Molecular Imaging Predicts Therapeutic Responses Earlier
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Molecular changes detected with a molecular imaging agent can happen almost immediately after treatment, even before there are changes in tumor size that CT and MRI can detect. “Sometimes size changes can be delayed and we have had patients who responded to treatment, but had no size change. You will miss some patients who were responding just because there was no size change,” shares Frederick C. Eilber, MD, an assistant professor of surgery, molecular and medical pharmacology at division of surgical oncology at David Geffen School of Medicine at the University of California at Los Angeles (UCLA).
“You can get a particularly relevant read-out on what is happening with the patient if there is a mechanistic link between the imaging agent and therapy,” says Martin G. Pomper, MD, PhD, professor of radiology, oncology and pharmacology and molecular sciences at Johns Hopkins University in Baltimore. Molecular imaging data provide the oncologist with the ability to tailor treatment for an individual patient based on molecular pathways of the tumor. Future clinical trials, with appropriate study design and regulatory guidance, will help in transitioning the use of molecular imaging to predict therapeutic responses during early treatment from the investigational level to clinical practice.
One of the earliest studies which showed that FDG-PET could predict response in the early phase of treatment was done by Richard Wahl, MD, and colleagues at University of Michigan Medical Center in Ann Arbor in 1993.
Breast cancer
Wahl’s study found that there was no significant decrease in FDG uptake after three cycles of treatment in non-responding breast cancer patients. Since then, there have been a number of studies done in breast cancer which have showed that repeat PET scans within the phase of one to two weeks of treatment is a good way of assessing early response and also predictive of later response. Some cases are predictive of overall disease survival and relapse or progression, says David Mankoff, MD, PhD, professor of radiology, medicine and bioengineering at University of Washington in Seattle. Another well-known study was published by Laura Kenny and colleagues at Imperial College London in 2007 using 18F-FLT PET. The study showed that FLT-PET could detect changes in breast cancer proliferation at one week after chemotherapy and 18F-FLT response preceded tumor size changes.Mankoff’s group is working on another PET tracer, 18F Fluoro-Estradiol (FES), which measures estrogen receptor expression in advanced breast cancers. FES may be particularly important in selecting patients who are most likely to respond to treatments directed at the estrogen receptor. “Not all breast tumors will express estrogen receptors, and the breast cancers which do not express estrogen receptors are unlikely to respond to treatment directed at the estrogen receptor,” he says.
Sarcomas
Molecular imaging is more sensitive than anatomic imaging in predicting response to therapy in sarcomas, Eilber notes, and allows the physician to determine if a therapy is working very early in the course of treatment. FDG-PET has been used to monitor the response to therapy in many cancers, but the question is how early can it be used? His group has determined that FDG PET/CT imaging predicts histopathologic treatment responses after one cycle of neoadjuvant chemotherapy in high-grade soft-tissue sarcomas.Gastrointestinal stromal tumor (GIST)
The earliest use of molecular imaging in predicting treatment response shown is at 24 hours. Gleevec (imatinib mesylate), the inhibitor of tryrosine kinase, is widely used in the treatment of gastrointestinal stromal tumor (GIST). Annick D. Van den Abbeele, MD, and colleagues at Dana-Farber Cancer Institute in Boston, demonstrated in 2002 that 18F-FDG PET imaging can predict within 24 hours who is going to respond to Gleevec treatment in GIST patients. A baseline scan is done before therapy, followed by a scan after Gleevec is given to the patient. The study found that patients who had much lower uptake of FDG on the post-Gleevec scan, when compared to the pre-Gleevec scan, were responders, while the patients who had the same FDG uptake on pre- and post-Gleevec scans were non-responders, notes Pomper.Prostate cancer
One marker that Pomper’s group is studying is the prostate-specific membrane antigen (PSMA). An important question regarding the imaging of prostate cancer is whether the patient has an indolent or aggressive form of the disease. PSMA may be a marker for aggressive disease. So by using PSMA in conjunction with several non-imaging markers, for example those from urine or blood, it might be possible to predict which patients have aggressive disease for which surgery would be indicated. Patients who do not have the “aggressive” marker combination could enter an active surveillance program, says Pomper. His group is currently working on several positron-emitting and other PSMA-binding ligands for clinical use.| Inside the ACRIN Trials |
| The American College of Radiology Imaging Network (ACRIN) since its creation in 1999 has established a dynamic clinical trials infrastructure and developed numerous protocols for altering and expanding the role of medical imaging and image-guided therapy in the diagnosis and treatment of cancer. ACRIN studies evaluate whether new imaging technologies or methods aid in either diagnosing cancer or predicting an individual’s response to a specific treatment or helping to monitor the spread of cancer to other parts of the body or slowing the growth of cancer. Investigators from more than 100 academic and community-based medical facilities in the United States and many international institutions have participated in ACRIN trials. At the start of its 10th year of operation in October 2008, ACRIN trials had accrued over 76,000 participants, collected more than 20 million images and published more than 50 scientific papers. In addition, more than $100 million has been distributed to participating facilities in support of carrying out ACRIN research protocols. Many ACRIN trials are underway with new PET tracers for predicting therapeutic responses early in various cancers. ACRIN clinical trial participation is open to radiologists from academic centers, community hospitals, and freestanding medical facilities, other cooperative groups, representatives of industry and health insurance payers. |
Hypoxia imaging
While not specialized on one specific cancer type, hypoxia imaging focuses on imaging difficult-to-treat cancers where the cells or parts of the cells have adapted to surviving without oxygen. A number of imaging agents are currently used to image hypoxia. The one that is most studied is 18F-fluoromisonidazole (18F-FMISO). “It’s best been studied in brain cancers, cervical cancers and head and neck cancers as well,” says Mankoff. Hypoxia also has been shown to be a resistant factor for radiation treatment and studies have demonstrated the use of PET to direct hypoxia-specific treatment. Rischin et al showed in the May 2006 issue of Journal of Clinical Oncology that uptake of 18F-FMISO by PET predicted the greater effectiveness of drug tirapazamine in patients with advanced head and neck cancer. In this study, only patients with 18F-FMISO uptake benefited from the addition of tirapazamine to radiotherapy for head and neck cancer. Mankoff says that it is therefore important to identify patients with significant hypoxia in tumors that can benefit from tirapazamine or similar drugs rather than using such drugs on all patients regardless of the presence of hypoxia.Another PET hypoxia tracer, 18F-labelled fluoroazomycin arabinoside (18F-FAZA) PET imaging, had predicted success of hypoxia-directed radiochemotherapy using tirapazamine in animal models, according to Beck et al in June 2007 issue of Journal of Nuclear Medicine.
Esophageal cancer
FDG-PET performed immediately after chemoradiotherapy (less than seven days) can predict prognosis in patients with postoperative recurrent esophageal cancer, according to a study published by Jingu et al in the April 2010 issue of The International Journal of Clinical Oncology. “We found that the SUVmax from PET scans taken even less than seven days after chemoradiotherapy correlated with local control and survival,” says study author Keiichi Jingu, MD, PhD, assistant professor at the department of radiation oncology, Tohoku University School of Medicine, Sendai, Japan. Jingu explains that the change in FDG metabolic activity between SUVmax before chemoradiotherapy and SUVmax after chemoradiotherapy reflects the overall malignancy of recurrent tumors including metastatic ability.Clinical validation
Although the data look very promising, Mankoff greatly supports the need for clinical trials that validate these measures. For the most part, oncologists are not used to having an effective early response, so they are unlikely to make a decision on changing treatment, he says. The most promising data came very early in single center trials and to move this into the clinical practice, it is going to take well designed perspective multicentric trials. “That’s the level of validation that oncologists expect for treatment and for imaging biomarkers,” Mankoff says. Participation in The American College of Radiology Imaging Network (ACRIN) trials can speed up the transition from investigational to clinical level.However, Johannes Czernin, MD, professor, Molecular & Medical Pharmacology, director, Nuclear Medicine Clinic, Positron Emission Tomography/Computed Tomography, David Geffen School of Medicine at UCLA, argues that oncologists have used CT-based criteria for response assessments that were never thoroughly validated.
A lot of these multicentric trials need to be validated with long-time survival, adds Eilber. The UCLA Group and others are validating whether PET-guided therapeutic decisions affect survival of sarcoma patients. Imaging modalities and imaging probes also need to evolve. Right now, we use FDG glucose and there is a lot of interest in other imaging probes that can either image a specific pathway or proliferation, says Eilber.
Eventually physicians will use molecular imaging to predict how treatment is going. How early you can use it depends on the malignancy and the effectiveness of the drugs as well as the type of tumors and whether imaging correlates with a molecular pathway, sums Eilber.