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PET and PET/CT in Radiation Therapy Planning

Sandip Basu, Guobin Song, Abass Alavi, and Eugene C. Lin

More Accurate Staging

Conventional imaging techniques may up- or downstage patients with a variety of cancers. When radiation therapy is employed for optimal management of the diseased sites, understaging may result in partial treatment, and overstaging may lead to unnecessary radiation toxicity to the site(s) without disease. Positron emission tomography (PET) allows accurate staging not only at the primary site, but also at the locoregional level and distant regions. Staging with fluorodeoxyglucose (FDG) PET may change the intent of treatment from curative to palliative in 10 to 26% of cases when a new distant metastasis is detected. Several studies have documented that the improved staging with FDG PET can be used to improve patient management and significantly impact RTP (Table 27.1) and therefore improve outcome and minimize toxicity.^1–4

Tumor Volume Delineation

1. The functional information from PET images can be fused to the anatomical data from computed tomography (CT) and/or magnetic resonance imaging (MRI) within the RTP system to aid in detecting tumor and delineating the target volume for RTP. There is a considerable interest on the impact of such combined information on treatment planning, as the interobserver variability is substantially reduced compared with when these modalities are individually used.
   
2. Thresholding is the most commonly adopted method to determine volumes automatically from PET images. Most algorithms have been derived from the study of spheres of various sizes with differing levels of background signal. Some investigators have chosen to use a threshold based upon a percentage of the maximum standardized uptake value (SUVmax); others have relied on a threshold based on an absolute SUVmax value.6 Contours are based upon the maximum in the lesion of interest, with values ranging from 30 to 50% of the SUVmax used by various investigators.
   
3. In lung cancer, incorporation of PET data improves tumor volume and dose coverage and spares normal tissues, leading to less toxicity with the potential option of escalating dose to tumor tissue. In esophageal cancer and in lymphoma, a PET scan can be used to include PET-positive lymph nodes in the target volume.
   
4. In most other tumor sites, not enough data are currently available to draw definitive conclusions, though a few studies demonstrate its promise.
   
5. Daisne et al7 compared CT, MRI, and PET with pathologic findings in head and neck patients. Smaller gross tumor volume (GTV) was observed with FDG PET for oropharyngeal, laryngeal, and hypopharyngeal tumors.
   
6. Three major issues to be addressed (the majority of studies are presently focused on this issues as well) are (a) whether it allows accurate tumor delineation; (b) whether its incorporation influences GTV, clinical target volume (CTV), and planning target volume (PTV); and (c) whether there is an improvement in treatment outcome.^7–9

Source: From van Baardwijk A, et al. The current status of FDG-PET in tumor volume definition in radiotherapy treatment planning. Cancer Treat Rev 2006;32(4):245–260. Reprinted with permission.
Abbreviations: CT, computed tomography; MRI, magnetic resonance imaging; PET, positron emission tomography.

Target Volumes in Radiation Therapy Planning

1. Gross tumor volume (GTV). Derived from the gross demonstrable extent and location of tumor identified with the CT or simulator images
   
2. Clinical target volume (CTV). Expanded GTV to include subclinical disease based on additional clinical information
   
3. Planning target volume (PTV). Expanded CTV by the addition of a variable margin to take into account internal organ movement as well as patient motion and setup uncertainties10,11
   
4. Biological target volumes (BTV). Derived from the biological information about tumors and surrounding normal tissue obtained from the PET component of PET/CT.12 BTV can have different implications based upon the PET radiotracer used for scanning; for example, BTV determined from FDG might be considered to represent the viable tumor cells and can be used to determine a minimum dose for the entire tumor. However, a BTV resulting from fluoromisonidazol (FMISO; a PET tracer for hypoxia) would represent a smaller tumor subvolume, where the maximum tumor dose requires delivery to the hypoxic cells associated with radioresistance.

Clinical Applications

Integration of PET images in radiotherapy planning has been primarily studied in non–small cell lung cancer (NSCLC),13–15 with some studies published on esophageal carcinoma,¹⁶ head and neck cancer (HNC),¹⁷ and rectal carcinoma.¹⁸

Study Results for Lung Cancer

1. A survey of the published findings shows that treatment volumes are significantly altered in 30 to 60% patients with NSCLC with the addition of biologic targeting with FDG PET.19
   
2. In a series of 44 patients of NSCLC, FDG PET altered the stage of the disease in 25% of the cases by downstaging the disease in a majority of them.²⁰ GTV based on FDG PET was on average smaller than the GTV defined by CT. Also, in a different study it was found that for the same radiotoxicity to the lungs, spinal cord, and esophagus, the dose to the tumor can be enhanced by 25%; this resulted in a potentially higher tumor control probability (24% for PET/CT planning compared with 6.3% for CT-only planning).²¹
   
3. FDG PET also alters the delineation of the GTV by discriminating tumor tissue from atelectasis or necrosis.^19,22,23 Modifications in target volume delineation allows delivering a tumoricidal dose to the target while minimizing the radiation dose to the uninvolved tissue.

Study Results for Head and Neck Carcinoma

Studies have shown excellent treatment outcomes in HNC patients treated with intensity-modulated radiation therapy (IMRT),24,25 in which many small pencil beams are used to conform the volume irradiated to any irregular shape. IMRT has the ability to deliver high doses of radiation to the tumor target with very high precision; thus, accurate tumor targeting and delineation are required more than ever.

Studies in patients with locally advanced head neck squamous cell carcinoma have demonstrated that PET/CT-based radiation treatment would significantly change the dose distribution.^26,27

PET/CT has also been found helpful in the management of occult primary head and neck tumors by determining a site of origin of the primary tumor in 60%.²⁸ This translates into reduced dose distribution to uninvolved mucosal sites compared with the results of CT scan only–based plans.

Dose Painting and Theragnostic Imaging

Dose Painting

Information obtained from other novel tracers like those of hypoxia, proliferation, apoptosis, and receptor expression can be integrated with that of FDG PET imaging, which provides greater insight into the biologic pathways involved in radiation responses.29–34 Taken together, these can be utilized by the new sophisticated software planning algorithms to deliver IMRT treatments,^35–39 where the intensity through the treatment beam is varied. Combining several IMRT treatment portals can result in complex cross-sectional dose distributions being achieved and even the delivery of high-dose areas within the target, a technique that has been referred to as “dose painting.”¹² This concept depends on the ability to visualize tumor subvolumes, which are potentially radioresistant, and then paint some additional dose restricted to those subvolumes.

PET/CT for Adaptive Radiotherapy during Course of Treatment: Theragnostic Imaging

This is based upon calculation of the mean dose delivery during the early part of the treatment and the tumor response during this initial period of therapy and revision of the subsequent treatment plan.40–43 This replanning of the radiotherapy during the course of treatment can help in substantial sparing of the surrounding nontarget tissues and is the major advantage of “theragnostic” imaging, a term coined by Bentzen.⁴³

Respiratory Gating of PET

1. The aim is to accurately target the dose of radiation to the “diseased” tissue volume with relative sparing of the surrounding normal tissue.
   
2. Gating systems that can be coupled with the development of treatment plans and target volumes in equivalent physiologic state are under active research. These will allow the radiation to be delivered in synchrony with physiologic motion such as respiration.44–47
   
3. These are especially relevant to the treatment of the thoracic neoplasms.

Future Developments for Incorporating PET into Routine Radiotherapy Planning

Promising Approaches

Summary

The literature with regard to the clinical impact and patient outcome of using PET/CT to modify dose in metabolically active tumor cells is evolving at this time, and further clinical studies are needed. The detailed structural and functional imaging information potentially improves RTP by minimizing unnecessary irradiation of normal tissues and by reducing the risk of geographic miss. The potential of PET to quantify metabolism and identify new imaging targets within tumor tissue such as cellular proliferation, hypoxia, tumor receptors, and gene expression, thereby helping in the biological optimization of dose delivery, is an exciting area of research.45–49 However, the impact of PET/CT-based IMRT dose painting RTP on tumor control and clinical outcome can only be determined with prospective research studies of patients.

References

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