very avidly compared to normal tissues. So you typically get targeted background ratios of 10 or 15 times higher in the cancer than in normal tissue within an hour of injecting the tracer.
PET can see that concentration?
Yes, you would use PET to scan the entire body looking for these foci with increased glucose metabolisms. It turns out that PET is a very sensitive method. It can detect tumors smaller than those seen on CT. It also can look into some of these enlarged masses and tell whether they are cancer or not. For example, enlarged lymph nodes that aren’t cancerous generally don’t have increased glucose metabolism. What we’ve found is that we see the changes in glucose metabolism quickly, but changes in tumor size lag behind. Glucose metabolism is an earlier index of whether something is going to work or not than just measuring the tumor size.
Is this being reimbursed? What other cancers does it work on?
PET imaging has become more routine practice. Medicare is actually paying and the techniques are now more available. PET can characterize spots on the lung as malignant or benign based on glucose metabolism. Malignant ones have higher glucose metabolism than benign. In lung cancer patients it can tell if the cancer has spread from a single spot in the lung to elsewhere in the body. If it’s isolated in the lung, it’s quite often curable by surgery. But if it has spread to the middle of the chest or elsewhere, it’s usually almost incurable. CT was sort of the standard method to make this assessment, but it turns out that CT is far less accurate than PET. There was a meta-analysis in Radiology showing that across a bunch of studies that PET is clearly the more accurate method. Previous studies by others have shown that CT and MR are about equivalent, so MRI doesn’t add anything in this setting.
Is this used for screening asymptomatic people?
Right now, it’s being used once a pulmonary nodule has been detected. PET is a non-invasive method that helps assess what it is. In some studies, PET has actually performed better than biopsy on the lesions, because PET looks at the whole lesion and needle biopsy only looks at a small portion of it. There also is some data to show that PET is actually better than a CT in the liver and the adrenal glands, which are common sites of metastases. Emerging data indicates that PET is probably better than a bone scan for determining whether the disease has spread to the bone. So in centers that have PET, we’re seeing a big increase in the application of PET for staging lung cancer compared to more traditional methods.
What about other functional imaging methods besides PET?
There is some recent progress with single-photon imaging, SPECT, which is more widely available. There is a recently approved radio-peptide called Neotech that binds to lung cancers more than it binds to benign lesions. It may offer some of the advantages of PET without the need to buy a PET scanner. But it’s much earlier in its development and less fully evaluated.
PET was pretty controversial when it came out, wasn’t it?
Yes, but it’s been around for almost 25 years. It was a research technique for the brain and somewhat for the heart. It’s only been in the last few years that it’s oncology applications have become really clear, and there have been large enough clinical studies done to show that it has some unique advantages over CT. Most PET centers that are doing any clinical volume, probably 90 percent of what they’re doing now is cancer.
PET also is very good in detecting colorectal cancer, and in telling whether there’s metastatic disease to the liver. Several papers show that PET is superior to CT for this. If you have a patient with an isolated metastasis in the liver, which nowadays many surgeons would just cut out, PET can help you see if there are any other lesions in the liver or the rest of the abdomen. So Medicare is now paying for PET scanning in colorectal cancer with suspected recurrence and a rising serum CEA level.
Other fairly common diseases, Hodgkin’s and non-Hodgkin’s lymphoma, are very well imaged with PET and FDG. Even end-stage lymphoma images quite well. You can tell if it’s in the bone marrow with a single PET test. CT is still very good for staging and following lymphoma, but sometimes a lymphoma mass that has been treated may shrink for a while and then not shrink any further.
Earlier you mentioned PET’s application for cancer therapy. Can you discuss that in more detail?
In terms of imaging, PET is really good, but if you can target the radioactivity selectively in the tumors, you also have the potential to treat the tumor. In other words if you can image it, you also have the potential to treat it with targeted radioactivity.
Are you talking simultaneous diagnosis and therapy?
That’s not being done with PET emitters because they have too short a half-life [about two-and-a-half hours]. But we’ve been working on a special antibody, I-131 labeled monoclonal antibodies to lymphoma and CD-20, which when you inject it, homes to the cancer. It will localize non-Hodgkin’s lymphoma and allow imaging, but more importantly, it will allow therapy. So if you inject high doses you can actually treat the patient.
So this is instead of chemotherapy?
Instead of having the chemo bomb everything, this selectively bombs the lymphoma and spares other normal tissue. Imaging is critical to planning the therapy since different patients handle radioactivity differently. Some get rid of it fast from of their bodies, and some clear it much more slowly. We use imaging to figure out how much of a dose to give each patient. We’ve actually treated several hundred patients here, and the Phase III trial has just been completed. It is still investigational in its use.
How does it work?
We inject a small dose of the tracer material, and then scan the patient at three time points after injection to figure out how quickly the radioactive material clears from the patient. By knowing how quickly it clears — and it can vary three- or four-fold from patient to patient — you know how much of a dose to administer. It’s designed to maximize the tumor dose and minimize the risk of toxicity to the patient. There was some data presented on it at the American Society of Hematology meeting in December 1999. There’s an 80 percent response rate with about half of the clinical trials complete. We published our first paper on it in the New England Journal of Medicine in 1993, but now it’s being done at about 30 or 50 U.S. sites.
What about other cancer types?
There are other diseases where PET has shown a lot of promise, but it’s not yet Medicare approved for. It’s really quite good in a wide variety of cancers right now. For example, head and neck cancer recurrence and esophageal and ovarian cancer. And this is just the glucose metabolism. We really haven’t scratched the surface on some of the other processes. There are some limitations to it. Prostate cancer and some kidney cancers don’t work as well.
The other thing is that glucose metabolism isn’t completely specific for cancer. Sometimes, active infections or inflammation can have high glucose metabolisms. So tracing a metabolic function is not completely specific tracer, but it is pretty specific. But you have to be aware of a few other things that have high glucose uptake.
What exciting developments does the future hold in cancer imaging?
There are new hybrid CT/PET scanner machines being made that let you look at both anatomical and functional imaging through the same machine. These have been developed and several institutions are looking at them. The University of Pittsburgh is one. Dr. Townsend built the first one, and I believe that General Electric also is involved in the development. The device provides the anatomic information of CT and the functional or molecular information of PET. Then you can combine them into a single image. We’ve done that here using computer fusion. In other words, we’ve acquired images on two separate machines and then used a computer to merge the images. I like to say that the future of cancer imaging is form and function fused.
There’s a lot more to PET than FDG. There are agents to look at DNA synthetic rates and amino-acid transport and at gene expression. You can look at almost anything with the method. We’ve really only begun to scratch the surface. In the next millennium, we’ll continue to see a lot of imaging of form, but we’re certainly going to be seeing a lot more functional imaging. I think we’re going to see that functional imaging is going to become a first-line test and that imaging form, in some instances, will be secondary. 
