STAR ABSTRACT Oncologic imaging in 2002 and beyond Hedvig Hricak MD The thrust of cancer care in the new millennium is implementing "risk adjusted, patient specific thera- py': Cancer is not one disease, it is many, it presents a remarkably differ- ent clinical behavior and treatment response even in the same host. Modern cancer treatment planning is guided by two key principles: 1) the choice of therapy must be based on evidence rather than opinion or habit, and 2) the volume and extent of dis- ease should be optimally assessed prior to treatment, in order to allow for the most effective patient-specific therapy. Imaging is emerging as an impor- tant adjunct to the clinical assessment of cancer, contributing to tumor detection, characterization, staging, treatment planning and follow-up. Diagnostic imaging is widening its scope from anatomy to adding infor- mation about metabolism and func- tion. The general forward direction of medical imaging aims toward increas- ing sensitivity and specificity, while decreasing invasiveness and minimiz- ing cost. Continuing increases in com- puter power have fueled the progress, followed by the rapid expansion of communication technology and by the advances in molecular biology. The revolutionary advances in molec- ular biology and genetics are being introduced into cross-sectional imag- ing offering great gains to Oncology. Novel imaging paradigms are being developed to provide non-invasive assessment of tissues at the cellular and molecular levels. Imaging modal- ities of the future will be increasingly biology-centered. At least three modalities are poised to participate in this revolution: magnetic resonance (MR), positron-emission tomogra- phy (PET) and optical imaging. Imaging algorithms are already evolv- ing in response to the changes in clin- ical treatment approaches, scientific discoveries and technological innova- tions. The technologic advances that are also impacting the daily practice of oncology are PACS , teleradiology and Computer-Aided Diagnosis (CAD). PACS has empowered many leading medical centers in the United States, Western Europe and Japan (with many other countries being in transi- tion) to become "film-less': The daily routine of "reading", flexibility in workflow, the ability to retrieve infor- mation in seconds and communicate the findings with referring physicians has dramatically changed the way we practice modern medicine. Teleradiology can provide access to sophisticated subspecialty-imaging interpretation worldwide and may help in overcoming the presently occurring shortage of radiologists in the industrialized world. Computer- Aided Diagnosis will, in the future, be an important component of modern imaging and will be essential in screening. CAD when fully developed 8 SA JOURNAL OF RADIOLOGY • December 2002 and implemented will be able to iden- tify normal appearing structures (as well as normal variants) making the reading by the radiologist unnecessary for a large portion of screened images. This may alleviate the staffing short- ages and reduce the cost of screening. Computer-aided diagnosis will be used in reading images obtained with most techniques. While already in clinical use for mammography, it will expand to the reading of screening procedures such as virtual CT colonoscopy and lung CT. Advances in cross-sectional imaging The increasing computer power in cross-sectional imaging has facilitated the acquisition of 3 dimensional data, permitting high-resolution volumet- ric acquisition of images, thus facili- tating diagnosis. Multi-row detector CT and 3D MR have also made virtu- al endoscopy possible and it is evolv- ing into an increasingly accepted clin- ical imaging technique. This tech- nique is presently being applied to practically every anatomic channel: colon, esophagus, stomach, small bowel, bronchial tree, blood vessels, urinary tract (including the bladder), etc. Virtual endoscopy promises to reduce the number of invasive proce- dures and limit conventional, invasive endoscopic procedures to targeted biopsy if the virtual studies disclose abnormalities. Fusion of images generated from different imaging modalities, such as MR, CT and PET, is showing that the advantages of two techniques can be maximized. The advantages of PET's ability to detect metabolic abnormali- ty are thus combined with the spatial STAR ABSTRACT resolution afforded by CT. PET-CT scanners are already in clinical use in multiple medical centers advancing oncologic diagnosis. Instruments pro- viding fusion of MR and CT are cur- rently being designed and will be of great value in diagnostic and radiation therapy planning. Scanners offering fusion of PET and MR will undoubt- edly follow. MR technology is versatile, and therefore very much in demand for functional and metabolic imaging. Functional MR has become extremely valuable in the preoperative evalua- tion of brain cancer guiding the sur- geon away from the motor and senso- ry centers. Mapping of foci of specific brain activity with functional MR! by displaying images of metabolic activi- ty data, as for instance for heat/pain sensation, motor, memory centers, etc., is becoming the basis of function- ally based medicine and will have an important future role in the study of mental diseases. Proton spectroscopic MR imaging is already used clinically in the study of brain and prostate carcinoma. Extension of MR spectroscopic tech- niques to breast cancer is underway in multiple centers. With this technique the spectroscopic information is superimposed as a grid on the MR image and the spectroscopy voxel can display the increased presence of Choline and NAA, supplying meta- bolic data from the brain tumors. This approach is particularly valuable in the differentiation of tumor recur- rence from necrosis following radia- tion therapy. For prostate cancer, the use of different three-dimensional spectroscopic imaging data on the ratio of choline and normally occur- ring citrate, has resulted in improved detection, diagnosis of extra-capsular spread, assessment of tumor aggres- siveness and surveillance of treatment. PET/CT • •Imaging Most PET/CT studies performed today are diagnostic FDG scans. The basis of cancer detection by FDG is the increase in glucose metabolism by cancer cells. The magnitude of elevat- ed FDG uptake and accumulation within tumors is most commonly expressed by the standardized uptake value (SVV), defined by the ratio of the activity per unit mass in the lesion, to the administered activity per unit patient mass. SVV values for FDG of >2.5 FDG have been successfullyused to differentiate between benign and malignant lesions. Tumor aggressive- ness may be correlated with a higher magnitude suv. The greatest advan- tage of PET/CT over other imaging modalities is its' thousand to million- fold higher sensitivity over other tech- niques. This permits glucose metabo- lism and countless other biochemical reaction rates to be measured by strict application of the tracer principle. Radiotracer quantities in the nan- nomolar concentrations, which do not perturb the body's metabolism, may be used to perform the measure- ments. Since the nannomolar range is the concentration range of most receptor proteins and tumor target antigens in the body, positron-emis- sion tomography is ideal for this type of imaging. Tumor uptake by FDG, and the resultant value of the test, is cancer site specific. The FDG radiotracer is not well suited for the detection of all can- cers; e.g. prostate cancer, especially when the cancer is low-grade. Several alternative tracers are currently under 9 SA JOURNAL OF RADIOLOGY • December 2002 clinical investigation and new ones, with a promising potential for tumor biology, are under development. IIC_ methionine, a tracer, which has been used to differentiate tumor from nor- mal tissue on account of elevated pro- tein synthesis is a candidate for this application. The rapid (10 minute) uptake and plateau of IIC-methionine within prostate cancers, allows whole body PET/CT imaging (with decay correction), in spite of the short 20- minute half-life of IIC methionine, with minimal interference from the bladder. The use of 18F-fluorodihy- drotestosterone has recently been studied in patients with metastatic prostate cancer in search for a non- invasive method to quantify androgen receptors (AR) by PET. The mismatch in positive findings between FDG and 18F-FDHT suggests the presence of variations in androgen dependence of the different sites, but histologic con- firmation of this finding has not yet been obtained. PET/CT can also be used as an adjunct to CT and MR! in measuring treatment response. The ability to dis- cern viable from necrotic tissue has been an important application of PET. However, the difficulty of sepa- rating viable tumor post therapy from inflammation has reduced the relia- bility of FDG as a quantitative index of response. Most analyses consist of an assessment of the change in Suv. As SUV is a concentration measure, a reduction in tumor volume can result in improved tumor perfusion, which would be manifested in an increase in the Suv. To circumvent this paradox where an increase in FDG could be a consequence of either tumor progres- sion or response, we have introduced the concept of total lesion glycolysis, which combines SUV with the vol- STAR ABSTRACT ume of FDG elevation. This semi- quantitative value is a practical and empirical method with which to test the hypothesis of the utility of FDG in the assessment of treatment response. The optimal choice of radiotracers for tumor diagnosis and follow-up depends on the organ site. The con- cept of using PET with multiple radiotracers, which answer different questions, is likely to become an important thrust in the future of nuclear medicine. Molecular • •Imaging Molecular imaging can be defined as the in vivo depiction and measure- ment of metabolic processes at the cellular and molecular level. This dif- fers from classical diagnostic imaging that focuses on anatomical abnormal- ities. The development of basic mole- cular biological assay techniques is providing more tools for the better understanding and treatment of dis- ease processes at a basic level. The development of transgenic and knockout animal models of human diseases, allows the systematic approach to the study of the genetic and molecular basis of cancer in a reproducible animal model system. Associated with these developments, the newly introduced reporter gene systems, have allowed the non-inva- sive imaging of fundamental biologi- cal processes, such as gene transcrip- tion. Utilizing the experience gained from the application of cellular and sequence specific DNA probes for flo- rescent microscopy of tissue sections, new approaches have been developed for the in vivo study of these process- es. This has resulted in new tech- niques, using reporter constructs and molecular probes, which allow the measurement and monitoring of transcriptional activity (both activa- tion and suppression) of endogenous genes in host tissue. These developments are providing exciting opportunities to assess specif- ic signal transduction pathways tar- geted by specific anti-tumor drugs. This should lead to individual patient- specific drug therapy. Imaging would be the guide for the optimal drug reg- imen and dose. It would be monitor- ing the therapeutic impact of the selected drug regimen by measuring the drug's effect on specific protein- protein interactions. From this research, new "end points" for moni- toring drug response may emerge. Clinicians would benefit from new quantitative methods for the identifi- cation of "partial response" and "com- plete response" reflecting changes in the metabolism and biology of the tumor. Purely anatomical descriptors, such as caliper diameter measuring tumor size will become obsolete. Imaging reporter constructs to monitor gene therapy is another approach of molecular imaging. It is now possible to monitor the distribu- tion, concentration and persistence of viral vectors and the level of therapeu- tic transgene expression by this non- invasive imaging technique. Further developments of imaging probes include radiolabeled sub- strates, targeted contrast agents and ligands, which allow the non-invasive elucidation of specific cell cycle sys- tems and signal transduction path- ways,which are altered in cancer. With the further development of molecular imaging techniques, it is anticipated that we will be able to visualize the actual molecular signatures of cancer 10 SA JOURNAL OF RADIOLOGY • December 2002 in patients. It should be possible with- in the next decade to visualize and determine which genes are being expressed in specific cancers and translate this information directly into better clinical management of an indi- vidual patient. At present, all the in vivo research in molecular imaging is being con- ducted on animals, mostly on mice and rats. New animal imaging instru- ments: Micro- PET, micro-CT and small animal MR have facilitated this research. These noninvasive approac- hes of obtaining measurable informa- tion in a sequential mode have pro- duced significant advances, as has the development of suitable receptors integrating and following reporter gene manifestations. Genetic imaging Genetic imaging is assuming increased importance. To be able to participate in genetic medicine, the information must be imaged at the molecular level. The directions of genetic imaging are: a) Gene expression using intracel- lular or extracellular reporter genes. An accepted technique in animal genetic imaging employs reporter genes such as Lucifer's (the firefly gene responsible for making it glow in the dark). b) Screening of populations at known risk ( either specific gene iden- tification or family disease history) in order to discover the earliest phase of disease. c) Providing guidance for and fol- low-up of gene therapy. Image-guided gene therapy, whether introducing good genes carried by adeno or retro- viruses or with stem cells carrying the good gene, is making slow advances. All present imaging techniques will be STAR ABSTRACT used to guide the micro-catheters or needles to the desired target. I Although progress is painfully slow there have been successes. Suggested reading 1. Blasberg G, Gelovani (Tjuvajev) J. Molecular- Genetic Imaging: A nuclear-based perspective. Molecular Imaging2002; 1(3):160-180. 2. Collins FS, Patrinos A, Jordan E, et al. New goals for the U.S. human genome project: 1998-2003. Science, 1998; 282: 682-689. 3. Dachman, AH; Kuniyoshi, JK; Boyle, CM; Samara, Y; Hoffmann, KR; Rubin, DT; Hanan, 1. CT colonography with three-dimensional problem solving for detection of colonic polyps. AJR. American Journal of Roentgenology, 1998; 171(4):989-995. 4. Feig SA,YafeeMJ. Digital mammography, com- puter-aided diagnosis and tele-mammography. Radiol Clin North Am, 1995; 3: 1205-1230. 5. Johnson CD, Dachman AH. CT Colonography: The Next Colon Screening Examination? Radiology 2000; 216: 331-341. 6. Kurhanewicz J, Vigncron DB, Hricak H, Narayan P, Carroll P, Nelson SJ. Three-dimen- sional H-1 MR spectroscopic imaging of the in situ human prostate with high (0.24-0.7-cm3) spatial resolution. Radiology, 1996; 198(3):795- 805. 7. Lander ES, et al. Initial sequencing and analysis of the human genome. Nature 2001 409: 814- 823. 8. Lee CC, Jack CR Jr, Riederer SJ. Use of func- tional magnetic resonance imaging. Neurosurg Clin NAm, 1996; 7(4):665-683. 9. Luboldt W, Bauerfeind P, Wildermuth S, Marincek B, Fried M, Debatin, JE Colonic Masses; Detection with MR Colonography. Radiology 2000: 216 383-388. 10. Moshage WE, Achenbach S, Seese B, Bachmann K, Kirchgeorg M. Coronary arterystenoses: three-dimensional imaging with electrocardio- graphically triggered, contrast agent-enhanced, electron-beam CT. Radiology, 1995, 196(3): 707-714. Il. Nelson SJ, Huhn S, Vigneron DB, et al. Volume MRT and MRSI techniques for the quantitation of treatment response in brain tumors: presen- tation of a detailed case study. J Magn Reson Imaging, 1997; 7(6):1146-1152. 12. Sidransky D. Emerging Molecular Markers of Cancer. Cancer2002;2(3):210-2J9. 13. Tang Y, Yamashita Y, Arakawa A, NamimotoT, Mitsuzaki K, Abe Y, Katahira K, Takahashi M. Pancreaticobiliary Ductal System: Value of Half-Fourier Rapid Acquisition with Relaxation Enhancement MR Cholangiopancreatography for Postoperative Evaluation Radiology 2000; 215: 81-88. 14. Tearney G), Brezinski ME, Southern JF, Bouma BE, Boppart SA, Fujimoto JG. Optimal Biopsy in Human Gastrointestinal Tissue Using Optical Coherence Tomography. T1JeAmerican Journal of Gastroenterology J 997, 92: 1800- 1804. 15. Varmus H, Weinberg RA. Genes and the Biology of Cancer, 1993. Scientific American Library, New York. 16. Venter JC, et al. The sequence of the human genome. Science 2001 291: 1304-1351. 17. Weissleder R, Mahmood U. Molecular Imaging. Radiology2001, 219: 316-333. Nuclear Medicine Physician I Radiologist - Australia Partnership Opportunity • Lifestyle Our client Is a well-respected and rapidly expanding Diagnostic Imaging Group comprising 16 Partners, Radiologists and Nuclear Medicine Physicians.They service a network of Private Practices, Public Hospitals and Private Hospitals cov- ering speciality, general Imaging and intervention procedures. Three of the sites Include nuclear medicine performing both adult and paediatric studies. The group is competitively placed with all modalities including MR!,an excellent skill base, state-of-the-art equipment, accreditation, a sound administrative structure and a considerable ITcommitment. Thisposition offers clinical variety including the opportunity for city based private and hospital work as well as rural work. Australia's capital city, Canberra, combines the advantages of a smaller city lifestyle with all the facilities one expects of a major capital city. It is close to the snow, coast and Sydney. Travel time to work, excellent schools, shops, recreation facilities and restaurants is minutes from home. Thispractice is unique in the Australian imaging industry as a totally medically owned and run comprehensive imaging partnership that wishes to remain so. Appropriate applicants can look forward to being offered the opportunity to Join this team. If you would like to remain in control of your professional career with the option of partnership, then consider the added benefits of a comprehensive progressive practice and life style In Canberra. Ideally we are seeking a Nuclear Medicine Physician with expertise in Ultrasound or a Radiologist with a sub-specialty interest. For more information please call Kerry McGill for a confidential discussion or forward your resume to: RECRUITMENT PROFESSIONALS Pty Ltd PO, Box 481 Balgowlah NSW 2093 Australia • Ph 09 61 2 9907 8633 Fax 09 61 2 9907 8644 Email: kmcgill@recruitprof.com.au 11 SA JOURNAL OF RADIOLOGY • December 2002 mailto:kmcgill@recruitprof.com.au