Metastatic breast cancer is the most advanced stage of a devastating disease. At this stage, cancer cells have spread past the breast and lymph nodes to other areas of the body. The spread is most often manifested in the bones, lungs, and liver, but the cancer may also spread to the marrow, brain, ovaries, and other regions.

There currently is no guaranteed cure, but chemotherapy treatment can help improve survival and enhance quality of life. Unfortunately, not all women respond to treatment. Determining a patient’s response as early as possible can help spare patients the false hope generated by ineffective treatment as well as unpleasant side effects such as nausea, vomiting, hair loss, and hematologic toxicity. Plus, if a treatment is deemed ineffective, physicians and patients can discuss possible alternatives.

“Would a patient want to continue with chemotherapy treatment if they weren’t responding? That is the question that needs to be asked,” says Norbert Avril, MD.

Anatomic Imaging limitations
Avril and fellow researchers in Germany recently published the findings of their study that indicates that chemotherapy efficacy in metastatic breast cancer patients can be assessed earlier with PET. Specifically, using radiolabelled glucose analogue F-18 fluorodeoxyglucose (FDG) to track the metabolism of cancer cells, the researchers determined that, compared with conventional imaging procedures, sequential FDG-PET imaging provides earlier evaluation of chemotherapy effectiveness.

The findings were reported in the July issue of the Society of Nuclear Medicine’s Journal of Nuclear Medicine (“Early Prediction of Response to Chemotherapy in Metastatic Breast Cancer Using Sequential 18F-FDG PET”).

According to Avril, senior author of the report and now an associate professor in the department of nuclear medicine at Queen Mary, University of London, FDG-PET performed at baseline and after the start of treatment provided response prediction as early as the first cycle of chemotherapy, while conventional imaging procedures—such as CT, MRI, plain film radiography, and ultrasound—do not reliably predict therapy response that early in treatment.

“What this means is that we now have an additional measure, one that is better than currently used CT,” says Avril. “It is not perfect right now, but it provides us with metabolic information we can use to predict response.”

Assessing Response
Usually, doctors assess response to chemotherapy after several cycles of treatment by detecting changes in tumor size by CT, MRI, or radiography. Avril and colleagues wanted to evaluate the use of sequential FDG-PET to predict treatment response after the first and second cycles of standardized chemotherapy.

When used with FDG, PET reveals information about the metabolism of glucose in organs and other tissues. Increased glucose uptake in active tumor tissue allows assessment of the metabolic activity of cancer cells by the accurate quantification of FDG uptake in tissue. PET has proven to be better than conventional imaging for staging and restaging various types of cancer, including breast cancer.

In FDG-PET, the patient receives an injection of the radiopharmaceutical FDG, which metabolizes at higher rates in cancer cells, and a radionuclide. As cancer cells metabolize glucose faster than normal cells, higher concentrations of FDG are drawn to cancerous areas. By tracking gamma ray signals emitted by the radionuclide, PET scans reveal FDG location, which directly translates into the glucose metabolism of cancer tissue.

Avril and colleagues were hoping to add to the scant information about the usefulness of FDG-PET for predicting response early in the course of chemotherapy treatment for metastatic breast cancer. Their study differs from similar studies in that they applied a thorough quantitative analysis to measure the metabolic activity for every metastatic lesion. “We followed a lesion to find out whether or not it was responding,” says Avril. “In previous studies involving metastatic cancer, researchers primarily described whether there was an increase or decrease in size. We used the standard uptake value [SUV], a method to measure the FDG uptake in PET images.”

As the researchers indicated in their paper, studies have demonstrated that SUVs provide highly reproducible parameters of tumor glucose use.

Three-Year Study
Working from the hypothesis that changes in FDG uptake early in treatment enables clinicians to better predict the effectiveness of chemotherapy, the researchers recruited 11 patients with 26 metastatic lesions to undergo sequential FDG-PET for monitoring treatment response. The study was conducted between February 1997 and February 2000. Fellow researchers and coauthors, all at the University Hospital Hamburg-Eppendorf, Hamburg, Germany, included Joerg Dose Schwarz, MD; Michael Bader, MD; Gabriele Hemminger, MD; and Fritz Janicke, MD, from the department of gynecology, and Lars Jenicke, MD, from the department of nuclear medicine. All patients were treated at the University Hospital Hamburg-Eppendorf and were followed either until death or until April 2004.

Patients were treated with chemotherapy every three weeks. Chemotherapy was discontinued in patients who showed progressive disease on conventional imaging. Patients with no change, partial remission, or complete remission received additional cycles of chemotherapy up to a maximum of 10 cycles.

Patients underwent conventional imaging, including ultrasound, plain film radiography, contrast-enhanced CT, and MRI, depending on the localization of the metastatic lesions. The imaging procedures were repeated after three cycles of chemotherapy (nine weeks), six cycles (18 weeks), and nine cycles (27 weeks).

The FDG-PET imaging was performed at baseline before chemotherapy, after the first cycle (three weeks) and second cycle (six weeks) of chemotherapy. The 11 patients underwent 31 FDG-PET examinations. Researchers semiquantitatively analyzed the FDG-PET images after the first two cycles for each metastatic lesion using SUVs normalized to the patients’ blood glucose levels. The images were compared with baseline images to determine changes in FDG uptake in metastatic tumor lesions.

In addition, whole-body FDG-PET images were viewed for overall changes in the FDG uptake pattern of metastatic lesions within individual patients. Metabolic response was compared with response on conventional imaging after the third and sixth cycles of chemotherapy.

Response was classified according to World Health Organization criteria:

• Complete response was defined as resolution of abnormal FDG uptake in metastatic lesions.

• Partial response was defined as a reduction in the intensity of uptake or in the number of metastatic lesions with increased uptake.

• No change was defined as no change in the number of metastatic lesions and in the intensity of uptake in metastatic lesions.

• Progressive disease was defined as an increase in the intensity of uptake or in the number of metastatic lesions.

For conventional imaging, patients with no change or partial or complete response were classified as responders to chemotherapy and patients with progressive disease were classified as nonresponders. Patients with FDG-PET scans showing partial or complete response were classified as responders to chemotherapy, and patients with scans showing no change or progressive disease were classified as nonresponders.

Results and Implications
Researchers reported that at the end of chemotherapy, assessment with conventional imaging procedures indicated that 17 metastatic lesions responded. In those lesions, SUV decreased to 72% (plus or minus 21%) after the first cycle and 54% (plus or minus 16%) after the second cycle, when compared with the baseline PET scan.

Conversely, FDG uptake in lesions not responding to chemotherapy declined only to 94% of baseline (plus or minus 19%) after the first cycle and 79% (plus or minus 9%) after the second cycle. The researchers reported that the differences between responding and nonresponding lesions were statistically significant after the first and second cycles, and that visual analysis of FDG-PET images correctly predicted the response in all patients as early as after the first cycle of chemotherapy. As assessed by FDG-PET, the overall survival in nonresponders was 8.8 months, compared with 19.2 months in responders.

First Cycle
The researchers concluded that sequential FDG-PET allowed prediction of response to treatment after the first cycle of chemotherapy. Thus, in patients with metastatic breast cancer, the effectiveness of chemotherapy can be evaluated earlier with FDG-PET than with conventional imaging. Furthermore, FDG-PET allows monitoring of multiple metastases using a single functional imaging procedure.

Avril believes the findings’ implications are significant. “Imaging modalities are now much more advanced than the therapeutic approach. With PET, we now have an ability [to] identify response even without a change in tumor size,” he says. “We don’t have to wait for changes, and that is very important.”

Avril says the ability to identify responses after one cycle of chemotherapy is an attractive development, as it basically offers an in vivo chemo-sensitivity testing. “You give one treatment to a patient, measure the glucose metabolism before and after, and if there is no change, this patient will likely not respond,” he explains. “No single method affects the final decision of whether to continue with chemotherapy, but this is more powerful than CT or MRI.”

At the same time, as Avril suggests, a physician shouldn’t be too swift to cut off chemotherapy following the testing. “You just can’t tell the patient, ‘you’re not responding, so you don’t get anymore chemotherapy.’ You have to see it in the overall context, and probably continue or give another chemotherapy, if it is not absolutely clear. Do another cycle and re-measure the activity. That is why we did it after the first and second cycle of chemotherapy,” he says.

Early Response Prediction
As for the significance of the findings, the authors write, “The use of FDG-PET as a surrogate endpoint for monitoring therapy response offers improved patient care by individualizing treatment and avoiding ineffective chemotherapy.”

Avril believes sparing patients the ordeal of ineffective therapy is important for both ethical and economical reasons. “Chemotherapy can cost several thousands of dollars, so we need to know if the treatment is working, even if we really don’t have a good alternative,” he points out. “But I think telling the patient the truth is, in itself, a good alternative. We can ask them if they really want to continue with the treatment, since they’re not responding, or could we do a more biological kind of treatment. That is where I see the importance.”

In addition, Avril says the results have important implications for phase 2 and phase 3 testing of new drugs. “Antiangiogenic drugs now being used starve the tumor but do not kill the tumor cells. Deprived of blood, tumors may remain [the] same size and not grow, which means a lot to patients. That kind of treatment can be as good as a very aggressive chemotherapy but is very difficult to assess with conventional imaging such as CT,” he explains. “Metabolic information gained from PET can help determine if treatment is effective.”

Further Research Needed
The question now, says Avril, is determining how to use FDG-PET in the clinical setting to predict response to chemotherapy in metastatic breast cancer. That determination, he says, will require more information gained from continued research. The researchers said the study suggests that a threshold of 20% may be sufficient to separate nonresponders from responders. Avril adds that the use of a 20% decrease in SUV after the first cycle of chemotherapy as a threshold for identifying nonresponders needs further evaluation.

“This needs to be confirmed in much larger trials before one can really use PET imaging to assess response,” adds Avril. “You need to know how to use this information, and the key question involves the threshold. Criteria need to be established. So, one cannot just use the 20% criteria as decrease in metabolic activity for endocrine treatment. If we do hormone treatment, the threshold may be completely different. That is what one has to study.”

He hopes to see other tracers besides FDG used in future studies. “FDG gives us an idea of the glucose metabolism, which is something that’s a bit arbitrary. But if you look at cell proliferation, this is something that could potentially be more specific,” he says.

As such, studies involving fluorothymidine (FLT) or F-18 fluorocholine PET could be revealing. “FLT or fluorocholine PET is more linked to cell proliferation, which is a key feature of malignant cells,” Avril explains. “We can image that, so that would be another direction of research. Also, the same studies should be repeated with FLT in larger settings with different chemotherapy or different treatments.”

Moreover, results should continue to be compared rigorously against CT and MRI as these modalities continue to develop. “There are going to be advances in technology—new sequences for MRI, for instance—and we need to do comparisons to see what serves the patient best,” says Avril.

— Dan Harvey is a freelance writer based in Wilmington, Del., and a frequent contributor to Radiology Today.