Non-FDG PET Tracers in Oncology

New Biomarkers Poised for Move Into Clinical Realm

The constant drive to predict and characterize cancerous tumor response to therapy that is earlier, better and more specific, as well as the success of the PET tracer FDG coupled with an established and emergent worldwide PET infrastructure are generating greater interest in the utilization of non-FDG radiotracers for oncology. Although these tracers show great promise for providing better patient care, economic and regulatory challenges have traditionally inhibited their deployment beyond the academic realm. However, with the advocacy of professional societies such as SNM and the Academy of Molecular Imaging (AMI), initiatives are underway that may soon bring these compounds into the clinical setting. Researchers say the next decade will hold the key.

Mark P.S. Dunphy, DO , from the department of radiology, nuclear medicine service at Memorial Sloan-Kettering Cancer Center, and Jason S. Lewis, PhD, chief of the radiochemistry service at the Sloan Kettering Institute for Cancer Research in New York City, recently reviewed non-18F-FD G PET tracers that are in the final stages of preclinical development or in the early stages of clinical application for monitoring the oncologic therapeutic response (Journal of Nuclear Medicine, May 2009, Vol. 50:106S-121S).

So where are we seeing promise? Thymidine analogs 18F-fluoro-deoxythymidine (18F-FLT) and 18F-deoxy-fluoro-arabinofuranosylthymine (18F-FMAU ) are two of the most promising agents for tumor imaging, according to Dunphy and Lewis.

“18F-FLT PET provides data on TK1 activity and is an index of cell cycling and tissue proliferation, and 18F-FMAU PET provides data on TK2 activity and is an index of mitochondrial mass in a tissue,” they wrote.

Because TK1 and TK2 are independent enzymes, each tracer has the capability to provide different types of information to diagnosticians. The authors observed that tumors often do not concentrate 18F-FLT as avidly as 18F-FD G, which can be of benefit for tumor delineation in some viscera and anatomic regions; such as the brain, mediastinum (including the heart) and intestines. 18F-FMAU has clearly visualized tumors (11 minutes after injection) in the breasts, brain, lungs and prostate in a pilot study, demonstrating that it may be a useful tumor imaging option.

Tumor hypoxia is an important determinant of the overall response of a tumor to conventional therapy. It is associated with increased tumor aggressiveness, manifested as higher rates of recurrence and metastasis and resistance to radiation and chemotherapy. Therefore, the imaging of tumor hypoxia could result in a significant improvement in the care of patients with cancer.

Two PET agents—Cu-labeled diacetyl-bis methylthiosemicarbazone (Cu-ATSM) and 18F-fluoromisonidazole (18F-FMISO)—are currently the leading candidates for hypoxia imaging. Pilot studies conducted with Cu-ATSM have demonstrated that the agent shows high contrast levels between hypoxic and normoxic tissues in as few as 10 to 15 minutes post-injection.

“Cu-ATSM has several well-known advantages over other radiopharmaceuticals used for PET imaging of hypoxia, including a simpler method for synthesis, faster clearance from normoxic tissue [allowing a short time between injection and imaging], and a simpler method for quantification,” Dunphy and Lewis wrote.

For in vivo PET , 18F-FMISO is the most extensively studied radiolabeled nitroimidazole—a class of compounds whose metabolism and tissue retention are dependent on tissue oxygenation. 18F-FMISO is lipophilic and therefore diffuses readily through cell membranes, the authors noted.

Imaging with 18F-MISO is challenged by both limited contrast ratio between hypoxic tumors and normal tissue and slow cellular washout, Dunphy and Lewis agree. “The main advantage of 18F-FMISO is that it is directly affected by tumor oxygenation, but the compound has two major limitations,” they wrote. “One is the limited contrast ratio between hypoxic tumors and normal tissues (T/B ratio of >1.2), reflecting the poor tissue uptake of 18F-FMISO in vivo. The other is the slow cellular washout of this tracer; a delay of approximately two hours after the injection of 18F-FMISO is needed to permit the clearance of this tracer from normal background tissues.”

Another category of PET agents under development is amino acid tracers, with 11C-methionine (11C-MET) being the most popular in oncology imaging. Although the compound has demonstrated great efficacy in differentiating tumor recurrence from radiation necrosis—which is useful for managing irradiated brain tumors—its short half-life has limited widespread use.

Also under investigation are agents for hormone receptor imaging in evaluating breast and prostate cancer such as 18F-fluoro-dihydrotestosterone (18F-FDHT) and 18F-fluoro-estradiol (18F-FES). In addition, 11C-labled therapeutic drugs as well as 11C-Acetate and 11C-Choline PET agents are receiving more investigative interest.

“These clinical PET tools should improve therapeutic planning and response assessment and should lead to improved patient outcomes,” observed Dunphy and Lewis.

Delivering the evidence

“Ironically, there are some people who believe that we still haven’t had the definitive trial to validate FDG,” says Robert W. Atcher, PhD. “The challenge for us is to sit down with our greatest critics and ask them what it is they believe we have not been doing and what it is we need to do so that it is definitive for any of the probes we’re investigating.”

Atcher, immediate past president of SNM and team leader for emerging medical technology with Los Alamos National Laboratory in New Mexico, notes that one of the challenges in financing large-scale clinical trials for many novel PET imaging agents is that there is no intellectual property involved.

“Because there’s no intellectual property for a radiopharmaceutical manufacturer to get some sort of patent protection, there’s not much incentive for them to help fund clinical trials,” he notes.

Although multi-national, multi-center molecular imaging trials face a variety of challenges—ranging from economics to turf issues—the persistence and perseverance of dedicated clinical researchers can sometimes beat the odds.

Vincent Gregoire, MD , PhD, professor of radiation oncology in the department of radiation oncology for molecular imaging and experimental radiotherapy at the Université Catholique de Louvain St-Luc University Hospital in Brussels, Belgium, is working on studies using conventional 18F-FD G, as well as other PET imaging agents.

He and colleagues are investigating the use of 18F-FDG PET for target volume selection for three-dimensional radiotherapy and intensity-modulated radiation therapy (IMRT ). Their on-going work, originally published in the JNM (Jan. 2007, Vol. 68: 68S-77S), seeks to validate the utilization of a variety of PET radiotracers for IMRT planning.

The group is conducting a study on hypoxic PET tracers. In addition, they have labeled EF 3 (2-2-Nitroimidazol-1-yl)-N-(3,3,3-trifluoropropyl)-acetamide) with 18F and have a clinical study underway that is comparing EF 3 with FMISO.

“The use of PET offers a great promise [for target volume selection], but it needs to be validated,” Gregoire says. “In HNSCC [head and neck squamous cell carcinoma], what we found is now validated into a multi-center phase II study. People need to share expertise, methodology and need to conduct multicenter studies. This is what my group tries to do. The next step [also under study] is to do ‘radiation dose painting’ based on PET . This requires the development of some tools able to incorporate the PET information on a voxel-by-voxel basis into the treatment planning systems; then we’ll need to do some clinical validation studies.”

Clinical Trials Network

The goal of SNM’s Clinical Trials Network (CTN) is to bring together the pharmaceutical industry, the imaging community, biomarker manufacturers and regulatory agencies worldwide and provide them with processes, standards and protocols to streamline the use of imaging in the development and testing processes for new pharmaceuticals.

The use of imaging in clinical trials can help pharmaceutical developers determine earlier in the development process whether a new product is clinically promising—accelerating the development of promising drugs and eliminating those without apparent patient benefit. However, including these investigational imaging biomarkers in clinical trials for investigational therapeutics poses challenges for a drug development company, including a lack of standardized imaging methods and challenging regulatory approval or paperwork requirements for the imaging biomarker.

The CTN has developed a Biomarker Use Pathway to coordinate the planning and data-collection of multicenter clinical trials that include the use of imaging biomarkers. The program is designed to facilitate the use of imaging biomarkers in Phase 1, 2 and 3 clinical trials, stimulate the development of additional novel biomarkers, and develop standardized and reproducible protocols for the use of these probes.

In February, the CTN received U.S. FDA approval of an SNM-sponsored centralized multi-center investigational new drug (IND) application for 18F-FLT . The centralized, multi-center IND application was made possible, in part, through a letter of cross-reference to a master FLT IND held by the U.S. Cancer Imaging Program at the National Cancer Institute (NCI). NCI’s IND was the result of significant work and investment by NCI and other collaborators toward their goal of making investigational radiopharmaceuticals available for drug development.

“We’re aware that we don’t have the resources needed to conduct large Phase 3 trials,” says Jim Tatum, MD , associate director of the division of cancer treatment and diagnosis at NCI. “Therefore, we strongly encourage imaging societies, academic institutions, cooperative groups and commercial sectors to work together to effectively lower this last barrier.”

FLT is probably at the top of the list of non-FDG agents that could next see U.S. regulatory approval for clinical use, says Michael M. Graham, MD , PhD, SNM president and professor of radiology and director of nuclear medicine at the University of Iowa College of Medicine in Iowa City.

“The next agents on the list are probably 18F-fluoro-L-DO PA (18F-FDO PA) and then 18F-FMISO ,” he says. “These agents are major directions we’re considering right now. I don’t know that one is better than the other, as they each address very different aspects of metabolism. FDO PA is a marker of amino acid transport and thus a marker of protein synthesis, and FMISO is a hypoxic imaging marker.”

Wei Chen, MD , PhD, assistant professor of medical and molecular pharmacology at the David Geffen School of Medicine at the University of California, Los Angeles, has conducted extensive work on FDO PA and FLT. In head-to-head studies of each agent, she and colleagues have demonstrated their superiority over FD G for brain tumor imaging.

“18F-FLT PET was more sensitive in evaluating recurrent high-grade gliomas then 18F-FD G,” she wrote in a study of imaging brain tumor proliferation (JNM, June 2005, Vol.46:6, pp. 945-952).

In a study comparing FDO PA with FDG published the following year in JNM (June 2006, Vol. 47:6, pp.904-911), she and colleagues evaluated the agents for their diagnostic accuracy in imaging brain tumors.

“Our results suggest that 18F-FDO PA PET is superior to 18F-FDG PET for visualizing low-grade tumors, evaluating recurrent tumors, and differentiating tumor recurrence from radiation necrosis,” she wrote.

The established U.S. and European manufacturing network for 18F-FDG means that 18F-labled PET agents will be easier to deliver to a clinical setting, Graham says. He notes that SNM’s CTN recently received support from Advanced Accelerator Applications, Erigal Limited and IBA Molecular in Europe, which enable its European clinical trial sites to obtain investigational imaging agents like FLT from a commercial provider instead of having to produce it themselves.

“Having established a distribution system for FD G, it’s going to be relatively simple to add in some other fluoro-18 agents,” he says. “Some of the larger radiopharmacies, like PET NET Solutions, are supplying small amounts of FLT and FDO PA in some local settings. So this is clearly a direction that the field is going. It depends on good multicenter, Phase 3 clinical trials that will deliver adequate data so that the FDA can approve a new drug application.”