Reducing uncertainty

Time is a critical variable in cancer treatment. The oncologist runs a race to introduce a therapy that can eradicate cancerous tumors before they spread beyond control.

The standard CT assessment of chemo- and radiation therapies has both aided and handicapped efforts to determine whether treatment is working. A reliance on anatomic measures of therapeutic response forces oncologists to wait at least six months to observe the effects of conventional chemotherapy or radiotherapy. By then, time has often run out for patients with resistant cancer, and alternative therapies will be fruitless.

But this harsh reality of oncologic practice is changing. Thanks to quantitative PET imaging and a new generation of molecularly based drugs, oncologists will no longer practice blindly. Preliminary studies indicate that early response measures are possible within weeks and in some cases within days of the completion of therapy. With more study, ineffective choices will be set aside as the oncologist turns to second, third, and even fourth-line treatments that increase the odds of success for one of the options.

The ability to measure early response places PET on the front lines in the pursuit of personalized medicine, said Dr. Annick Van den Abbeele, director of nuclear medicine at Dana-Farber Cancer Institute in Boston. Its value will grow as oncologists become increasingly capable of tailoring therapy to the specific genetic characteristics of individual cancer cases.

The groundwork for this approach to cancer management was established in 1993, when Dr. Richard Wahl at Johns Hopkins University found that metabolic changes associated with successful breast cancer chemotherapy could be detected with fluorine-18 FDG-PET months before anatomic changes appeared.

Wahl's finding remained just another interesting research development until the use of PET for imaging early response to cancer therapy exploded into prominence in 2002. Van den Abbeele performed the key study, which demonstrated that F-18 FDG-PET could reveal dramatic changes in gastrointestinal stromal tumor (GIST) metabolism, indicative of a positive response to the tyrosine-kinase inhibitor Gleevec, less than 24 hours after its administration. With further investigation, she discovered that the initial response also predicted long-term response.

Van den Abbeele's results contradicted conventional assumptions about the relationship between glucose metabolism and the reaction of cancer cells to therapy, and it made radiologists and oncologists aware of the new technique's implications.

"We were amazed by the powerful information we gained from functional imaging-in this particular case with FDG-PET-and how homogeneous the response was among the tumors that responded positively and those that showed a lack of response," she said.

Van den Abbeele's experience encouraged researchers to develop early response protocols for many types of cancers and molecularly targeted drugs. Their influence has extended to pharmaceutical drug testing, where some FDA trials now use FDG metabolism as a surrogate measure of therapeutic response.

In addition to GIST, promising results have been reported for FDG-PET measures of early response of Hodgkin's and aggressive non-Hodgkin's lymphoma, and esophageal, lung, and breast cancers. For most of these diseases, evaluations of early response are possible within one to three months after initiation of therapy. Preliminary studies are leading to randomized, multicenter trials that will reproduce results prospectively among large patient populations.

MOST IMPORTANT ROLE

Reporting early response could become the most important role for PET in cancer management, according to Wahl, who is now director of nuclear medicine and PET at Johns Hopkins. Its potential impact would be greatest among the 70% to 80% of patients who do not respond to treatment. The long delays before results can be analyzed require that most cancer patients undergo expensive, potentially lethal chemo- or radiation therapies that do not work.

"If you could comfortably and confidently terminate ineffective therapies earlier, it would be good for the patient and the healthcare system," he said.

In addition to identifying unproductive therapies, early response would enable the oncologist to either modify dosages or move on to alternative treatments that may work, said Dr. Ronald H. Blum, an oncologist and director of cancer centers and programs at Albert Einstein College of Medicine in New York City.

"To have the availability of functional PET to give us an earlier response of benefit or no benefit is a tremendous advantage," he said.

Access to more therapeutic options emphasizes the importance of early response measurement. Blum notes that 5-fluorouracil was the only chemotherapy available to treat colon cancer five years ago. Now, therapeutic options include oxaliplatin, Avastin, and Erbitux, and the pharmacopeia of treatments available for other cancers is also expanding.

Researchers are certain that early response monitoring will require more quantification than community-based radiologists now use. The standard uptake value, which began appearing frequently in the radiological literature around 2000, is the leading candidate to become the standard unit of measurement for early response. Most researchers use SUVMAX, a measure of peak FDG uptake, because it is more reproducible than other uptake measures, said Dr. David A. Mankoff, director of nuclear medicine at the University of Washington.

MORE DISCIPLINE REQUIRED

Radiologists will have additional responsibilities when they monitor early response quantitatively as opposed to qualitatively assessing images. They will need to minimize the influence on glucose uptake of sources other than metabolic changes caused by the therapy itself. Applications call for strict protocols controlling for F-18 half-life and the potential effects of diet, exercise, blood glucose levels, delays between probe administration and imaging, and other factors, said Dr. Wolfgang Weber, an associate professor of radiology at the University of California, Los Angeles.

"All this can be done easily, but you must be more consistent than with other procedures in your use of FDG. You have to follow a strict protocol," Weber said.

FDG-PET early response imaging also imposes a higher standard of scientific discipline on nuclear medicine and radiology researchers, said Dr. Barry A. Siegel, director of nuclear medicine at the Mallinckrodt Institute of Radiology.

Siegel characterizes the research thus far as exploratory and phase II studies that are good enough to establish clinical criteria for predicting response but insufficient for changing physician behavior. To influence oncological practice, imaging scientists must think like oncologists and apply their research methods, he said.

"If we want to be players in the game, we have to be as evidence-based as the people we do business with," Siegel said.

For an example of how this may be achieved, Siegel cited a 2003 study by Weber on the prediction of response of non-small cell lung cancer to chemotherapy with FDG-PET (J Clin Oncol 2003;21(14):2651-2657). At the time, Weber was working with Dr. Marcus Schwaiger's PET research group at the Technical University of Munich. Earlier experience had suggested that the test/retest reproducibility of FDG-PET SUV measurement was about plus/minus 10% (one standard deviation). A metabolic response could thus be declared if the difference in the uptake rate reached plus/minus 20%, or two standard deviations, Siegel said. Early response FDG uptake patterns from responders and nonresponders were then examined, and that analysis revealed a clear difference in objective response and survival.

Testing will not end there, however. The Technical University's findings have formed the basis for negotiations between the National Cancer Institute and the American College of Radiology Imaging Network to repeat the trial, according to Siegel. After verification, a multicenter clinical trial is envisioned to test the response criteria on a large, randomized patient population. As suggested in a paper by biostatistician Daniel J. Sargent, Ph.D., the metabolic nonresponders from the first cycle of chemotherapy could be randomized to either continue with chemotherapy or to receive a second-line therapy such as salvage surgery or radiation (J Clin Oncol 2005;23[9]:2020-2027). In addition to this line of research, various National Institutes of Health cooperative research groups, including ACRIN, are beginning to finance the cost of other expensive trials that weigh the clinical benefits of proposed early response imaging protocols, Siegel said.

LUNG CANCER APPLICATION

In Melbourne, Australia, Dr. Rodney Hicks, director of the Centre for Molecular Imaging at the Peter MacCallum Cancer Institute, is using FDG-PET to measure early response of NSCLC to chemoradiation. FDG-PET imaging is performed before treatment and six to nine weeks after it.

Complete responders are monitored with follow-up imaging. Partial and nearly complete responders go directly to salvage surgery, and nonresponders and patients with progressive disease receive second-line chemotherapy.

Hicks credits this protocol for the 21% five-year survival rate of the institute's stage III NSCLC patients. Elsewhere, a 16% survival rate is expected for stage II patients.

The research at the University of Munich extends to early response evaluations of esophageal cancer, an investigation that Weber continued after moving to UCLA. His study of 42 patients with advanced adenocarcinoma of the distal esophagus found that a 35% decrease in FDG uptake recorded two weeks after the beginning of the first cycle of chemotherapy indicated a positive tumor response. The negative predictive value of the test was 95% (J Clin Oncol 2004;22[5]:900-908).

Nuclear medicine chair Dr. Stanley J. Goldsmith and associate professor Dr. Lale Kostakoglu have applied early response techniques with lymphoma patients at New York Presbyterian Hospital since the 1990s. Lymphoma is a good model for FDG-based evaluation because of its lack of inflammatory reaction to radio- or chemotherapy, Kostakoglu said.

The New York Presbyterian approach to early response, initially developed with a dual-head coincidence imaging camera, takes into account the increasing use of chemotherapies before radiotherapy to treat lymphomas. Kostakoglu uses measurements of FDG-PET early response to differentiate patients who require follow-up radiotherapy from those who do not.

FDG-PET imaging is performed before treatment and at another point during three cycles of chemotherapy. Some oncologists request it seven days after the first 21-day cycle of chemotherapy for Hodgkin's lymphoma or seven days after the first 28 days of chemotherapy for non-Hodgkin's disease. Others wait until after the second or third cycle.

The imaging protocol does not call for quantification. FDG uptake entirely disappears from the original tumor mass in complete responders, and they avoid radiotherapy. Residual uptake is observed in partial responders, nonresponders, and patients with progressive disease. These patients are then prescribed radiation therapy, Kostakoglu said.

GAUGING BREAST CANCER THERAPY

At the University of Washington, Mankoff is developing an early response protocol for patients with locally advanced breast cancer who received neoadjuvant chemotherapy before surgery. FDG-PET is performed near the midpoint of the four to six-month treatment regimen. For extended courses of therapy, PET imaging is repeated before surgery. His experience suggests that a positive response corresponds with at least a 50% decline in FDG uptake.

The history of FDG-PET measurement of early breast cancer therapy response illustrates how protocols evolve as new chemotherapies are introduced and older ones lose favor. Dr. Farrokh Dehdashti, a professor of radiology at Washington University in St. Louis, and Dr. Joanne Mortimer, an oncologist now at the University of California, San Diego, developed an FDG-PET protocol in 1999 that predicted the response of metastatic breast cancer to tamoxifen therapy. The approach was unique because high FDG uptake signified a positive response reflecting a metabolic flare effect that followed successful chemotherapy.

A different strategy was required when oncologists shifted to aromatase inhibitors, Dehdashti said. Patients at the Mallinckrodt Institute now undergo baseline FDG-PET imaging before overnight treatment with three divided 30-mg doses of anastrozole and then receive another FDG-PET examination the next day. Follow-up assessments of the first 50 patients to follow this protocol were pending in April. Interim analysis suggests that the results will be similar to the positive findings of the original tamoxifen study.

ACRIN TRIALS

Since her protocol's initial success, Van den Abbeele has tested it on four generations of kinase-inhibiting therapies for GIST. She is a principal investigator, with Dr. Burton Eisenberg, a surgical oncologist at Dartmouth-Hitchcock Medical Center, of a multicenter ACRIN trial involving 63 patients. The purpose of the study is to test the effectiveness of neoadjuvant therapy and to determine whether FDG-PET is more accurate than CT for predicting recurrence.

Another ACRIN trial is examining whether SUV measurements of FDG-PET performed three months after chemoradiotherapy can predict long-term outcomes of locally advanced NSCLC. Siegel is working with radiation oncologist Dr. Mitchell Machtay of Thomas Jefferson University and Dr. Abass Alavi, chair of nuclear medicine at the University of Pennsylvania, on this nonrandomized trial of 188 subjects.

Kostakoglu is collaborating with physicians at Duke University, the Mayo Clinic in Rochester, MN, and Roswell Park Cancer Institute in Buffalo, NY, in a three-year outcomes study of early response FDG-PET of lymphoma, for which 160 patients will be recruited.

Several groups are addressing standardization problems associated with SUV measurement. The nuclear medicine section of the National Electrical Manufacturers Association proposes using phantoms to calibrate scanners involved in multisite trials. Some of these studies are limited to specific makes and models of equipment. In the ACRIN lung cancer trial, equipment vendors will collaborate to determine how results can be standardized, said Dr. David Rollo, medical director of Philips Medical Systems. The National Cancer Institute has sponsored several workshops on protocol standardization, including one in February that took note of many unresolved issues.

BETTER PET PROBES

The quest for methods that report therapeutic response faster than FDG has led to the development of F-18-3´-fluoro-3´ deoxy-L-thymidine (FLT) as well as F-18 2´-fluoro-5-methyl-1-beta-D-arabinofuranosyluracil (FMAU). Both tracers have shown promise for measuring cellular proliferation in much the same way that FDG detects glucose metabolism rates.

Animal and laboratory experiments strongly suggest that effective cancer therapy is reflected in reduced cell division before changes in cellular metabolism can be seen, said Dr. Anthony Shields, a professor of oncology at Karmanos Cancer Institute in Detroit. Preliminary studies indicate that F-18 FLT-PET can measure reduced cell proliferation in lung cancer a week after chemotherapy. Human clinical testing of F-18 FLT is expected to accelerate now that the FDA has granted an investigational new drug application for the agent. Other agents that measure hypoxia and pH, which also affect response, are being investigated.

Early response imaging has implications for personalized therapies that use characteristics of the patient's genome to attack cancer, Van den Abbeele said. Specific mutations, such as exon 9 and exon 11, are associated with the fastest and most complete positive responses to tyrosine-kinase inhibition therapy of GIST.

Such information can be used to tailor therapy for individual patients.

"You can be assured soon after starting drug therapy that you are doing the right thing," Van den Abbeele said. "If you do not see a response, you need not subject the patient to a therapy that is costly and without benefit."

Mr. Brice is senior editor of Diagnostic Imaging.