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EDITORIAL
Comparative effectiveness research for molecular imaging Keywords: clinical trials n molecular imaging n PET n standardization
Molecular imaging is the visualization, characterization and measurement of biological processes at molecular and cellular levels in humans and other living systems. Although the methodology used in ‘molecular imaging’ includes nuclear medicine, along with both PET and single-photon emission computed tomography imaging, magnetic resonance spectroscopy, optical imaging and ultrasound, most of the clinical molecular imaging being performed today is with nuclear medicine methods. Molecular imaging is used widely in the areas of cardiology, neurology and oncology. The following discussion focuses on one major application in oncology, but many of the issues raised also apply to the other areas. In oncology, PET-computed tomography imaging with F‑18 fluorodeoxy glucose (FDG) is one of the prominent nuclear medicine methods for staging and follow-up in a wide number of different types of tumors. FDG is an analog of glucose and shows high uptake in most tumors because of their increased metabolic rates and their inefficient utilization of glucose. This results in relatively high sensitivities for the detection of tumors, although the specificity is somewhat lower because other physiologic processes, such as inflammation, can result in high uptake of FDG. There is a large body of literature reporting on the sensitivity and specificity of FDG PET in various settings in oncology. There are fewer papers reporting on the effect of the studies on change in management. There are a few papers on cost–effectiveness, essentially no literature on the effect on outcome and nothing on comparative effectiveness research. It is probable that some useful comparative effectiveness research can be carried out with retrospective data and with registries, which may be useful for showing the efficacy of FDG for staging or surveillance of several types of malignancies. However, for new indications that use new agents, clinical trials will be essential. There is a real need for such studies. The only widely accepted current imaging approach for evaluating tumor response to therapy is change in tumor size measured in 1D or 2D with computed tomography imaging. It is clear that metabolic changes have to precede shrinkage of a tumor during therapy. There are a number of studies that show that FDG uptake decreases relatively early following initiation of chemotherapy and that it can predict responders versus nonresponders with reasonable accuracy. The most compelling studies are in lymphoma. FDG is not the only agent used in PET imaging. There are numerous other molecular imaging agents that have been studied in research projects. Many of these agents will probably be more useful than FDG in specific settings, but none have been US FDA approved. These agents include probes of other metabolic pathways, such as fluorothymidine for DNA synthesis, amino acids for protein synthesis and acetate for lipid synthesis. Other agents have been developed to image neoangiogenesis, apoptosis, hypoxia and a wide range of cell-surface receptors. A real problem in trying to establish the clinical utility of these agents is the large number of agents and the lack of a concentrated effort to bring any
10.2217/CER.12.1 © 2012 Future Medicine Ltd
1(2), 113–114 (2012)
Michael M Graham*
“Molecular imaging has the promise to
become an important methodology in the development of personalized medicine.”
*Department of Radiology 3863 JPP, University of Iowa, 200 Hawkins Drive, Iowa City, IA 52242, USA Tel.: +1 319 356 4302 Fax: +1 319 356 2220 [email protected]
part of
ISSN 2042-6305
113
EDITORIAL
Graham
one of them forward to approval. Ironically, the NIH funding mechanism, which strongly favors innovation, does not provide funding for the large clinical trials needed to show reproducible clinical performance. Instead, it tends to favor moving on to develop new agents. “A successful study will require a true
collaborative effort between the oncologists and the imagers, ideally as coprincipal investigators.”
Molecular imaging has the promise to become an important methodology in the development of personalized medicine. If one of the metabolic imaging agents can be shown to reliably identify responders versus nonresponders for a specific chemotherapy treatment of a specific tumor (e.g., erlotinib treatment of non-small-cell lung cancer), it would not only identify the patients who should continue the treatment, but perhaps more importantly, it would also identify those who would not benefit. This would lead to a shift to another therapy and would also avoid the cost and side effects of ineffective therapy. It is probable that such an approach would not be used by itself, but would be combined with other studies, such as immunohistological characterization of the tumors prior to therapy. “The molecular imaging community is beginning to come together to address these issues and to try to define a viable path forward that will lead to implementation of well-designed trials.” There is no well-defined pathway that will lead to the incorporation of such an approach into the practice of clinical oncology. Clearly, well-designed clinical trials will have to be carried out. Such trials should include comparison with standard treatment algorithms in a balanced way that will allow fair evaluation of the new approach compared with the old. It will probably be quite important to also incorporate cost data and quality-of-life data, to examine the cost–effectiveness and the effect on outcome. A successful study will require a true collaborative effort between the oncologists and the imagers, ideally as coprincipal investigators. There are several significant considerations that have to be addressed to ensure a successful study:
114
J. Compar. Effect. Res. (2012) 1(2)
■■
The imaging has to be performed in a standardized way. This means detailed specification in the directions to the imaging sites, as well as training of personnel, evaluation of the imaging and ancillary equipment and evaluation of the quality of the imaging agent synthesis;
■■
The study has to be carried out relatively rapidly; in 2–3 years. This is because the equipment and software is steadily being updated and the methodology will change during the study;
■■
The study has to be funded. This can be a significant problem, since many of the likely molecular imaging agents are not patented and no single company will benefit from approval of the agent. This problem arises not only because some academic sites choose not to patent their agents, but also because the development timeline is so long that often a 17-year patent has expired before the critical clinical trials can be performed.
Two major forces have become stronger in recent years that make it increasingly clear that it is essential to carry out well-designed comparative effectiveness trials in molecular imaging. These are an increasing emphasis on evidencebased medicine and guidelines and the increasing pressure on Medicare to rein in the cost of healthcare in the USA. Although the molecular imagers may ‘know’ that their methodology is a powerful clinical tool that should be more widely used, this will not happen unless they can convince both the regulators (FDA and Centers for Medicare & Medicaid Services) and the clinical practitioners of the value of the methodologies. This will clearly require high-quality studies. The molecular imaging community is beginning to come together to address these issues and to try to define a viable path forward that will lead to implementation of well-designed trials. Financial & competing interests disclosure The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.
future science group
EDITORIAL
Comparative effectiveness research for molecular imaging Keywords: clinical trials n molecular imaging n PET n standardization
Molecular imaging is the visualization, characterization and measurement of biological processes at molecular and cellular levels in humans and other living systems. Although the methodology used in ‘molecular imaging’ includes nuclear medicine, along with both PET and single-photon emission computed tomography imaging, magnetic resonance spectroscopy, optical imaging and ultrasound, most of the clinical molecular imaging being performed today is with nuclear medicine methods. Molecular imaging is used widely in the areas of cardiology, neurology and oncology. The following discussion focuses on one major application in oncology, but many of the issues raised also apply to the other areas. In oncology, PET-computed tomography imaging with F‑18 fluorodeoxy glucose (FDG) is one of the prominent nuclear medicine methods for staging and follow-up in a wide number of different types of tumors. FDG is an analog of glucose and shows high uptake in most tumors because of their increased metabolic rates and their inefficient utilization of glucose. This results in relatively high sensitivities for the detection of tumors, although the specificity is somewhat lower because other physiologic processes, such as inflammation, can result in high uptake of FDG. There is a large body of literature reporting on the sensitivity and specificity of FDG PET in various settings in oncology. There are fewer papers reporting on the effect of the studies on change in management. There are a few papers on cost–effectiveness, essentially no literature on the effect on outcome and nothing on comparative effectiveness research. It is probable that some useful comparative effectiveness research can be carried out with retrospective data and with registries, which may be useful for showing the efficacy of FDG for staging or surveillance of several types of malignancies. However, for new indications that use new agents, clinical trials will be essential. There is a real need for such studies. The only widely accepted current imaging approach for evaluating tumor response to therapy is change in tumor size measured in 1D or 2D with computed tomography imaging. It is clear that metabolic changes have to precede shrinkage of a tumor during therapy. There are a number of studies that show that FDG uptake decreases relatively early following initiation of chemotherapy and that it can predict responders versus nonresponders with reasonable accuracy. The most compelling studies are in lymphoma. FDG is not the only agent used in PET imaging. There are numerous other molecular imaging agents that have been studied in research projects. Many of these agents will probably be more useful than FDG in specific settings, but none have been US FDA approved. These agents include probes of other metabolic pathways, such as fluorothymidine for DNA synthesis, amino acids for protein synthesis and acetate for lipid synthesis. Other agents have been developed to image neoangiogenesis, apoptosis, hypoxia and a wide range of cell-surface receptors. A real problem in trying to establish the clinical utility of these agents is the large number of agents and the lack of a concentrated effort to bring any
10.2217/CER.12.1 © 2012 Future Medicine Ltd
1(2), 113–114 (2012)
Michael M Graham*
“Molecular imaging has the promise to
become an important methodology in the development of personalized medicine.”
*Department of Radiology 3863 JPP, University of Iowa, 200 Hawkins Drive, Iowa City, IA 52242, USA Tel.: +1 319 356 4302 Fax: +1 319 356 2220 [email protected]
part of
ISSN 2042-6305
113
EDITORIAL
Graham
one of them forward to approval. Ironically, the NIH funding mechanism, which strongly favors innovation, does not provide funding for the large clinical trials needed to show reproducible clinical performance. Instead, it tends to favor moving on to develop new agents. “A successful study will require a true
collaborative effort between the oncologists and the imagers, ideally as coprincipal investigators.”
Molecular imaging has the promise to become an important methodology in the development of personalized medicine. If one of the metabolic imaging agents can be shown to reliably identify responders versus nonresponders for a specific chemotherapy treatment of a specific tumor (e.g., erlotinib treatment of non-small-cell lung cancer), it would not only identify the patients who should continue the treatment, but perhaps more importantly, it would also identify those who would not benefit. This would lead to a shift to another therapy and would also avoid the cost and side effects of ineffective therapy. It is probable that such an approach would not be used by itself, but would be combined with other studies, such as immunohistological characterization of the tumors prior to therapy. “The molecular imaging community is beginning to come together to address these issues and to try to define a viable path forward that will lead to implementation of well-designed trials.” There is no well-defined pathway that will lead to the incorporation of such an approach into the practice of clinical oncology. Clearly, well-designed clinical trials will have to be carried out. Such trials should include comparison with standard treatment algorithms in a balanced way that will allow fair evaluation of the new approach compared with the old. It will probably be quite important to also incorporate cost data and quality-of-life data, to examine the cost–effectiveness and the effect on outcome. A successful study will require a true collaborative effort between the oncologists and the imagers, ideally as coprincipal investigators. There are several significant considerations that have to be addressed to ensure a successful study:
114
J. Compar. Effect. Res. (2012) 1(2)
■■
The imaging has to be performed in a standardized way. This means detailed specification in the directions to the imaging sites, as well as training of personnel, evaluation of the imaging and ancillary equipment and evaluation of the quality of the imaging agent synthesis;
■■
The study has to be carried out relatively rapidly; in 2–3 years. This is because the equipment and software is steadily being updated and the methodology will change during the study;
■■
The study has to be funded. This can be a significant problem, since many of the likely molecular imaging agents are not patented and no single company will benefit from approval of the agent. This problem arises not only because some academic sites choose not to patent their agents, but also because the development timeline is so long that often a 17-year patent has expired before the critical clinical trials can be performed.
Two major forces have become stronger in recent years that make it increasingly clear that it is essential to carry out well-designed comparative effectiveness trials in molecular imaging. These are an increasing emphasis on evidencebased medicine and guidelines and the increasing pressure on Medicare to rein in the cost of healthcare in the USA. Although the molecular imagers may ‘know’ that their methodology is a powerful clinical tool that should be more widely used, this will not happen unless they can convince both the regulators (FDA and Centers for Medicare & Medicaid Services) and the clinical practitioners of the value of the methodologies. This will clearly require high-quality studies. The molecular imaging community is beginning to come together to address these issues and to try to define a viable path forward that will lead to implementation of well-designed trials. Financial & competing interests disclosure The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.
future science group
