Katherine Lameka • David Leung • Chaitanya R. Divgi
1. HISTORICAL PERSPECTIVE
• Prior to molecular imaging, tumor delineation was based on morphologic alterations in anatomy.
• Early techniques utilized two-dimensional (2D) “conventional simulators” to define the tumor margin, in which x-ray tubes on a gantry mimicked the optical and alignment properties of a linear accelerator. A portal film—an image generated using the beam from the treatment port—was generated, but the image quality was poor because the high energy of the beam resulted in very low contrast.1
• Advances in cross-sectional imaging techniques improved tumor delineation. Three-dimensional (3D) computed tomography (CT) offered superior spatial resolution, while magnetic resonance provided excellent soft-tissue contrast.
• A more recent development, four-dimensional CT planning (4D CT), also known as respiration-correlated CT scanning, incorporates tumor movement. Spatial and temporal information on organ mobility is generated by scanning while synchronously recording respiration waveforms, with resultant improvement in delineation of morphologic characteristics without the “blurring” typically associated with respiration or other movement. With 4D CT planning, coverage of the target volume is ensured with potential reduction in toxicity of chemoradiotherapy.2
• While CT and MRI provide anatomic information, they do not distinguish between malignant and benign tissue, which is particularly significant when assessing the tumor response. Specifically, anatomical imaging has limits in the presentation of tumor extension when tumor-bearing structures have a yet-unchanged anatomy, or when tumor and normal tissues have similar density, similar magnetic properties, or a similar contrast enhancement.3
• With the development of newer radiation therapy technologies such as stereotactic body radiotherapy (SBRT), intensity-modulated radiotherapy (IMRT) and particle therapy, and image-guided therapy, the role of molecular imaging has become increasingly important (Fig. 2-1).
2. ADVANCES IN MOLECULAR IMAGING
• Molecular imaging can provide unique and valuable information directly related to the tumor biology. The most common technique currently employed is 2-[18F]-fluoro-2-deoxyglucose (FDG) positron emission tomography (PET, now used often with co-registered CT), which has been largely successful in estimating glucose metabolism in the settings of tumor detection, staging, and determining treatment response.
• Other radiotracers that demonstrate tissue characteristics, such as tissue hypoxia and cell proliferation, are discussed elsewhere in this chapter and in other chapters of this book (Fig. 2-2).
• In addition to assessing the simultaneous anatomic and biologic information, an additional advantage of PET-CT is that there is no time interval between PET and CT, and CT densities can be used for radiation dose calculation.4
• In cases where tumor response depends on determination of residual disease versus normal tissue, the lesion could be investigated with PET-CT.5 The addition of PET imaging also has value in discriminating small soft-tissue lesions versus subtle density variations.6
• Other advantages relate to delineation of tumor tissue from adjacent normal tissue, which is often challenging with CT or MRI. In a study to determine interobserver variation in gross tumor volume definition in lung cancer using CT, and its clinical relevance, Van de Steene et al. determined that large interobserver variability exists for several reasons, including impossible differentiation between pathologic structures and tumor or between normal structures and tumor. This suggests that, for example, in lung cancer adjacent to areas of atelectasis or near the thoracic wall, the addition of PET may help to define hypermetabolic tissue.7
FIGURE 2-1. Non-small cell lung cancer. The only method for GTV delineation in this patient was through the information obtained from an FDG PET/CT, which delineated the tumor, separating it clearly from the rest of the collapsed right lung.
• A drawback of PET-CT is that spatial resolution is 4 to 6 mm versus 1 mm for CT. Also, blurring occurs, particularly around edges. However, a PET scan is performed over a multitude of breathing cycles in free-breathing condition and therefore provides an image of the lesion representing the true time-averaged volume within which the lesion moves during patient respiration. The resulting image ideally shows an increase in lesion size representing the localization of the tumor throughout the whole breathing cycle, which may have additional value in determining the extent of tumor motion during treatment, thus helping to delineate the PTV.3
3. FDG PET/CT PROTOCOL AT COLUMBIA UNIVERSITY/NEW YORK PRESBYTERIAN HOSPITAL
• Patient preparation: NPO for at least 6 hours, including gum, candy, or cough drops.
• Blood glucose level is evaluated, and should be <200 mg/dL.
• Radiopharmaceutical and dose: 12 mCi FDG; 0.14 mCi/kg for pediatric, up to 12 mCi.
• Instrumentation: Siemens Biograph 40 PET-CT scanner or Biograph 64 mCT scanner.
1. Patient completes questionnaire.
2. The date and time the patient had something to eat or drink is documented.
3. Patient’s height and weight is obtained.
4. Blood glucose level is checked.
5. Intravenous access is obtained and verified with normal saline flush.
6. Proper dose of FDG is administered.
7. IV access is flushed with 10 cc of saline.
8. IV access is removed.
9. Oral contrast is not administered for patients with primary head and neck neoplasms. For all other patients, 1–2 cups of oral contrast (2% barium diluted 1:1 with water) are given after administration of FDG and prior to imaging (the “uptake phase”).
10. Patient is to sit or lie down in a “quiet” uptake room for a period of 60 ± 10 minutes.
11. 30 minutes postinjection, a second cup of oral contrast is given, if indicated/tolerated.
12. Prior to scan, the patient is asked to void urine and remove all metallic objects from the field of view.
13. Patient is positioned on the scan table with arms above the head.
14. Study is acquired from vertex to toes or from canthomeatal line to mid-thigh.
a. Vertex-to-toes scans are acquired for
i. Cutaneous T-cell and B-cell lymphoma
ii. CNS lymphoma
iii. Mycosis Fungoides (common form of CTCL Sezary’s disease)
b. Canthomeatal line to mid-thigh scans are acquired for all other cancer types.
c. Head and neck cancer patients should have additional images from the skull base to the apices with the arms down.
i. Includes only patients with primary head and neck and thyroid cancers, not lymphoma.
FIGURE 2-2. Pretreatment (A,B,C) and posttreatment (D,E,F) imaging of a 70-year-old woman with adenocarcinoma of the right lung with pathologic confirmation of subcarinal nodal extension on mediastinoscopy. Pretreatment imaging demonstrated a 1.9-cm right middle lobe nodule (A) that was FDG (B) and FLT avid (C). Patient underwent radiation therapy and chemotherapy. Posttherapy imaging showed no change in size (D) but significant decrease in FDG uptake (E), and complete metabolic response by FLT (F).
4. TARGET VOLUME DEFINITION
• In addition to anatomical delineation of gross tumor volume, the “biological tumor volume” can be assessed using PET.
• Various methods have been described to determine the gross tumor volume (GTV) which is defined as the detectable tumor burden.
• The standard uptake value (SUV) method is a popular method to assess the tumor response to treatment.8 The most commonly used definition of SUV is the ratio of lesion activity FDG concentration (mCi/mL) to whole body FDG concentration (injected dose divided by the weight of the patient in grams).9
• Lowe et al. established the absolute-threshold method of SUV, which was defined as 2.5 for lung cancer, and compared it with visual assessment.10 In an analysis of solitary pulmonary nodules (SPNs), they found that PET had an overall sensitivity and specificity for detection of malignant nodules of 92% and 90%, respectively, suggesting that FDG PET can accurately characterize indeterminate SPNs and provides a nonsurgical method to evaluate indeterminate SPNs. This could lead to a reduction in the need for invasive tissue biopsy.
• Visual analysis provided a slightly higher, but not statistically significant, sensitivity of 98% and a lower specificity of 69%. For SPNs ≤1.5 cm (34 of 89), the sensitivity and specificity of SUV and visual analysis were 80% and 95%, and 100% and 74%, respectively.10
• The source-to-background ratio (SBR) method utilizes automatic volume segmentation of functional imaging based on a relationship between source-to-background ratio and the isoactivity level to be used, and is independent of a priori knowledge of the lesion of interest. It is valid for small (<2 mL) and/or poorly contrasted (S/B < 1.5) lesions.11
• Geets et al. developed a gradient-based segmentation method, which associate the boundaries of an object of interest with the gradient intensity crests observed in the image. When applied on denoised and deblurred images, it was shown to be more accurate than the source-to-background ratio method.12
• A watershed clustering method has also been developed. Riddell et al. described the application of morphologic segmentation—the watershed algorithm—which they found to be a promising technique for reducing the acquisition time and eliminating the effects of noise in PET transmission scans. The algorithm is based on the concept that mathematical morphology treats gray-level images as topographies. The gray levels define altitudes, with maxima at the top of peaks and minima at the bottom of valleys.13
• Hatt et al. developed an approach called fuzzy locally adaptive Bayesian (FLAB) algorithm, validated on homogeneous objects, and then improved it by allowing the use of up to three tumor classes for the delineation of inhomogeneous nonspherical lesions with non-uniform uptake (3-FLAB). FLAB automatically estimates parameters of interest from the image, maximizing the probability of each voxel to belong to one of the considered classes. This probability is estimated for each voxel as a function of its value and the values of its neighbors relative to the voxel’s statistical distribution in the image, which corresponds to an estimation of the noise within each class.14
• Existing relationship between PET lesion size and percentage maximum activity concentration within the target volume can be predicted by a model developed by Nehmeh et al. This model was developed by an iterative method based on a mathematical fit that determined dependence of the threshold value on target size, contrast, and maximum activity concentration of FDG PET target volumes in 3D PET acquisitions using Monte Carlo simulations. This model also shows dependence of the threshold value on target/background, which could be eliminated by background subtraction.15
• In certain cancers, it is also important to define the nodal target volumes, which provides a basis for selective nodal irradiation (SNI). In some cancers, such as esophageal or lymphoma, PET-positive lymph nodes can be included in the target volume.
5. NEED FOR NEW MOLECULAR TRACERS
• While FDG PET has been shown to be useful in assessing the metabolic activity of tumors, other tumor characteristics can be analyzed to predict tumor response and to modify radiation treatment planning. For example, characteristics such as accelerated tumor cell repopulation, tumor cell hypoxia, and intrinsic radioresistance, all of which can be heterogeneous across a given tumor volume, are related to resistance to radiation and need to be counteracted to increase the effectiveness of radiotherapy.16,17
• In a rat model of malignant tumor, Zhao et al. found that intratumoral FDG distribution corresponds well to the expression levels of Glut-1, Glut-3, and HK-II. The elevated expression levels of Glut-1, Glut-3, and HK-II, induced by hypoxia (hypoxia inducible factor-1, HIF-1), may be contributing factors to the higher [18F]-FDG accumulation in the CT region.17
• By accurately assessing these characteristics, it is possible to selectively “boost” radioresistant areas while decreasing the dose to less resistant zones, resulting in higher tumor control with similar side effects.18
• FDG uptake shows metabolic activity of tumor cells, which is indirectly related to the proliferative activity and oxygenation status of tumors.
• Although hypoxia causes an increase in glycolytic flux (the Pasteur effect)19 the high tumor uptake of FDG is the result of glycolytic ATP production under nonhypoxic conditions, which is known as aerobic glycolysis or the Warburg effect.20 Therefore, [18F]-FDG PET cannot be used to reliably distinguish hypoxic from normoxic tumors because of the large variations in baseline glucose metabolism and variable magnitudes of the Pasteur effect.21
5.1. Hypoxia Imaging
• Hypoxia has been imaged using nitroimidazole-based radiopharmaceuticals such as [18F]-fluoromisonidazole (FMISO) and [18F]-fluoroazomycin arabinoside (FAZA). The 2-nitroimidazole moiety acts as a bioreductive molecule trapped inside the cell constituents under hypoxic conditions.16
• Lin et al. conducted a dose-escalation planning study that relied on changes in spatial distribution of hypoxia as detected by FMISO images. The study was designed to evaluate how changes in tumor hypoxia, according to serial [18F]-fluoromisonidazole (FMISO) PET imaging, affect the efficacy of intensity-modulated radiotherapy (IMRT) dose painting. They concluded that the changes in spatial distribution of tumor hypoxia, as detected in serial FMISO PET imaging, compromised the coverage of hypoxic tumor volumes achievable by dose-painting IMRT. However, dose painting always increased the equivalent uniform dose,22 which is defined as the biologic equivalent dose that if given uniformly will lead to the same cell kill in the tumor volume as the actual non-uniform dose distribution of the hypoxic volumes.23,24
• FMISO has also been investigated for prediction of early tumor response in treatment of head and neck cancer.25
• Piert et al. compared FAZA with FMISO in detection of tumor hypoxia and verified the oxygenation dependency of FAZA uptake. They concluded that FAZA has the advantage of a more rapid blood clearance than in FMISO, resulting in a higher signal-to-background ratio.26
• [125I]-iodoazomycin arabinoside IAZA, which is more lipophilic than FAZA, undergoes perfusion into areas not delineated by the perfusion marker [99mTc]-hexamethylpropyleneamine oxime in an animal stroke model, indicating good penetration into poorly perfused tissue.27
• Another tracer used for tumor hypoxia is 2-(2-nitro-1H-imidazol-1-yl)-N-(2,2,3,3,3-pentafluoropropyl)-acetamide (EF5) labeled with [18F]-fluorine (Fig. 2-3). In a study of 15 patients with head and neck cancer, Komar et al. evaluated the potential of this tracer for noninvasive detection of hypoxia with PET, by comparing blood flow with regional uptake of [18F]-EF5, and found the tracer to be a promising tool in hypoxia imaging. They also characterized the time course of uptake of intravenously injected [18F]-EF5 in the head and neck area to determine the most suitable PET protocol for this tracer.28
• Cu(II)-diacetyl bis(N-methylthiocarbazone) (Cu-ATSM) has also been investigated for noninvasive PET imaging of tumor hypoxia in head and neck cancers.29,30
• Dehdashti et al.31 investigated the feasibility of clinical imaging with 60Cu-ATSM in 19 patients with NSCLC. The mean tumor-to-muscle ratio for [60Cu]-ATSM was significantly lower in responders (1.5 ± 0.4) than in nonresponders (3.4 ± 0.8) (P = 0.002). However, the mean SUV for [60Cu]-ATSM was not significantly different in responders (2.8 ± 1.1) and nonresponders (3.5 ± 1.0) (P = 0.2).
FIGURE 2-3. Right apical lung tumor imaged with F-EF5, a hypoxia tracer. The solid-head arrow identifies the hypoxic lung mass in this coronal PET/CT image. The dashed arrow at the left diaphragm illustrates an issue that may confound interpretation—that of motion. CT images can be obtained in a single breath-hold, while PET images are acquired over several minutes, with the resultant respiratory motion artifact.
FIGURE 2-4. Color-washed images in transaxial (A) and coronal (B) projections illustrate regions of heterogeneous Cu(II)-diacetyl-bis(N-methylthiosemicarbazone) (Cu-ATSM) intensity within the gross tumor representing the presence of tumor hypoxia. (From Chao KSC, Bosch WR, Mutic S, et al. A novel approach to overcome hypoxic tumor resistance: Cu-ATSM-guided intensity-modulated radiation therapy. Int J Radiat Oncol Biol Phys 2001;49:1171–1182, with permission.)
• Chao et al.29 demonstrated the ability of PET to select a [60Cu]-ATSM-avid or hypoxic tumor subvolume (hGTV) in head and neck cancer. This study provided proof of principle that assessment of tumor hypoxia can be performed by using PET (Figs. 2-4 and 2-5).
5.2. Protein Synthesis Imaging
• [11C]-methionine is a radiotracer currently used for imaging of protein synthesis. Methionine is a naturally occurring essential amino acid crucial for the formation of proteins. [11C]-methionine PET is particularly useful in imaging of brain tumors, as the high background glucose (and therefore FDG) metabolism can mask adjacent pathology.
• Matsuo et al. evaluated the ability of [11C]-methionine positron emission tomography (MET-PET) to delineate target volumes for brain metastases and to investigate to what extent tumor growth is presented by magnetic resonance imaging and MET-PET. They concluded that tumor volumes defined by MRI and MET-PET differ substantially, suggesting that MET-PET may significantly improve the definition of target volumes in patients with brain metastases. Using MET-PET imaging, the biologic characterization of tissue can be combined with an accurate presentation of the anatomy. Moreover, MET-PET is a better tool for the precise delineation of target volumes, which is an essential step in RT planning. The study indicated that when tumor volume is ≥0.5 mL, a 2-mm margin beyond the GTV-MRI volume significantly improves the coverage of the GTV-PET.32
• Another marker available for protein synthesis measurement is [18F]-fluorethyltyrosine (FET).
• Pauleit et al. compared FET-PET with FDG PET. In 21 patients with head and neck cancer, FET-PET, FDG PET, and CT were done 1 week before surgery. The main advantage of FET was that it allowed better discrimination between tumor and inflammatory tissue. Sensitivity was higher for FDG PET than for FET (93% vs 75%).33
• Choline is a marker of phospholipid synthesis, required for the production of phosphatidylcholine, a component of cell membranes. Rapidly proliferating brain tumor cells contain large amounts of phosphatidylcholine; therefore measurement of the rate of phospholipid synthesis in brain tumors provides information on phosphatidylcholine metabolism which can be imaged using [11C]-choline.34
• Kwee et al. examined patients with brain tumors of different origins, including metastases, with [18F]-fluorocholine (FCHO), and demonstrated distinctly higher lesion-to-normal brain tissue ratios (LNRs), as compared with gliomas and benign lesions.35
• Rottenburger et al. compared the use of [11C]-methionine (MET) and [11C]-choline (CHO) in the positron emission tomography imaging of brain metastases in correlation to the histopathology findings in stereotactic biopsy and found that CHO holds promise for the imaging of brain metastases because of the significantly higher LNRs in tumor tissue as compared with MET, without evidence of a lower specificity of CHO uptake.36
FIGURE 2-5. Delineation of the gross tumor volume (GTV) and its ATSM-avid fraction by PET/CT imaging fusion. (From Chao KSC, Bosch WR, Mutic S, et al. A novel approach to overcome hypoxic tumor resistance: Cu-ATSM-guided intensity-modulated radiation therapy. Int J Radiat Oncol Biol Phys 2001;49:1171–1182, with permission.)
• [11C]-Choline has also been shown useful in imaging of prostate cancer. This radiotracer was pioneered by Hara et al. and was shown to be superior to FDG PET owing to the lack of its urinary accumulation and higher uptake in the prostate cancer itself.37
• The largest patient population studied to date (n = 358 men) has shown [11C]-choline PET/CT to have a sensitivity of 85%, specificity of 93%, PPV of 91%, NPV of 87%, and accuracy of 89% for the overall detection of recurrent prostate cancer in clinically suspected cases.38,39
5.3. Proliferation Imaging
• [18F]-fluorothymidine (FLT) is a useful tracer for assessment of tumor cell proliferation. FLT is moved into the cell via human nucleoside transporters and trapped intracellularly by the cytosolic enzyme thymidine kinase 1, the activity of which increases during DNA synthesis. Thus, FLT trapping is related to thymidine kinase 1 activity and to proliferation, enabling tumor proliferative activity to be monitored.16,40,41
• Investigations by Menda et al. and Troost et al. demonstrated that signal intensity changes, which were proportional to cellular response to treatment, often preceded changes in tumor response and could potentially provide a means of early tumor response assessment (Fig. 2-2) and help to modify the treatment protocol.42,43
• Bading and Shields performed a literature review of cell proliferation imaging and mentioned a variety of tracers including TdR, FLT, FMAU (1-(29-deoxy-29-fluoro-1-b-D-arabinofuranosyl)-thymine), FBAU (1-(29-deoxy-29-fluoro-b-D-arabinofuranosyl-uracil)bromouracil), and others. They determined that while proliferation imaging looks promising in the field of radiation oncology, further investigations are needed.44
• [18F]-annexin is a radiotracer used for assessment of apoptosis. Annexin V (also known as annexin A5), a natural human phosphatidylserine-binding protein, is by far the most widely used phosphatidylserine-directed agent. The use of annexin V offers several advantages, including its very high affinity for apoptotic cells (low- to sub-nanomolar dissociation constants), ready production by recombinant DNA technology, and absence of in vivo toxicity.45
• In several animal model series using [18F]-annexin V studying chemically induced apoptosis, Yagle et al. demonstrated that the uptake of [18F]-annexin V correlated with in vitro markers of apoptosis in rat liver. They further showed that [18F]-annexin V and its metabolites clear rapidly from the body, principally by urinary excretion, so that the background uptake is sufficiently low to allow imaging within a relatively short time after administration.46
• A novel agent ML-10 has been found to have potential as an apoptosis imaging agent in animal models. It putatively is more likely to identify those cells that are irrevocably committed to apoptotic death, and is currently in Phase 2 clinical trials in patients with head and neck as well as other cancers.47
5.5. Growth Factor Receptor Imaging
• Epidermal growth factor receptor (EGFR) controls signal transduction pathways associated with the three radiotherapy resistance mechanisms. EGFR can be visualized with PET imaging.
• Uptake of cetuximab can be quantified by PET imaging of [89Zr]-cetuximab or labeling of other ligands. This method is a potentially useful technique for noninvasive assessment of cetuximab uptake. In in vivo tumor imaging experiments on tumor-bearing NMRI-nu mice at multiple time points after injection, Aerts et al. demonstrated the uptake of [89Zr]-labeled cetuximab in the EGFR-positive tumors. They concluded that [89Zr]-labeled cetuximab imaging probe is a promising tool for noninvasive evaluation of cetuximab uptake, but there was a disparity between in vivo EGFR expression levels and cetuximab uptake.48
5.6. Other Tracers
• The positron-emitting radiohalogen 124 Iodine [124I] with its 4.2-day half-life has been investigated for in vivo detection and quantification of longer term biologic and physiologic processes. Because of the long half life, it is especially suited for in vivo studies of the prolonged time course of uptake of higher molecular weight compounds like monoclonal antibodies (MAbs) in solid tumors, as well as allowing for serial scanning protocols over a period of several days49 (see Fig. 2-6).
• [18F]-Sodium fluoride (NaF) has highly specific bone uptake (Fig. 2-7), rapid clearance from the blood pool because of minimal protein binding, and dosimetry similar to that of [99mTc]-MDP, and has been shown to be useful for localizing and characterizing both malignant and benign bone lesions. In addition, NaF PET has been shown to be more accurate than planar imaging or SPECT with [99mTc]-MDP. The addition of correlative imaging, such as CT, MRI, or hybrid imaging with PET/CT, further improves the specificity and accuracy of NaF PET.50
FIGURE 2-6. PET/CT with [124I]-girentuximab in a patient with clear cell renal cell carcinoma (right kidney, arrow). The vertebral metastasis (dashed arrow) is also seen very clearly. This antibody targets carbonic anhydrase-IX and may thus have relevance as a hypoxia imaging biomarker. (A) Coronal CT slice, bone window; (B) [124I]-girentuximab PET; and (C) Fusion image.
6. SPECIFIC TUMOR DISCUSSION
• Individual tumor types pose unique challenges to radiation therapy that warrant specific investigations and treatment modifications.
FIGURE 2-7. PET/CT bone scan with [18F]-NaF. A 51-year-old man with prostate cancer, status post-prostatectomy and radiation therapy, later presented with rising PSA of 2.1. CT of chest, abdomen, and pelvis, as well as [99mTc]-MDP bone scan were all negative. NaF bone PET demonstrated lesions in the skull, bilateral ribs, and pelvis. Subsequent [99m Tc]-MDP (methyl diphosphonate) bone scan became positive in many of these locations, confirming the clinical suspicion of osseous metastases.
• For non–small cell lung cancer (NSLC), radiation treatment volumes may be reduced by excluding FDG or FLT negative mediastinal lymph nodes. This can lead to reduction in toxicity or enable radiation dose escalation.4 Also, the relationship between PET/CT detected inflammatory changes in irradiated normal tissues and metabolic response at tumor sites in patients with NSCLC receiving radical radiotherapy has prognostic significance.
• Hicks et al. investigated this relationship and concluded that postradiotherapy inflammatory changes detected by FDG PET are positively correlated with tumor response, suggesting that tumor radioresponsiveness and normal tissue radiosensitivity may be linked. He also concluded that prognostic stratification provided by PET is not compromised by inflammatory changes if a meticulous visual response assessment technique is used.51
• About two-thirds of patients with squamous cell carcinoma of the head and neck present with locally advanced disease (stage III or IV without distant metastases). The main reasons for radiotherapy being preferred to surgery especially for advanced disease are its less invasive nature and its potential for normal (contiguous) organ preservation.16
• Inhibition of EGFR by the monoclonal antibody cetuximab enhances the radiotherapy effect and improves locoregional control and survival in stage III–IV head and neck cancer. EGFR controls signal transduction pathways associated with the three radiotherapy resistance mechanisms.52
7. CURRENT CHALLENGES AND FUTURE
• Today’s PET imaging technology faces a variety of challenges, some of which were discussed by Erdi, including a need for faster throughput, elimination of contrast artifacts, and elimination of motion artifact using respiratory gating techniques.6
• With the advances in biotechnology and computers, in the near future, it will be possible to give a “cocktail” of tracers to the patients and to scan them with multiple imaging modalities at the same time. However, since all positrons are detected identically regardless of source, [C11]- and [F18]- will be indistinguishable. Sequential studies are thus needed with PET, but not with SPECT/CT. Ling et al. described the concept of multidimensional radiotherapy (MD-CRT), which is the basis of integrating physical and biologic conformality. “Biological target volumes” incorporate multiple-tracer uptake datasets.53
• More recently, the potential role of four-dimensional (4D) PET/CT in radiation treatment planning, relative to standard three-dimensional (3D) PET-CT, was examined by Aristophanous et al. In their study, 10 patients with non–small cell lung cancer had sequential 3D and 4D FDG PET-CT scans in the treatment position prior to radiation therapy. The authors concluded that 4D PET may better define the full physiologic extent of moving tumors and improve radiation treatment planning for lung tumors. In addition, reduction of blurring in free-breathing images may reveal additional information regarding regional disease.54
1. Mah D, Chen CC. Image guidance in radiation oncology treatment planning: the role of imaging technologies on the planning process. Semin Nucl Med 2008;38(2):114–118.
2. Spoelstra FO, Senan S. Novel tools in radiotherapy. Ann Oncol 2008;19(Suppl 7):vii294–299.
3. Nestle U, Weber W, Hentschel M, Grosu AL. Biological imaging in radiation therapy: role of positron emission tomography. Phys Med Biol 2009;54(1):R1–R25.
4. Lammering G, De Ruysscher D, van Baardwijk A, et al. The use of FDG-PET to target tumors by radiotherapy. Strahlenther Onkol 2010;186(9):471–481.
5. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 2009;45(2):228–247.
6. Erdi YE. The use of PET for radiotherapy. Curr Med Imaging Rev 2007;3(1):3–16.
7. Van de Steene J, Linthout N, de Mey J, et al. Definition of gross tumor volume in lung cancer: inter-observer variability. Radiother Oncol 2002;62(1):37–49.
8. Lucignani G, Paganelli G, Bombardieri E. The use of standardized uptake values for assessing FDG uptake with PET in oncology: a clinical perspective. Nucl Med Commun 2004;25(7):651–656.
9. Kim CK, Gupta NC, Chandramouli B, Alavi A. Standardized uptake values of FDG: body surface area correction is preferable to body weight correction. J Nucl Med 1994;35(1):164–167.
10. Lowe VJ, Fletcher JW, Gobar L, et al. Prospective investigation of positron emission tomography in lung nodules. J Clin Oncol 1998;16(3):1075–1084.
11. Daisne JF, Sibomana M, Bol A, Doumont T, Lonneux M, Gregoire V. Tri-dimensional automatic segmentation of PET volumes based on measured source-to-background ratios: influence of reconstruction algorithms. Radiother Oncol 2003;69(3):247–250.
12. Geets X, Lee JA, Bol A, Lonneux M, Gregoire V. A gradient- based method for segmenting FDG-PET images: methodology and validation. Eur J Nucl Med Mol Imaging 2007;34(9):1427–1438.
13. Riddell C, Brigger P, Carson RE, Bacharach SL. The watershed algorithm: a method to segment noisy PET transmission images. IEEE Trans Nucl Sci 1999;46(3):713–719.
14. Hatt M, le Rest CC, Descourt P, et al. Accurate automatic delineation of heterogeneous functional volumes in positron emission tomography for oncology applications. Int J Radiat Oncol 2010;77(1):301–308.
15. Nehmeh SA, El-Zeftawy H, Greco C, et al. An iterative technique to segment PET lesions using a Monte Carlo based mathematical model. Med Phys 2009;36(10):4803–4809.
16. Bussink J, van Herpen CML, Kaanders JHAM, Oyen WJG. PET-CT for response assessment and treatment adaptation in head and neck cancer. Lancet Oncol 2010;11(7):661–669.
17. Zhao S, Kuge Y, Mochizuki T, et al. Biologic correlates of intratumoral heterogeneity in 18F-FDG distribution with regional expression of glucose transporters and hexokinase-II in experimental tumor. J Nucl Med 2005;46(4):675–682.
18. van Loon J, van Baardwijk A, Boersma L, Ollers M, Lambin P, De Ruysscher D. Therapeutic implications of molecular imaging with PET in the combined modality treatment of lung cancer. Cancer Treat Rev 2011;37(5):331–343.
19. Porter JR. Louis PASTEUR: achievements and disappointments, 1861. Bacteriol Rev 1961;25:389–403.
20. Warburg O. On respiratory impairment in cancer cells. Science 1956;124(3215):269–270.
21. Busk M, Horsman MR, Jakobsen S, Bussink J, van der Kogel A, Overgaard J. Cellular uptake of PET tracers of glucose metabolism and hypoxia and their linkage. Eur J Nucl Med Mol Imaging 2008;35(12):2294–2303.
22. Carrasco P, Jornet N, Duch MA, et al. Comparison of dose calculation algorithms in phantoms with lung equivalent heterogeneities under conditions of lateral electronic disequilibrium. Med Phys 2004;31(10):2899–2911.
23. Lin Z, Mechalakos J, Nehmeh S, et al. The influence of changes in tumor hypoxia on dose-painting treatment plans based on 18F-FMISO positron emission tomography. Int J Radiat Oncol Biol Phys 2008;70(4):1219–1228.
24. Niemierko A. Reporting and analyzing dose distributions: a concept of equivalent uniform dose. Med Phys 1997;24(1):103–110.
25. Lee N, Nehmeh S, Schoder H, et al. Prospective trial incorporating pre-/mid-treatment [18F]-misonidazole positron emission tomography for head-and-neck cancer patients undergoing concurrent chemoradiotherapy. Int J Radiat Oncol Biol Phys 2009;75(1):101–108.
26. Piert M, Machulla HJ, Picchio M, et al. Hypoxia-specific tumor imaging with 18F-fluoroazomycin arabinoside. J Nucl Med 2005;46(1):106–113.
27. Lythgoe MF, Williams SR, Busza AL, et al. The relationship between magnetic resonance diffusion imaging and autoradiographic markers of cerebral blood flow and hypoxia in an animal stroke model. Magn Reson Med 1999;41(4):706–714.
28. Komar G, Seppanen M, Eskola O, et al. 18F-EF5: a new PET tracer for imaging hypoxia in head and neck cancer. J Nucl Med 2008;49(12):1944–1951.
29. Chao KSC, Bosch WR, Mutic S, et al. A novel approach to overcome hypoxic tumor resistance: Cu-ATSM-guided intensity-modulated radiation therapy. Int J Radiat Oncol Biol Phys 2001;49(4):1171–1182.
30. Lewis JS, McCarthy DW, McCarthy TJ, Fujibayashi Y, Welch MJ. Evaluation of 64Cu-ATSM in vitro and in vivo in a hypoxic tumor model. J Nucl Med 1999;40(1):177–183.
31. Dehdashti F, Mintun MA, Lewis JS, et al. In vivo assessment of tumor hypoxia in lung cancer with 60Cu-ATSM. Eur J Nucl Med Mol Imaging 2003;30(6):844–850.
32. Matsuo M, Miwa K, Shinoda J, et al. Target definition by C11-methionine-PET for the radiotherapy of brain metastases. Int J Radiat Oncol Biol Phys 2009;74(3):714–722.
33. Pauleit D, Zimmermann A, Stoffels G, et al. 18F-FET PET compared with 18F-FDG PET and CT in patients with head and neck cancer. J Nucl Med 2006;47(2):256–261.
34. Hara T, Kosaka N, Shinoura N, Kondo T. PET imaging of brain tumor with [methyl-11-C]choline. J Nucl Med 1997;38(6):842–847.
35. Kwee SA, Ko JP, Jiang CS, Watters MR, Coel MN. Solitary brain lesions enhancing at MR imaging: evaluation with fluorine 18-fluorocholine PET. Radiology 2007;244(2):557–565.
36. Rottenburger C, Hentschel M, Kelly T, et al. Comparison of C-11 methionine and C-11 choline for PET imaging of brain metastases: a prospective pilot study. Clin Nucl Med 2011;36(8):639–642.
37. Hara T, Kosaka N, Kishi H. PET imaging of prostate cancer using carbon-11-choline. J Nucl Med 1998;39(6):990–995.
38. Giovacchini G, Picchio M, Coradeschi E, et al. [(11)C]choline uptake with PET/CT for the initial diagnosis of prostate cancer: relation to PSA levels, tumour stage and anti-androgenic therapy. Eur J Nucl Med Mol Imaging 2008;35(6):1065–1073.
39. Murphy RC, Kawashima A, Peller PJ. The utility of 11C-choline PET/CT for imaging prostate cancer: a pictorial guide. AJR Am J Roentgenol 2011;196(6):1390–1398.
40. Buck AK, Schirrmeister H, Hetzel M, et al. 3-deoxy-3-[(18)F] fluorothymidine-positron emission tomography for noninvasive assessment of proliferation in pulmonary nodules. Cancer Res 2002;62(12):3331–3334.
41. Rasey JS, Grierson JR, Wiens LW, Kolb PD, Schwartz JL. Validation of FLT uptake as a measure of thymidine kinase-1 activity in A549 carcinoma cells. J Nucl Med 2002;43(9):1210–1217.
42. Menda Y, Ponto LLB, Dornfeld KJ, et al. Kinetic analysis of 3’-deoxy-3’-(18)F-fluorothymidine ((18)F-FLT) in head and neck cancer patients before and early after initiation of chemoradiation therapy. J Nucl Med 2009;50(7):1028–1035.
43. Troost EG, Bussink J, Hoffmann AL, Boerman OC, Oyen WJ, Kaanders JH. 18F-FLT PET/CT for early response monitoring and dose escalation in oropharyngeal tumors. J Nucl Med 2010;51(6):866–874.
44. Bading JR, Shields AF. Imaging of cell proliferation: status and prospects. J Nucl Med 2008;49(Suppl 2):64S–80S.
45. Tait JF, Smith C, Levashova Z, Patel B, Blankenberg FG, Vanderheyden JL. Improved detection of cell death in vivo with annexin V radiolabeled by site-specific methods. J Nucl Med 2006;47(9):1546–1553.
46. Yagle KJ, Eary JF, Tait JF, et al. Evaluation of F-18-annexin V as a PET imaging agent in an animal model of apoptosis. J Nucl Med 2005;46(4):658–666.
47. Hoglund J, Shirvan A, Antoni G, et al. 18F-ML-10, a PET tracer for apoptosis: first human study. J Nucl Med 2011;52(5):720–725.
48. Aerts HJWL, Dubois L, Perk L, et al. Disparity between in vivo EGFR expression and (89)Zr-labeled cetuximab uptake assessed with PET. J Nucl Med 2009;50(1):123–131.
49. Koehler L, Gagnon K, McQuarrie S, Wuest F. Iodine-124: a promising positron emitter for organic PET chemistry. Molecules 2010;15(4):2686–2718.
50. Grant FD, Fahey FH, Packard AB, Davis RT, Alavi A, Treves ST. Skeletal PET with 18F-fluoride: applying new technology to an old tracer. J Nucl Med 2008;49(1):68–78.
51. Hicks RJ, Mac Manus MP, Matthews JP, et al. Early FDG-PET imaging after radical radiotherapy for non-small-cell lung cancer: inflammatory changes in normal tissues correlate with tumor response and do not confound therapeutic response evaluation. Int J Radiat Oncol Biol Phys 2004;60(2):412–418.
52. Bonner JA, Harari PM, Giralt J, et al. Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. New Engl J Med 2006;354(6):567–578.
53. Ling CC, Humm J, Larson S, et al. Towards multidimensional radiotherapy (MD-CRT): biological imaging and biological conformality. Int J Radiat Oncol Biol Phys 2000;47(3):551–560.
54. Aristophanous M, Berbeco RI, Killoran JH, et al. Clinical utility of 4D FDG-PET/CT scans in radiation treatment planning. Int J Radiat Oncol Biol Phys 2012;82(1):e99–e105.