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| | SYMPOSIUM | | | | | Year : 2010 | Volume : 47 | Issue : 2 | Page : 126-133 | | | PET/CT-guided radiation therapy planning: From present to the future
T Gupta1, S Beriwal2
1 Department of Radiation Oncology, Advanced Centre for Treatment Research and Education in Cancer (ACTREC), Tata Memorial Centre, Navi Mumbai, India
2 Department of Radiation Oncology, University of Pittsburg Cancer Institute, Pittsburg, PA, USA
| Date of Web Publication | 5-May-2010 | Correspondence Address:
T Gupta
Department of Radiation Oncology, Advanced Centre for Treatment Research and Education in Cancer (ACTREC), Tata Memorial Centre, Navi Mumbai
India
  | 6 |
DOI: 10.4103/0019-509X.63000 PMID: 20448373 Molecular imaging using 18F-fluoro-deoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) has been successfully used in the diagnosis, initial staging, and response assessment of various malignant tumors. Advances in radiation therapy planning and delivery have ushered in the era of high-precision conformal radiotherapy allowing generation of dose distributions that conform closely to the shape of the target volume while minimizing high-dose regions in the surrounding normal tissues. Traditionally, radiation therapy planning has relied heavily on CT imaging, but recent times have witnessed tremendous enthusiasm for the use of PET/CT-guidance in radiotherapy planning. This has been largely stimulated by widespread availability and integration with treatment planning systems. However, several issues need to be addressed and challenges overcome to realize the full potential of this exciting technology. Integrating PET/CT fusion imaging into routine clinical practice can be challenging due to technical, administrative, financial, geographic, and personnel issues. Concerted efforts are urgently needed for the development of guidelines for appropriate application of this technology using standardized methodology. There is accumulating evidence that incorporating PET/CT imaging in radiotherapy planning for lung cancer, head and neck cancer and cervical cancer has a significant impact. This review highlights the promises and pitfalls of PET/CT imaging in radiotherapy treatment planning with a critical appraisal of the current best evidence for its application in the modern radiotherapy clinic, and provides a sneak preview into the future of such technology.
Keywords: Imaging, outcomes, PET/CT, radiotherapy, treatment planning
How to cite this article:
Gupta T, Beriwal S. PET/CT-guided radiation therapy planning: From present to the future. Indian J Cancer 2010;47:126-33 |
| » Introduction | |  |
Anato-metabolic imaging using 18F-fluoro-deoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) has been successfully used in the diagnosis, initial staging, and response assessment in various malignant tumors with high diagnostic accuracy. [1],[2] In recent times, there has been tremendous enthusiasm in the use of PET-guided radiation therapy planning [3],[4] largely stimulated by the widespread commercial availability of advanced imaging technologies and their integration with treatment planning systems. The advent of dual-modality integrated PET/CT systems offers a unique opportunity of improving target localization and facilitating treatment planning for radiation therapy in contemporary oncologic practice. However, several issues need to be addressed and challenges overcome to realize the full potential of this exciting technology. This has provided international impetus for the development of consensus guidelines for appropriate application using standardized methodology. [5],[6] This review highlights the promises and pitfalls of PET/CT imaging in radiotherapy treatment planning with a critical appraisal of the current best evidence for its application in the modern radiotherapy clinic, and provides a sneak preview into the future of such technology.
| » Radiation Therapy Planning | | |
Radiation therapy planning can be defined specifically though not only limited to the process of image-acquisition, volume delineation, dose-fractionation prescription, assigning of treatment fields and beam-modifiers, evaluation of dose distribution, and quality assurance before final approval for treatment delivery. The standard imaging technique used in radiotherapy planning is CT as it provides both good anatomic detail for defining target volumes and the electron density data required for dose calculations. Images for use in radiotherapy treatment planning must be acquired with the patient in the treatment position, on a flat couch top and with the use of appropriate immobilization devices. The radiotherapy planning process using CT data is based upon the definition of a number of target volumes defined by the International Commission on Radiation Units and Measurements (ICRU) Report 50 and 62. [7] Gross Tumor Volume (GTV) is defined as any grossly palpable or visible disease identified and delineated on axial CT images. The GTV is expanded three-dimensionally depending upon natural history of disease, patterns of spread, and likelihood of microscopic disease being present in seemingly normal surrounding tissues. The CTV is further expanded in three dimensions to create the Planning Target Volume (PTV), to account for set-up errors (patient and organ motion). The CTV to PTV margin is variable and depends on site, technique and institutional practice. In addition to these target volumes, the radiation oncologist also needs to define the surrounding normal structures as organs-at-risk (OARs) on axial CT images throughout the region of interest.
Advances in radiation therapy planning and delivery
Over the last couple of decades, advances in radiation therapy planning and delivery have ushered in the era of high-precision conformal radiotherapy [8],[9],[10] allowing generation of dose distributions that conform closely to the shape of the target volume while minimizing high-dose regions in the surrounding normal tissues. In general, anatomical cross-sectional CT images are used to delineate treatment volumes and design multiple uniform intensity fields that are shaped using multi-leaf collimators. Intensity Modulated Radiation Therapy (IMRT) is an advanced form of conformal radiotherapy wherein the beam intensity is modulated to produce highly conformal dose distributions [Figure 1] around irregular and complex shaped target volumes. The improved dose conformity and steep dose-gradients necessitate more accurate patient localization to avoid the chance of geographic miss, as high-precision radiotherapy is poorly tolerant of set-up errors. This can be partly overcome by the use of daily volumetric image guidance i.e. Image-Guided Radiation Therapy (IGRT) for enhanced set-up accuracy. Modern radiotherapy departments are equipped with volumetric image-guidance for precise alignment of the patient with respect to the beam line. Rapid advances in technology allow highly sophisticated treatment planning coupled with extremely accurate localization and precise radiation dose delivery. However, the technology for target volume delineation i.e. accurately defining what regions or tissues need to be targeted is still not very robust and continues to evolve.
PET/CT-guided radiation therapy planning
One distinct advantage of PET/CT in radiotherapy planning is its potential to improve tumor delineation, reducing intra-observer and inter-observer variability and making treatment volumes more standard across individuals and institutions.
Ways to use PET images for planning
PET for radiation therapy planning can be used in several ways - visual aid for target delineation, fusion of PET and CT images acquired from separate scanners, or a planning PET/CT scan done on an integrated PET/CT unit with the patient in treatment position. Separately acquired diagnostic PET or PET/CT images in the non-treatment position can be successfully co-registered with the planning CT acquired in the treatment position on a flat couch under immobilization, with reasonable accuracy using contemporary fusion algorithms. [11] Integrated PET/CT systems produce anatomic and metabolic images with the patient in the same position and during a single procedure, greatly simplifying image registration. [12] PET/CT imaging protocols used in radiation therapy planning must be rigorous and consistently applied. The PET/CT suite is effectively a link in the chain of radiation therapy quality control. [12],[13],[14] Positioning tools should include a firm flat couch top, immobilization devices, laser beams for patient alignment and a wide-bore scanner (>70cm). The PET and CT images thus acquired are complementary as well as supplementary. [3],[13],[14] PET images can identify areas of disease not readily visible on CT alone. CT images can provide improved spatial resolution helping to anatomically localize sites of involvement. Also, the low noise CT data can be used to generate patient-specific map of attenuation coefficients for correcting PET emission data for errors from photon attenuation, scattered radiation, and other physical degrading factors such as partial volume effect. [3],[13],[14] Thus dual-modality PET/CT can improve both the visual quality and the quantitative accuracy of the correlated radiotracer data. This improvement, however, comes at a cost in terms of increased radiation dose compared to stand alone PET systems.
| » Impact on target volume delineation | | |
The first generation of studies involving PET and/or PET/CT in the radiotherapy clinic was reported in late 1990s. Most of the studies dealt with the impact of such imaging on overall oncologic management. It is now widely accepted and acknowledged that PET/CT impacts significantly on planning in the modern radiation therapy clinic. PET/CT not only has a having direct impact on target volume delineation in a wide variety of cancers, but can also lead to a significant change in the therapeutic approach in 10-30% of patients as compared to other reference imaging modalities. The most robust evidence for this comes from a prospective blinded trial [15] involving 111 patients with lung cancer (n = 38), head-neck cancer (n = 23), breast cancer (n = 8), cervical cancer (n = 15), esophageal cancer (n = 9), and lymphoma (n = 18), who underwent hybrid PET/CT imaging at the time of radiation therapy planning. A physician blinded to the PET dataset designed a treatment plan using all clinical and CT information. The treating physician subsequently designed a second treatment plan using the hybrid PET/CT dataset, which was compared with the original plan. In 76/111 (68%) patients, the PET/CT data resulted in a change in one or more of the following: GTV, loco-regional extension, prescribed dose, or treatment modality selection. In 35/76 (46%) cases, the change resulted in a major alteration in the overall therapeutic management (dose, field design, or modality change).
A detailed discussion on PET/CT-guided radiotherapy planning for various sites is beyond the scope of this review. The reader is referred to excellent contemporary reviews [13],[14],[16] for an exhaustive discussion on the current best evidence in the indexed medical literature. Herein, we briefly discuss the three common sites viz. lung cancer, head- neck cancer, and cervical cancer, wherein PET/CT-guided radiation therapy planning is being increasingly applied.
Lung Cancer: Thoracic radiotherapy with curative intent for non-small cell lung carcinoma (NSCLC) is challenging due to the presence of respiratory tumor motion as well as normal lung and spinal cord tolerance being well below intended tumoricidal doses. It is also well appreciated that respiratory motion has a strong effect on the inferred activity distribution in PET imaging that can result in differences in localization of lesions in PET scans versus CT scans. [17],[18] The resultant mis-localizations vary depending upon the size and location of the tumor. [18] The advent of four-dimensional CT allows us to measure the motion of tumors and define a motion envelope for targeting. [19] The same approach has been used to create four-dimensional PET, which uses four-dimensional CT for attenuation correction and could be used to plan free-breathing radiotherapy under free-breathing conditions. Preliminary studies confirm that if respiratory motion can be controlled or compensated for, the effect of motion artifacts can be largely reduced. The high sensitivity and specificity of PET/CT for mediastinal lymph node involvement and superior capacity to discriminate between tumor extent and atelectasis significantly alters the target volumes with a potential to either reduce dose to OARs or deliver increased doses to the tumor and thereby improve outcomes. [20] Overall, in most studies, a significant impact of PET-derived contours on treatment planning was demonstrated in 30-60% of plans with respect to the CT-only target volume, with an observed change in volume of 20-25%. [13],[14],[21] [Figure 2] is a typical example of an FDG-avid lung cancer with adjacent area of atelectasis that was FDG non-avid and could not be differentiated from the primary tumor on CT alone.
Head-Neck-Cancer: Head and neck squamous cell carcinoma (HNSCC) was one of the earliest disease sites wherein IMRT was considered promising due to the presence of complex target volumes (irregular shape, large volume, and different areas at different risk of harboring disease mandating different doses) and critical surrounding normal tissues. [22] The main advantage of FDG-PET for HNSCC appears to be in identifying metastatic nodal disease that is equivocal on CT scans for inclusion in the IMRT planning [Figure 3]. The decision to designate a node as involved or not with disease translates into the difference between delivering tumoricidal doses applicable for gross disease (66-70Gy) versus delivering prophylactic dose for elective at-risk nodes (54-56Gy). Several studies [23],[24] that have examined the role of PET/CT in the context of radiotherapy planning have concluded that that there are significant quantitative and qualitative differences between PET-derived and CT-derived tumor volumes in a large proportion of these patients. [13],[14],[25],[26]
Cervical Cancer: The high sensitivity and specificity of FDG-PET/CT for initial staging and restaging of cervical cancer has prompted its application in radiation therapy planning. [27] In a pilot study, [28] 51 patients with loco-regionally advanced cancer of the cervix (stages IIB-IIIB) were treated with a combination of external beam radiotherapy and brachytherapy with or without concurrent cisplatin. The radiation portals were based on fused PET/CT images. PET imaging led to a change in extent of disease in 19 (37%) patients and modified radiation fields in 9 (17.5%) patients as compared to CT alone. Nine patients (17.5%) showed progression while 42 (82.5%) patients were alive and disease-free at a median follow-up of 17 months. Grigsby and colleagues have been actively pursuing PET-guided IMRT planning in carcinoma cervix for the last few years. [29],[30]
The single biggest advantage of PET-guidance in such a scenario is the detection and inclusion in target volume of gross para-aortic and pelvic lymph nodes [Figure 4], which might have been equivocal on CT imaging. A recent prospective study [30] on PET/CT-guided dose-escalated IMRT to the PET positive para-aortic lymph nodes reported excellent target volume coverage with conformal avoidance of bowel and kidneys. In addition, PET has been shown to provide valuable additional information for brachytherapy planning in patients with gynecological cancers. [31]
Limitations of PET-guided planning
However, there are valid criticisms that have hindered the widespread application of FDG-PET/CT in the radiation therapy clinic. One of the main difficulties is the delineation of the treatment volume from noisy PET data. Identification of lesion edges in general is not a trivial problem in PET imaging. [13],[14] The major problems encountered in functional volume quantitation are image segmentation and imperfect system response function. The difficulty in image segmentation is compounded by the low spatial resolution and high-noise characteristics of PET images. [12],[14] Despite the difficulties and known limitations, several image segmentation approaches have been proposed including threshold, region growing, classifiers, clustering, edge detection, Markov random field models, artificial neural networks, deformable models, and Atlas More Details-guided approaches. [13],[14],[32] Manual delineation of target volumes using different window level settings and look up tables is the most common and widely used technique in the clinic. However, the method is highly operator-dependent with wide inter-observer variability. Semi-automated or fully-automated delineation techniques offer an advantage over manual techniques by improving reproducibility. Given the plethora of proposed techniques, there has been considerable heterogeneity in the methods used for PET-guided target volume delineation across most studies. Even today, there is no consensus on the most optimal methodology to define the tumor edge while using PET/CT for radiation therapy planning.
Most of the studies of PET/CT-guided radiotherapy planning have involved small number of patients that are limited to either dosimetric comparisons or change in management decisions. Very few studies have actually provided any correlation with histology or demonstrated improvements in outcome. Some other potential problems of PET/CT-based target volume delineation include issues such as data transfer and compatibility between imaging systems and radiation therapy planning software, patient or organ motion, and partial volume effects. A collaborative effort between nuclear medicine physicians, radiologists, and radiation oncologists is desirable to fully exploit the potential of PET/CT-guided radiation therapy planning.
| » Impact of PET-guidance on outcome | | |
One of the early interim endpoints commonly employed in appraising the outcomes of high-precision techniques is the pattern of failure following treatment and their correlation with target volume coverage. It is indeed reassuring to note the patterns of failure after PET/CT-guided radiotherapy and their location relative to the PET defined biological target volumes [Table 1]. The vast majority of failures following such treatment are within the PET-defined volumes [33],[34],[35],[36],[37],[38],[39] which could be the basis for designing dose escalation studies in some cancers. Another interesting aspect that emerges from such analyses is the correlation of sites of failure with several aspects of cellular metabolism. Recent developments in molecular imaging have created opportunities to unravel the complexity of tumor biology. Integration of such contemporary functional imaging techniques with radiation therapy planning could provide a closer view of the biologic pathways involved in radiation response that could be used for differential dosing of tumor sub-volumes. [3],[40],[41] Theragnostic imaging to individualize radiation dose prescription and delivery in four-dimensions including time has tremendous potential to emerge as the next paradigm in radiation oncology. [42],[43]
There have been recent reports of improved outcomes with PET-guided planning. The largest prospective dataset documenting improved outcomes comes from Washington University [44] in patients with cervical cancer. A total of 317 patients were treated with a combination of whole-pelvis and split-field irradiation using an institutional step-wedge technique. Another 135 patients were treated with PET/CT guided IMRT, using pseudo-step-wedge intensity modulation to match the target dose distribution of the conventional technique. Both groups had similar stage distribution, histology, brachytherapy, and concurrent chemotherapy. With a mean follow-up of 52 months for living patients, 178 patients (39IMRT, 139non-IMRT) had recurred. Patients in the PET/CT guided IMRT group showed better overall and cause-specific survival (P < 0.0001). Only eight patients in the PET/CT-guided IMRT group developed Grade 3 or worse large bowel or bladder complications which was significantly lesser compared to 54 patients in the non-IMRT group (P = 0.0351).
In a large retrospective study, [35] 115 patients with locally advanced NSCLC treated with definitive PET-guided conformal radiation therapy with or without concurrent chemotherapy were analyzed for survival, local regional recurrence, and distant metastases. With a median follow-up of 18 months (range 3-44 months) for all patients, the median overall survival, two-year actuarial overall survival and disease-free survival were 19 months, 38%, and 28%, respectively. Majority of the patients died from distant metastases (overall rate of 36%). The rate of isolated failure in excluded nodal regions was extremely low (much lower than earlier series), justifying their exclusion from radiotherapy portals based on PET guidance. In a recent study, 51 patients with lung cancers - primary stage I NSCLC (n = 26), recurrent lung cancer (n = 12), or solitary lung metastases (n = 13) - were treated with PET/CT based hypo fractionated stereotactic body radiotherapy to a dose of 60Gy in three fractions with respiratory tracking. [45] With a median follow-up of 12 months, the local control was 85%, 92%, and 62% in patients with stage I NSCLC, recurrent lung cancer, and solitary lung metastasis respectively. Only 2 (7%) patients who had reduced FDG avidity at response imaging later progressed locally. The one-year overall survival rates were 81%, 67%, and 85% among the patients with primary NSCLC, recurrent lung cancer, and solitary lung metastases, respectively which were deemed superior to historical controls.
In a recent case control study, [46] 45 patients with stage IVA pharyngeal carcinoma treated with definitive chemo radiation with PET/CT-guided IMRT from were compared with 86 patients treated without PET/CT and 3D-conformal radiotherapy after matching with respect to gender, age, stage, grade, and tumor location. Median follow-up was 18 months (range, 6-49 months) for the PET/CT-IMRT group and 28 months (range, 1-168 months) for controls. PET/CT and treatment with IMRT improved cure rates compared to patients without PET/CT and IMRT. Overall survival of patients with PET/CT and IMRT was 97% and 91% at one and two years respectively, compared to 74% and 54% for patients without PET/CT or IMRT (P = 0.002). The event-free survival rate of PET/CT-IMRT group was 90% and 80% at one and two years respectively, compared to 72% and 56% in the control group (P = 0.005). In another outcome's analysis [47] of 42 patients of HNSCC treated with PET/CT-guided IMRT, the three-year overall survival and disease-free survival was 74.1% and 66.9% respectively at a median follow-up of 32 months. Seven recurrences were identified in the study cohort with a cumulative risk of 18.7%, which was comparable to other contemporary series of high-precision conformal radiotherapy.
| » Future directions | | |
Novel markers in development
18F-FDG remains the gold-standard tracer for PET imaging in oncologic practice. However, with better understanding of the molecular biology of cancer, there is an increasing demand to develop novel markers to image various aspects of cell biology. [14],[48] Some of the important non-FDG tracers include markers of hypoxia (18F-fluoromisonidazole, 18F-fluoroazomycinarabinofuranoside, 64Cu-ATSM, and 18F-EF5); tumor proliferation (18F-fluorothymidine); and amino acid metabolism (11C-methionine, 11C-tyrosine, and 18F-fluoroethyltyrosine). In addition, new tracers that specifically bind to certain intra- or extra-cellular compounds of various tumors such as 18F-DOPA (metabolism of amine precursor uptake and decarboxylase tumors), 68Ga-labeled peptides (neuro-endocrine tumors), 11C-acetate or 11C-choline, and 18F-choline (cell membrane and fatty acid metabolism) have also been developed.
Integrated MRI/PET
The combination of MRI and PET in a single gantry for simultaneous acquisition can help bridge the gap between systems and molecular diagnosis. Both PET and MRI offer richly complementary information about disease and their integration into a combined system can produce hybrid technology that is significantly better than the sum of its parts. [14] Significant progress has been made resulting in the design of preclinical hybrid MRI/PET. A high-resolution PET scanner which is insensitive to magnetic fields, has been developed to slip-fit into a 3 Tesla whole MRI bore (BrainPET) for human brain imaging. [49] The feasibility of MRI-guided attenuation correction and the prospective applications of whole-body MRI/PET systems are under way. [50]
| » Conclusion | | |
Radiation therapy planning has traditionally relied very heavily on CT imaging. Increasingly, FDG-PET/CT is being incorporated into the treatment planning process and promises to improve target volume delineation in a wide variety of cancers. Incorporating PET/CT fusion imaging for conformal radiation therapy planning in routine clinical practice can be challenging due to technical, administrative, financial, geographic, and personnel issues and requires careful attention to detail. The use of PET/CT for target volume selection should be considered within the framework of its sensitivity and specificity for various tumor types and also mandates specific tuning of parameters, such as image acquisition, processing, and segmentation. There is accumulating evidence that PET/CT-guidance has significant impact on radiotherapy planning in cancers such as NSCLC, HNSCC, and carcinoma cervix. However, its impact on patient outcomes has yet to be robustly and consistently demonstrated. The potential benefits of improved staging and more accurate target localization can promote integrated PET/CT to become the gold-standard for radiotherapy simulation and planning. Theragnostic imaging with various molecular imaging probes is an emerging and exciting area of research that has the potential to revolutionize the practice of radiation oncology in the future.
| » References | | |
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[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1]
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