PET-Based Radiation Therapy Planning

PET-Based Radiation T h e r a p y Pl a n n i n g Christina K. Speirs, MD, PhD, Perry W. Grigsby, MD, Jiayi Huang, MD, Wade L. Thorstad, MD, Parag J. Parikh, MD, Clifford G. Robinson, MD, Jeffrey D. Bradley, MD* KEYWORDS
PET
Radiation therapy
Simulation
Treatment planning

KEY POINTS
Tumor uptake by 2-deoxy-2-[18F]fluoro-D-glucose can be visualized by PET imaging, which provides staging information as well as volumetric data about the primary and regional sites of disease.
Computed tomography (CT) simulation continues to be the standard for radiation treatment (RT) planning because of radiation dose computation. PET imaging provides primary and nodal information that is prognostic and should be incorporated in treatment planning for radiation therapy.
There are idiosyncrasies associated with RT planning that are individual to each site and must be weighed in treatment planning using PET/CT.

PET with 2-deoxy-2-[18F]fluoro-D-glucose (FDG) is rapidly becoming an integrated imaging modality for radiation treatment planning in multiple types of cancers. Fluorine 18 (18F) is a radionuclide that is created by bombarding an H218O-enriched target with protons in a cyclotron. FDG is a glucose analogue that has 18F in place of the 2’ hydroxyl group (Fig. 1A) and is transported intracellularly by the GLUT1 transporter and metabolized by hexokinase and glucose 6-phosphatase, similar to glucose (see Fig. 1B). In contrast to glucose, FDG does not undergo glycolysis because of the presence of the 18F and is instead trapped within the cell. Although FDG uptake is not specific to tumors and can be concentrated in cells involved in inflammation and infection, increased FDG uptake is a characteristic of multiple tumor types, and its visualization with PET imaging has been integrated in RT planning for multiple treatment sites, particularly for lung and gynecologic cancers. In this article, the use of PET imaging in simulation and

treatment planning is described. Although other approaches exist and are certainly valid, in this article, the methods that we have found to work for our patient populations and represent our institutional practice are discussed. Readers who are interested in other approaches are welcome to peruse the other institutional descriptions listed in the References.

PET/Computed Tomography Simulation Method Patients undergoing PET/computed tomography (CT) simulation are asked to fast for 4 hours before their appointment (Fig. 2). Therapists place the patient in the treatment position with appropriate immobilization devices in the radiation oncology department, per physician instructions, and the standard CT simulation is performed. The patient is then accompanied by a simulation therapist to the nuclear medicine department. After intravenous catheter access, the blood glucose level is measured to ensure that the patient is not hyperglycemic (>150 mg/dL in

Disclosure Statement: The authors have no financial (or other) conflicting issues to disclose. Department of Radiation Oncology, Siteman Cancer Center, Center for Advanced Medicine, Washington University, 4921 Parkview Place, Saint Louis, MO 63110, USA * Corresponding author. Washington University, School of Medicine, 660 South Euclid Avenue, Campus Box 8224, St Louis, MO 63110. E-mail address: [email protected] PET Clin 10 (2015) 27–44 http://dx.doi.org/10.1016/j.cpet.2014.09.003 1556-8598/15/$ – see front matter Ó 2015 Elsevier Inc. All rights reserved.

pet.theclinics.com

INTRODUCTION

Speirs et al

28

A

B

Fig. 1. FDG structure and mechanism. (A) The FDG chemical structure. FDG is a glucose analogue that has 18F in place of the 2’ hydroxyl group. (B) The mechanism of FDG uptake. Similar to glucose, FDG is transported intracellularly by the GLUT1 transporter and metabolized by hexokinase and glucose-6-phosphatase, but thereafter it is trapped within the cell, because it cannot undergo glycolysis.

nondiabetic patients, >200 mg/dL in diabetic patients), because this may confound tumor uptake of FDG. For gastrointestinal (GI) visualization, patients may be asked to drink an oral contrast agent (MD-Gastroview, 590 mL [20 oz]). FDG is then given intravenously, at a dose determined by body weight (range 10–24 mCi). To minimize activity in the urinary tract for gynecology patients, a Foley catheter is inserted, 20 mg furosemide and intravenous fluids (1000–1500 mL 0.45%–0.9% normal saline) are given, and the patient waits 60  10 minutes for FDG absorption. A water-soluble iodinated oral contrast agent, such as MD-Gastroview (diatrizoate meglumine and diatrizoate sodium solution; Mallinckrodt, Saint Louis, MO), can also be given at the discretion of the physician. After positioning on the scanner table by a radiation therapist in the same position/immobilization devices used earlier, the patient is scanned on a Siemens Biograph 40 TruePoint or an mCT

Biograph 40 (the latter contains time of flight capabilities for patients with large body habitus). After a standard topogram, most scans include a single acquisition of PET/CT data. In gynecology patients, this scan is followed by a final highresolution CT (which can be used as the CT simulation data set for these patients in place of the earlier scan). The topogram directives are based on the primary tumor site (eg, patients with thoracic tumors are scanned from the mandible to the adrenal glands, and patients with gynecologic tumors are scanned from the liver to midfemur). Depending on the scanner used, the PET/ CT images are reconstructed with and without attenuation correction in a 168  168 or a 200  200 matrix (4-mm slice thickness, 3-mm interval), with a zoom of 1 and a 1-mm Gaussian filter. A three-dimensional (3D) ordered subset expectation maximization (OSEM) algorithm is used for reconstruction. The high-resolution CT has a 3-mm slice thickness and a 3-mm interval.

Fig. 2. The integration of PET in the radiation treatment planning workflow, showing the workflow used for patients who have gynecologic cancer. PET is used for diagnosis and treatment planning for both external beam radiation and brachytherapy. CTV, clinical tumor volume; MTV, metabolic tumor volume; PA, para-aortic.

PET-Based Radiation Therapy Planning Exceptions to these conditions are made with (1) head and neck (H&N) patients, in whom images have no post-reconstruction filtration and the zoom is increased to 1.2, and (2) pediatric patients less than 20 kg, in whom images have no post-reconstruction filtration and the zoom is increased to 1.5. After image collection, the fused PET/CT images are reviewed by our dosimetrists. This data set is then fused to the CT simulation data set, using a treatment planning software system such as Velocity. The exception to this practice is gynecology patients, in whom the high-resolution CT scan obtained in the nuclear medicine department is the primary data set. The fusion is reviewed by a physician for use with target delineation. Special attention is given to the primary tumor location and volume, as well as the sites of lymph node (LN) involvement. For gynecologic sites, the primary maximum standardized uptake value (SUVmax) is used for target delineation; the method for this is discussed further in the gynecologic cancer section.

LUNG CANCER Non–Small Cell Lung Cancer Appropriate staging with imaging and pathology evaluation is critical to the diagnosis of non–small cell lung cancer (NSCLC), because stage is the most important prognostic factor. Of patients with NSCLC, 60% to 80% are diagnosed at stages III to IV, and these patients often do not benefit from surgery as first-line treatment.1–3 PET/CT is recommended by the National Comprehensive Cancer Network (NCCN) for evaluation of all pulmonary nodules suspicious for lung cancer, no matter the stage. A positive PET result is defined by the NCCN as containing an SUV (see later discussion for SUV calculation) higher than that of the mediastinal blood pool, although false-negative results can occur because of high blood glucose levels, small tumor size, low cellular density caused by cavitation or cystic components, or histology. For example, mucinous carcinomas can show false-negative results in as many as 41% of tumors,4 whereas adenocarcinoma in situ/bronchoalveolar carcinoma and carcinoid tumors may have lower FDG avidity than other NSCLC tumors of comparable size. Evaluation of a pulmonary nodule  involved LNs by CT alone prioritizes the size of the primary lesion (increased concern for malignancy in solid nodules >8 mm and nonsolid nodules >10 mm) and the LNs, although this can be misleading. Results from the American College of Surgeons Oncology Group (ACOSOG) Z4031 study, in which FDG-PET scans were used for the diagnosis of NSCLC in 51

enrolling sites (n 5 682), showed that the sensitivity and specificity was 82% and 31%, respectively. The negative predictive value (NPV) and the positive predictive value (PPV) were 85% and 26%, respectively, and increased lesion size increased the accuracy of diagnosis. The falsepositive rate was 12%, and the false-negative rate was 15%, and the latter occurred with all histologies (adenocarcinoma, squamous, bronchoalveolar, and neuroendocrine cells).5 Because involvement of the LNs increases the stage, PET/CT analysis of the LNs is part of diagnostic evaluation. In a study by Pieterman and colleagues,6 PET imaging (vs CT) was found to increase sensitivity (91% in PET vs 75% in CT) and specificity (86% in PET vs 66% in CT) of LN involvement, findings that have been corroborated by other studies.7,8 The generation of hybrid PET/ CT scanners allowed further anatomic localization of involved structures that had increased FDG uptake. In a retrospective study by Bille´ and colleagues of patients with potentially resectable NSCLC, the accuracy of PET/CT imaging was evaluated and presented per patient and per nodal station. The sensitivity was found to be 54.2%/57.7% (per patient/per nodal station), the specificity was 91.9%/98.5%, the PPV was 74.3%/74.5%, the NPV was 82.3%/96.8%, the accuracy of mediastinal LN (which denotes N2 disease) detection was 80.5%/95.6%, and the accuracy of detecting N2/N3 disease was 84.9%/95.3%. Other studies have shown that the use of PET/CT imaging increased the accuracy of LN staging from 56% to 78% and improved the distinction of hilar and mediastinal involvement.9–12 Halpern and colleagues13 reported that blinded analysis of PET/CT yielded better staging accuracy than PET alone. Therefore, PET/CT analysis correlates increased size with increased FDG uptake to increase the accuracy of testing. However, imaging cannot supplant the use of biopsy/resection for surgical staging, because the false-negative rate of PET/CT is 5% to 10% (see earlier discussion of contributing factors), and the PET/CT sensitivity for determining LN involvement is correlated with LN size (32.4% in LNs <10 mm, 85.3% in LNs >10 mm).14,15 PET/CT imaging is also used to evaluate whether there are distant metastases, which is an important determinant in whether a patient with NSCLC can receive definitive chemoradiation (vs chemotherapy alone, with RT used for palliation only). PET/CT is able to identify distant metastases in 11% of patients with NSCLC in whom other screening methods have been negative, with an 82% sensitivity and 93% specificity for distant metastases alone.6,16 In addition, multiple studies have shown that PET/CT performs better

29

30

Speirs et al than a bone scan to detect osseous metastases.17–20 As discussed earlier, the diagnosis of stage IV NSCLC requires biopsy confirmation of sites that seem to be involved on PET imaging before the pursuit of nonsurgical therapies. Prognostic information may also be extracted from PET/CT imaging. The International Association for the Study of Lung Cancer21 published a metaanalysis of 21 studies showing that a high SUV (relative to the median SUV threshold of each study) correlated to an increased risk of death with an overall hazard ratio (HR) of 2.04. Recently published results of American College of Radiology Imaging Network (ACRIN) 6668/Radiation Therapy Oncology Group (RTOG) 0235,22 a prospective analysis of the effect of PET findings on survival, showed that in patients with stage III NSCLC, increased SUVpeak (the mean SUV in a w1 cm circular region encompassing the SUVmax, vs the SUVmax, which was defined as the highest single voxel within the region of interest [ROI]) after treatment correlated with survival in a continuous variable model. Pretreatment SUVmax and SUVpeak did not. In a subset analysis,22 a post-treatment SUVpeak or SUVmax greater than 5 indicated a worse prognosis for overall survival. More recently, Markovina and colleagues23 performed analysis on these patients showing that the post-treatment SUVpeak or SUVmax was associated with inferior localregional control (P<.01). Al-Sarraf and colleagues24 reported that patients with a primary SUVmax greater than 15 not only had decreased overall survival, but had increased risk of advanced LN involvement and decreased nodal stage-specific survival after resection. Although the prognostic value of SUVmax is more controversial in patients with early stage NSCLC,25–27 a study by Agarwal and colleagues28 showed that in preoperative PET scans, the HR increased by 1.28 for each doubling of the SUVmax. Diagnostic imaging aside, the information on PET/CT scans also affords more accurate radiation treatment planning. If a PET/CT scan is performed within 60 days of biopsy confirmation of disease and within 28 days of the planned initiation of RT, we fuse it to a standard CT simulation to use for RT planning. RT planning begins with the CT  PET simulation. Four-dimensional (4D) CT is used in our lung cancer treatment planning to reduce blurring of the target structures, which is inherent with respiratory motion, by using amplitude binning of the patient’s respiratory cycle. For clinics that do not have 4D CT imaging capabilities, alternatives to optimize treatment reproducibility and encompass the tumor target are available. These options include increasing the margin size of the target contoured on a midventilation breath scan, or

performing the simulation CT and subsequent treatment with breath-hold techniques (the type of breath hold depends on the patient’s anatomy and location of the tumor). For our stereotactic body radiation therapy (SBRT) patients, the physician evaluates motion of the tumor target during simulation and may choose to use abdominal compression to ensure that tumor motion is less than 1 cm. PET/CT images are often used for SBRT planning for patients who have early stage lung cancer and are always used on our patients who have stage III lung cancer who are undergoing definitive chemoradiation. Once the PET/CT images are moved into our treatment planning system, the fusion of the PET/CT is reviewed by the physician. FDG-avid areas are outlined (also referred to as segmentation or contouring) for target delineation as part of the gross tumor volume (GTV) with correlation to the maximum intensity projection (MIP) on the 4D CT to generate an internal target volume (ITV), which is expanded by 2 sequential margins to account for microscopic tumor extension (clinical tumor volume [CTV]) and planning uncertainty (planning target volume [PTV]) (Fig. 3). Physicians may also incorporate additional relevant clinical information, including the physical examination and other radiographic study findings. One of the advantages of PET/CT for target delineation is that the PET images can better distinguish tumor from atelectatic lung than CT alone, thus reducing needless normal tissue toxicity.29 Furthermore, in our institutional prospective study on the use of PET/ CT in RT planning for NSCLC,29 the incorporation of PET imaging changed the target volume in 58% of patients and identified nodal involvement in 38% of patients. Another study by MacManus and colleagues30 showed that as many as 34% of patients initially intended for definitive chemoradiation were converted to palliative therapies based on their PET/CT findings. The use of PET/CT imaging for contouring was also shown to decrease interobserver variation by Caldwell and colleagues31 in as many as 77% of planned patients. However, tumor contouring in RT planning with PET/CT does require special consideration. There is limited spatial resolution of the edge of the FDG avid region (4.5–7 mm), increasing reliance on the CT images for the edge of the target. In addition, there is possible underestimation of the tumor SUV signal in small tumors secondary to tumor motion and the partial volume effect. In an effort to circumvent these limitations, several studies have used autocontouring using an SUV cutoff. Paulino and colleagues32 used an SUV threshold of 2.5 for inclusion in the tumor volume. In contrast, Biehl and colleagues33 used tumor size

PET-Based Radiation Therapy Planning

Fig. 3. PET/CT coregistration/fusion for treatment of a stage III superior sulcus non-small cell lung cancer (NSCLC) patient. An 88-year-old man with stage III (T4N0M0) NSCLC. This patient underwent a diagnostic PET/CT and a 4D CT simulation. The 4D CT was evaluated and the MIP was used to generate an ITV accounting for tumor motion. The images were coregistered before tumor segmentation/contouring. The axial (A), sagittal (B), and coronal views (C) are shown. The ITV, CTV, and PTV were outlined in red, light green, and light blue, respectively. Treatment was given with concurrent chemotherapy.

to threshold SUV levels, because no single tumor SUV threshold sufficed for accurate tumor delineation (tumors >5 cm: 15%  6%, 3–5 cm: 24%  9%, <3 cm, 42%  2%). A third study by Nestle and colleagues34 used thresholding by a tumor/background intensity ratio, although they determined that this was an inadequate method. Hoetjes and colleagues35 used a partial volume correction (PVC), which, in brief, was performed with 3 methods: (1) the point spread function (PSF, which allows representation of an unresolved object in a focused optical system) was incorporated into image reconstruction; (2) the images were submitted to iterative deconvolution to remove signal distorting effects; or (3) a tumor volume mask with PSF smoothing was compared with the uncorrected image set to calculate spillin/spill-out factors, which altered the image volume. All methods were found to be equivalent. Although we use a 4D CT simulation data set as our standard for RT planning, the visualization of

LNs can be unreliable, even in patients who receive intravenous contrast. Previous data by Aristophanous and colleagues36 have shown that the use of 4D PET/CT may be more accurate in recapitulating the movement of lung tumors compared with a 3D PET/CT data set. In addition, data from Lamb and colleagues37 have shown that the 4D PET MIP correlated better to the 4D CT MIP than the ungated PET MIP. In addition, use of 4D PET in patients with hilar or mediastinal involvement resulted in a tumor ITV that required as much as a 13-mm isotropic expansion of the ungated PET nodal volume to encompass the FDG avid region, which resulted in the inclusion of more normal tissue in the ITV.38 There is an ongoing study to address the use of PET-adaptive RT planning in patients with stage III NSCLC to increase dose and spare normal tissue toxicity, should the tumor burden have a response midtreatment to chemoradiotherapy (CRT). In RTOG 1106, patients are randomized to arm 1

31

32

Speirs et al (standard arm), in which they receive RT to 60 Gy in 30 fractions with concurrent weekly carboplatin/ paclitaxel, or arm 2, in which they receive RT to 46.2 Gy in 21 fractions with carboplatin/paclitaxel with PET-adaptive planning and resimulation at weeks 3 to 4 (Fig. 4). All patients undergo a midtreatment PET/CT scan regardless of randomization. In arm 2, adaptive planning for the final 9 fractions leads to patients receiving dose escalation to as high as 80.4 Gy in 30 fractions, as long as all the standard tumor coverage and normal tissue constraints are still met. This study is based on previous prospective data from the University of Michigan showing that reduction of the metabolic tumor volume (MTV, delineated by PET) midway through treatment can allow for target volume reduction and dose escalation, without violating normal tissue constraints or increasing treatment time. Dose escalation using conventional fractionation to a dose of 74 Gy has been shown to be inferior to 60 Gy in terms of both overall survival and local control in stage III NSCLC.39 However, the idea of adaptive radiation therapy using midtreatment PET/CT to focus a hypofractionated boost to residual disease may be beneficial in exploiting the therapeutic window between tumor control and normal tissue toxicity. The RTOG 1106 phase 2 randomized trial continues to accrue as a test of this hypothesis.

Small Cell Lung Cancer Although the prognosis for small cell lung cancer (SCLC) is poor, overall survival has increased with evolving treatment practices. Stage-specific 2-year and 5-year survival rates for SCLC have improved over time as measured by treatment

decade (regional 2-year/5-year: decade 1, 15%/ 6.8% / decade 3, 22%/11%; distant 2-year/ 5-year: decade 1, 3.4%/1.3% / decade 3, 5.6%/1.9%).40 SCLC is most often staged as limited stage (LS, disease can reasonably fit into 1 radiotherapy portal) versus extensive stage (ES). Although restricted in use, surgical resection can be used for T1-2N0 patients, although most LS patients receive concurrent chemotherapy and thoracic radiation. ES patients receive chemotherapy alone as first-line therapy, with possible consolidative RT, depending on response to chemotherapy. The NCCN recommends PET/CT imaging if LS disease is suspected. In our prospective institutional study,41 patients who had LS disease as defined by CT chest/abdomen/pelvis and MR imaging brain and bone scan underwent an additional FDG-PET scan. PET had 100% sensitivity to the primary or nodal disease. Eight percent of patients were upstaged to ES disease, which was confirmed by imaging (using other modalities) or biopsy. Twenty-five percent of patients had additional regional involvement identified that led to altered treatment planning. These findings have been echoed in other studies.42 In a study by Kamel and colleagues,43 FDG-PET scans in 24 patients who have SCLC were used for staging. Thirteen percent of patients were upstaged from LS to ES, whereas 4% were downstaged from ES to LS. Nineteen percent of patients had their RT target altered because of the PET findings. For extrathoracic metastases, PET performs better than CT (Brink and colleagues44: sensitivity of PET 98% vs CT 83%, specificity of PET 92% vs CT 79%), except for brain metastases, in which cranial MR imaging/CT had a

Fig. 4. The tumor response to chemoradiation in patients with stage III NSCLC can be used for PET-adaptive radiation treatment planning, per RTOG 1106. The goal of RTOG 1106 is to use the PET tumor response at midtreatment to increase the tumor dose and spare normal tissue toxicity in patients randomized to the experimental arm, should the tumor burden have a response midtreatment to chemoradiation. In this example, (A) is the patient’s PET/CT simulation before treatment and (B) is the patient’s PET/CT imaging 3 weeks later, after the patient received 47.5 Gy in 19 fractions (at 2.5 Gy/fraction). Treatment was given with concurrent chemotherapy.

PET-Based Radiation Therapy Planning sensitivity and specificity of 100%. For sites of involvement shown on PET/CT that will alter the patient’s assigned stage, biopsy confirmation should be performed before change in treatment management. RT planning for SCLC begins with PET/CT imaging, which should be performed immediately before RT initiation. Radiation and platinumbased/etoposide chemotherapy are given concurrently for LS patients. If PET imaging is greater than 4 weeks previous, we often obtain a limited PET/CT of the thorax for radiation planning purposes. All FDG-avid thoracic disease is contoured on the PET/CT. Although past trials have treated the mediastinal nodes electively regardless of involvement (as in Turissi and colleagues45), multiple studies of selective nodal irradiation that target only those nodes involved by PET have shown low rates of isolated regional node recurrence.46–48 In a study by Van Loon and colleagues,46 the rate of isolated regional node recurrence was 3% when PET was used for RT planning, versus 11% with CT planning in their previous phase 2 study, suggesting that PET is the best modality with which to plan radiation treatment.47 For target delineation, the involved PET/CT volume (1 any regional LN 1.5 cm in short axis) is contoured as the GTV, then, 2 sequential margins are used for expansion to the CTV and PTV, respectively. There has been a phase 1 study in which a thresholded portion of the PET volume was used to determine response to chemotherapy after 1 cycle (before RT).49 This MTV reduction was found to correlate with survival (2% increase in survival for every 1% decrease in thresholded volume), but this technique is not in widespread use.

GYNECOLOGIC CANCER PET imaging has been regularly used for treatment planning at our institution for gynecologic cancers since 2005. In this section, the use of PET imaging for the planning of cervical, vulvar, vaginal, ovarian, and endometrial cancers is discussed, with an emphasis on cervical cancer. Cervical cancer staging recommendation by the NCCN includes CT or PET/CT imaging to define the primary tumor and sites of regional and distant metastasis. Determining which patients have pelvic LN, para-aortic (PA) LN, or distant metastasis is important, because it differentiates the patients who can undergo surgery from the patients who will receive definitive CRT. Multiple studies have identified the efficacy of PET in staging patients with cervical cancer. In preoperative PET imaging of patients with early stage disease that is clinically visible (International

Federation of Gynecology and Obstetrics [FIGO] 1B1 or higher), the primary is identified in 100% of cases, and the pelvic LN sensitivity and specificity are 30% to 50% and 90%, respectively.50–52 Advanced cervical cancer has increased risk of spread (in order) to the pelvic, PA, and distant (eg, supraclavicular) LNs, and the pelvic and PA LN sensitivity with PET imaging in these patients is greater than 90% and 95%, respectively.53–56 We have previously described our method for using PET imaging in our treatment planning.50,57–60 Patients are often treated with a combination of external beam pelvic radiation (using intensity-modulated radiation therapy [IMRT]) and concurrent brachytherapy. Therefore, patients receiving definitive chemoradiation are treated with a split pelvis field, in which the dose to the primary tumor contour (based on the PET scan and termed the MTVCERVIx) is treated to a lower dose (most commonly 20 Gy) than the remainder of the surrounding pelvic LNs (which are usually treated to 50.4 Gy) during the external beam radiation treatment. The use of a split field to cool the central pelvic dose allows the primary tumor to be boosted with concurrent vaginal brachytherapy using tandem and ovoids (see later discussion). Unlike our other treatment planning approaches, we use autocontouring for patients with cervical cancer to delineate the primary tumor, which is based on previous data (discussed later). Information from the PET scan is critical for target delineation, so patients without recent diagnostic PET scans that can be fused to the CT simulation data set undergo a PET/CT simulation before treatment planning (as described in the introduction in the section on PET simulation method, see Fig. 2). At the time of contouring, the SUVmax (a correlate of the peak tumor activity) is measured within the primary tumor using a volumetric tool in the imaging software. The primary tumor SUVmax is a prognostic indicator for cervical cancer survival,61 and we have used it since 2005 as a parameter for tumor delineation. SUVmax 5

tissue radioactivity concentration ðnCi=mLÞ injected dose ðnCiÞ=patientweight ðgÞ

The primary tumor is based on a 40% SUVmax thresholding method previously described by Miller and Grigsby.59 A PET-based 3D volume depends on the high tumor/background ratio (often >10:1) of FDG uptake and is automatically generated to (1) provide an accurate primary tumor volume assessment for treatment and (2) reduce interobserver and intraobserver error. A 3D tumor ROI includes any voxel falling within a

33

34

Speirs et al 40% threshold of the SUVmax, which is then enlarged by a region-growing morphologic operation. The 40% threshold has been validated by multiple studies, including a recent study by Zhang and colleagues,62,63 which identified a 40% SUVmax as the optimal threshold for correlation with the pathologic tumor volume. The MTVCERVIx is extrapolated from this ROI by the number of voxels within this outline and the known volume of a single voxel. The contour may be manually adjusted by the physician for up to 25% of patients with adjacent high activity of the urinary tract/bladder included in the automatically generated contour. Each of our PET simulation scans and fused PET diagnostic scans is evaluated by nuclear medicine radiologists, and the results of this evaluation inform our contouring process, especially regarding the inclusion of nodal involvement. In cases of uncertainty regarding the tumor delineation, the physician reviews the studies with nuclear medicine specialists to ensure that the appropriate targets are contoured. The primary tumor volume does not correlate with the SUVmax or survival.61 Furthermore, the primary tumor histology can affect the SUVmax value. In a study by Kidd and colleagues,64 the mean SUVmax was 11.91 (range 2.5–50.39) in squamous cell carcinomas (SCC) of the cervix, 8.85 (range 6.53–11.26) in adenosquamous cell carcinomas, and 8.05 (range 2.83–13.92) in adenocarcinomas. In addition, the mean SUVmax correlated with tumor differentiation, with an SUVmax of 8.58 for well-differentiated, 11.56 for moderately differentiated, and 12.23 for poorly differentiated tumors. Contouring of the nodal involvement sites is also performed with PET imaging. PET LN status has been identified as the best parameter for survival outcome, and a PET-based nomogram for patients who have cervical cancer incorporating the cervical tumor volume, SUVmax, and PET LN status had better correlation to the clinical outcome than the assigned FIGO stage.57 There is no correlation of primary tumor volume with LN involvement, but the SUVmax is correlated with risk of LN metastasis.59,61 For the nodal contours (termed CTVNODAL), the vessels are contoured from the bifurcation of the common iliac vessels to the midfemoral heads with a 7-mm expansion to include the common iliac, external iliac, and internal iliac LNs. Should the PA LNs be involved, the superior border of the LN CTV (CTVNODAL) contour is raised to above the PA nodes for their inclusion, because of their importance in survival outcome.65 The contours for the MTVCERVIx and CTVNODAL targets are

modified to exclude bony structures such as the pelvic bones, femoral heads, and vertebral bodies, and are expanded by 5 mm for setup uncertainty to create the PTV (PTVFINAL) (Fig. 5). Planning is aimed to provide 95% of the prescription dose to 100% of the volume of the PTVFINAL and to minimize normal tissue receiving the 110% dose. If their performance status permits, patients are treated with concurrent chemotherapy (usually cisplatin). We treat patients with IMRT, as our institutional study has shown an improvement in overall and cause-specific survival.58 The small bowel and bone marrow dose is decreased with IMRT, likely contributing to the reduced GI and genitourinary (GU) toxicity in these patients (6%  grade 3 toxicity in IMRT vs 17% in non-IMRT patients).58 For vulvar and vaginal tumors, a diagnostic PET or PET/CT simulation is performed, because these scans can better identify the primary tumor than CT alone (100% of intact vaginal primaries with PET vs 43% with CT alone) and have a sensitivity of 67%, specificity of 95%, PPV of 86%, and NPV of 86% for identifying groin metastases in vulvar patients.66,67 For endometrial tumors, there are some data evaluating the use of PET/CT before treatment that show high uptake in the primary tumor (84%), as well as moderate sensitivity (50%– 67%) and high specificity for detecting LN metastasis. However, as with ovarian cancer, the use of PET/CT is more widespread with recurrent endometrial tumors.68,69 Finally, uterine sarcomas have relatively higher FDG uptake, so PET/CT imaging may prove helpful for delineating these targets for treatment.70,71 Future directions for the use of PET in the treatment of gynecologic malignancies include developing our understanding of the PET treatment with patient outcome,72 including measurement of intratumoral heterogeneity (the derivative [(dV/dt)] of thresholding from 40% to 80% of the SUVmax), which is significantly associated with tumor volume, LN metastases, tumor response at 3 months, risk of pelvic recurrence, and progression-free survival.73,74 In particular, the p16 status and the textural features of intratumoral heterogeneity have stood out as important contributors to the PET tumor response.74,75 PET/ MR imaging has been shown in early studies to offer increased sensitivity, specificity, and accuracy for detecting recurrence and metastases in patients with gynecologic malignancy than MR imaging or PET/CT alone (sensitivity, specificity, accuracy, respectively; PET/MR imaging: 91.3%, 100%, 93.3% vs PET/CT: 82.6%, 100%, 86.7%).76 Further analysis

PET-Based Radiation Therapy Planning

Fig. 5. PET/CT fusion for treatment of a patient who has cervical cancer. A 43-year-old woman with FIGO IIIB SCC of the cervix. She underwent a PET and CT simulation for external beam radiation treatment planning; the axial (A), coronal (B), and sagittal (C) views are seen. The MTVCERVIx (red) was automatically contoured using a 40% threshold of the SUVmax (please see text for further details). The CTVNODAL was outlined in light green, and the PTVNODAL was outlined in light blue. This patient also received intracavitary brachytherapy (plan not shown). Treatment was given with concurrent chemotherapy.

of the correlation between pathologic and imaging tumor volumes, as in the studies by Zhang and colleagues, will also be critical to determine the optimal margins for microscopic disease extent used in treatment planning.

HEAD AND NECK CANCER PET/CT is recommended as diagnostic imaging by the NCCN for (H&N) cancer when stage III to IV disease or when an occult primary is suspected. Guidelines on the use of FDG-PET scans by Fletcher and colleagues77 do not recommend routine diagnostic FDG-PET imaging, because it does not add much benefit to CT or MR alone. In addition, physiologic FDG uptake in the nasopharynx and Waldeyer ring can sometimes muddy interpretation, causing either contouring based on CT alone or overcontouring for primary tumors in these regions. In the case of an occult primary, FDG-PET imaging can identify a primary lesion in 20% to 50% of cases, although these must be

proved by biopsy, because there is a 56% falsepositive rate.77,78 However, as the incidence of transoral visualization continues to increase, the benefit of PET in identifying occult primary tumors may be mitigated. In a pilot study by Karni and colleagues,79 transoral visualization led to identification of a primary tumor (most often in the oropharynx) in 94% of patients, and 89% of patients were able to undergo immediate transoral laser microsurgery without subsequent recurrence at 30 months of follow-up. For nodal evaluation, a meta-analysis by Kyzas and colleagues80 showed that the addition of PET imaging offered a small 5% to 10% benefit over other imaging modalities, which was decreased even further in patients with clinically node-negative disease (sensitivity 50%).81 Despite its limited use in initial diagnosis, the use of FDG-PET imaging was found to change staging in 10% to 36% of patients, and the RT volume in 14% to 60% of patients.81–84 Some studies show that the PET-derived MTV is smaller than

35

36

Speirs et al the CT-generated GTV,32,85 whereas other studies show that the MTV is often larger than the CTGTV.86–88 Once the PET/CT images are obtained, how does one approach GTV contouring with H&N patients? As in other treatment sites, there have been multiple studies investigating methods of segmentation with H&N cancer. In a study by Schinagl and colleagues,85 5 methods were used: (1) visual interpretation; (2) use of an SUV threshold of 2.5, (3) thresholding using autocontouring at 40% or (4) 50% of the SUVmax, or (5) adaptive thresholding based on the tumor/background ratio. When performed, the use of an SUV threshold of 2.5 was found to be uninformative, but the other MTV contours varied widely based on method. That tumor thresholding leads to dramatic changes in tumor volume treatment planning has also been shown by Ford and colleagues.89 In their study, a 5% change in threshold led to a 200% change in volume, which markedly altered the dosimetric coverage. To show this point, these investigators found that changing the threshold from 44% to 52% changed the dose given to 95% (D95) of the PTV from 77.7 Gy to 72.3 Gy. Segmentation has also been shown to be important for nodal volume delineation, especially when enlarged LNs on CT are not FDG-avid.90 The SUV is predictive of outcome in patients who have H&N cancer. In a study by Garsa and colleagues,91 the total MTV on 86 patients with oropharyngeal SCC was associated on multivariate analysis with an increased risk of disease progression and death. MTV volumes greater than 20.5 mL increased the risk of death by 4.13-fold, regardless of p16 status. These findings were also seen in studies by Murphy and colleagues92 and Tang and colleagues.93 Another study by Chu and colleagues94 suggests that when the MTV tumor volume is assessed on serial PET/CT scans before RT initiation, the calculated MTV tumor velocity (absolute change in MTV/time in weeks) was predictive of disease-free survival and overall survival. There has also been work correlating the pathologic tumor volume on surgical specimens from postoperative patients who have H&N cancer with the imaging-defined volume. Of course, pathologic evaluation of tumor specimens is subject to sampling bias and is not 100% definitive for tumor delineation, although it assists in verifying the edge of a tumor seen on imaging. In a study by Daisne and colleagues,95 patients with H&N SCC imaged before surgery with CT, MR imaging, and FDGPET imaging showed that when correlated to the surgical specimen, the pathologic tumor volume was found to be consistently smaller than the

GTV generated from any of the 3 imaging modalities, although the FDG-PET volume was the most accurate. For example, CT or MR imaging missed 15% to 20% of the FDG avid mass. Ten percent of the macroscopic tumor was missed on imaging (usually superficial tumor extension). Another study by Murphy and colleagues96 analyzed the predictive factor of MTVs thresholded at multiple levels, but the correlation with the pathologic tumor volume assessed on the surgical specimen was found to be poor overall (R2 range 5 0.29–0.58). At our institution, we use PET/CT simulation or fusion of PET/CT images to the CT simulation data set to contour the tumor volume (MTV). Radiation treatment of H&N cancer is given by IMRT, which has been described previously by our institution and others.91,97–99 PET limitations such as the variable volume in relation to CT, 5-mm to 10-mm resolution, physiologic uptake in the oropharynx, and superficial mucosal extension are all taken into account when delineating the MTV of the primary and nodal regions. The MTV is then expanded to generate the CTV and PTV for treatment delivery (Fig. 6). If treatment is given postoperatively, anatomic changes are carefully reviewed to ensure that the previous area of gross disease and the regions at risk are included in the target volume. Depending on physician discretion, elective nodal regions may also be contoured based on the CT simulation data set. In this scenario, the primary tumor/MTV is treated concurrently to a higher dose (eg, a simultaneous integrated boost) using a method called dose painting, which has been described previously.85,91,100–102 Identifying methods to escalate dose to the tumor is especially important after the results of a Danish study from Due and colleagues.103,104 In 39 patients with a complete response after definitive chemoradiation followed by subsequent disease relapse, the local-regional recurrences originated within the pretreatment MTV 54% of the time, with 96% of local-regional recurrences found within the high-dose region. Furthermore, the recurrence density (number of recurrences within a target volume measurement) was highest in the GTV and increased with the percent SUVmax, suggesting that insufficient dose to these subvolumes could have contributed to local-regional failure. Therefore, efforts are under way to escalate dose to these at-risk regions for more effective treatment. In addition, adaptive PET radiation therapy in patients who have H&N cancer is in early phase clinical trials and could aid in identifying a subset of patients who benefit from adaptive dose escalation based on their PET treatment response.

PET-Based Radiation Therapy Planning

Fig. 6. PET/CT fusion for treatment of a patient who has H&N cancer. A 54-year-old man with stage IVA SCC of the right vallecula with involvement of the right neck. The patient underwent CT simulation with fusion of the diagnostic PET/CT. The axial (A), sagittal (B), and coronal (C) views are shown. The high-dose volume GTV, CTV, and PTV were outlined in red, light green, and light blue, respectively, and the low-dose PTV (including the elective nodal volume) was outlined in yellow. The patient was treated with concurrent cisplatin chemotherapy.

GASTROINTESTINAL CANCER PET imaging is not uniformly used in GI cancers. For rectal cancer, PET/CT is not recommended, unless the patient has equivocal findings on CT/ MR imaging or there is a strong contrast allergy. However, PET imaging is routinely used in diagnosis and RT planning for esophageal and anal cancer. In addition, new work is ongoing to use PET imaging in the treatment of directed liver therapy with radioembolization.

Esophageal Cancer Radiation therapy is given preoperatively or definitively for esophageal cancer, often in conjunction with concurrent chemotherapy. Although CT imaging is superior for determining the radial extent of disease, PET imaging can offer additional information on the longitudinal extent of involvement, particularly where distal stenosis by tumor can obfuscate CT findings. In a study by Leong and colleagues,105 the GTV contours generated from

FDG-PET and CT were compared. The contours were discordant in 75% of cases, especially regarding the caudal extent of involvement. Sixty-nine percent of the CT-GTV contours missed FDG avid areas detected by PET, and in 45% of those patients, this would have led to a geographic miss of grossly involved disease. In another study, physicians initially created GTV contours based on the CT data set, although this could be changed with the subsequent fusion of FDG-PET images.106 Fifty-three percent of the contour alterations made after PET fusion changed the initial CT-based PTV, resulting in a significant change in the dose to the total lung in 74% of patients. These data suggest that PET/CT is the optimal method to evaluate the primary tumor volume. FDG-PET imaging is also the most accurate method of detecting LN involvement, and can be especially helpful in celiac node or supraclavicular metastasis. Studies comparing FDG-PET with CT or endoscopic ultrasonography in patients with esophageal SCC showed 57% sensitivity, 97%

37

38

Speirs et al specificity, and 86% accuracy using PET for detecting nodal metastases, which was higher than other modalities.107,108 After PET/CT fusion to the CT simulation data set, the FDG-avid area (including nodal involvement) is contoured and correlated to CT imaging. The GTV is usually expanded by a larger margin longitudinally than radially, because of the submucosal extension of adenocarcinoma tumors. Clinical trials are ongoing to investigate the role of PET-adaptive therapy in the chemoradiation of patients who have esophageal cancer. The complete metabolic response (CMR) measured by PET has been shown to correlate strongly with survival.109 Cancer and leukemia group B (CALGB) 80803 is currently accruing patients who have resectable esophageal cancer who are randomized to induction FOLFOX or carboplatin/paclitaxel, followed by an interval PET scan. If the patient has less than 35% metabolic response

by PET/CT, they undergo crossover into the other chemotherapy treatment arm, to be delivered concurrently with RT. The primary end point is pathologic complete response rate, assessed on surgical resection.

Anal Cancer Definitive chemoradiation with 5-fluorouracil and mitomycin C is the standard of care for all anal cancers, except for small anal margin tumors. The NCCN guidelines recommend PET/CT imaging as part of the diagnostic workup for anal cancers staged as T3-T4N0 or TanyN1 disease. PET/CT imaging is better than CT alone at identifying the primary tumor (PET/CT 88% vs CT 76%) and perirectal/pelvic LN metastases (PET/ CT 26% vs CT 17%). Compared with CT or ultrasonography, PET/CT imaging upstages 14% to 37% of patients and changes the treatment volumes in 12% to 17% of patients.110,111

Fig. 7. PET/CT fusion for treatment of a patient who has anal cancer. A 52-year-old woman with stage III SCC of the anus. The patient underwent CT simulation with fusion of the diagnostic PET/CT. The axial (A), sagittal (B), and coronal (C) views are shown. The high-dose GTV, CTV, and PTV were outlined in red, light green, and light blue, respectively. The patient also had the bilateral pelvic and inguinal LNs treated to a lower dose (volume not shown). The patient was treated with concurrent 5-fluorouracil and mitomycin C chemotherapy. Please note the region of FDG uptake in the bladder, which was not included in the treatment volumes.

PET-Based Radiation Therapy Planning For RT planning, we use PET/CT routinely. PET/ CT images are fused to the CT simulation data set, and the GTV is contoured based on the guidelines of RTOG 0529, a phase 3 trial investigating GI and GU toxicity with IMRT-based dose painting (to give a simultaneous integrated boost to areas of gross disease).112 The primary tumor and areas of nodal involvement are contoured to form the MTV. A lower dose is delivered electively to the perirectal and pelvic nodes, so the mesorectum as well as the bilateral external iliac, internal iliac, and inguinal vessels are contoured with an expansion to comprise the CTV. The CTV is expanded on with the CTV of the primary lesion to form the final PTV (Fig. 7). For more information on target delineation in anal cancer, please refer to the atlas by Myerson and colleagues.113 PET/CT also provides prognostic information, which has previously been shown in a study by Schwarz and colleagues.114 In this study, patients underwent PET/CT imaging before and 1 month after definitive chemoradiation. Complete metabolic responders (CMR) were found to have improved progression-free survival (CMR 95% vs Partial metabolic responders [PMR] 22%) and cause-specific survival (CMR 94% vs PMR 39%) compared with partial metabolic responders.

Liver Metastases Hepatic tumors can occur from hepatocellular carcinoma or metastases and are associated with survival of 33% to 46%.115,116 Liver-directed therapies such as transarterial chemoembolization, transarterial chemoinfusion, radiofrequency ablation, and yttrium 90 (90Y) microsphere radioembolization are treatment options for patients with primary or metastatic hepatic malignancy that is unresectable. Salem and colleagues117 reported a 68% decrease in the size of treated hepatic lesions, but there is no routine method to assess posttreatment microsphere deposition in the tumor with high spatial resolution. Because 90Y decay contains a positron emission component, pilot studies showing dosimetric evaluation of microsphere localization after radioembolization have been performed with PET/CT imaging.118,119 At our institution, a PET/MR scanner is available for patient use, and there is an ongoing clinical trial studying the feasibility of evaluating 90Y microsphere localization after radioembolization for both primary and metastatic hepatic disease. Functional imaging using diffusion-weighted MR imaging may provide an additional parameter to confirm PET biodistribution in areas of diffusionrestricted viable tumor that cannot be visualized with CT. It remains to be seen whether

postprocedure PET/MR imaging and long-term follow-up of patients provide clinical validation on the use of PET/MR as a viable method to guide the management of patients with hepatic malignancy.

SUMMARY The use of PET/CT for radiation treatment planning is increasing because it integrates normal tissue anatomic information, tumor volume, and tumor activity. Tumor volumes generated by FDG-PET imaging are subject to multiple variables (such as resolution, partial volume effects, physiologic uptake, histology, and method of deconstruction/ registration), which must be carefully weighed during treatment planning. Because of this situation, the physical examination and other diagnostic imaging modalities continue to provide important information and should not be ignored. FDG-PET imaging may also provide prognostic information at diagnosis or after initial treatment that can be important in determining further management. The future of PET/CT target delineation likely includes more studies involving PET-adaptive contours based on treatment response, as well as pathologic correlation of tumor specimens with PET/CT/MR imaging–generated tumor contours to optimize treatment planning.

ACKNOWLEDGMENTS The authors would like to thank Martin Schmitt in the Department of Nuclear Medicine, Siteman Cancer Center, Center for Advanced Medicine, Washington University, St Louis, MO for his technical expertise related to this article. In addition, we thank Dr. Albert Chang (Department of Radiation Oncology, UCSF), as well as Carol Bertelsman, Michael Watts, Julie Whited, and Barbara Kienstra within our Department of Dosimetry for their assistance with the figure preparation.

REFERENCES 1. Pearson FG. Current status of surgical resection for lung cancer. Chest 1994;106:337S–9S. 2. Jemal A, Murray T, Samuels A, et al. Cancer statistics, 2003. CA Cancer J Clin 2003;53:5–26. 3. Chang AJ, Dehdashti F, Bradley JD. The role of positron emission tomography for non-small cell lung cancer. Pract Radiat Oncol 2011;1(4):282–8. 4. Berger KL, Nicholson SA, Dehdashti F, et al. FDG PET evaluation of mucinous neoplasms: correlation of FDG uptake with histopathologic features. Am J Roentgenol 2000;174(4):1005–8. 5. Grogan EL, Deppen SA, Ballman KV, et al. Accuracy of FDG-PET to diagnose lung cancer in the

39

Speirs et al

40

6.

7.

8.

9.

10.

11.

12.

13.

14.

15.

16.

17.

ACOSOG Z4031 trial. J Clin Oncol 2012;30(Suppl) [abstract: 7008]. Pieterman RM, van Putten JW, Meuzelaar JJ, et al. Preoperative staging of non-small-cell lung cancer with positron-emission tomography. N Engl J Med 2000;343:254–61. Gould MK, Kuschner WG, Rydzak CE, et al. Test performance of positron emission tomography and computed tomography for mediastinal staging in patients with non-small-cell lung cancer: a metaanalysis. Ann Intern Med 2003;139(11):879–92. Dwamena BA, Sonnad SS, Angobaldo JO, et al. Metastases from non-small cell lung cancer: mediastinal staging in the 1990s–meta-analytic comparison of PET and CT. Radiology 1999;213(2):530–6. Cerfolio RJ, Ojha B, Bryant AS, et al. The accuracy of integrated PET-CT compared with dedicated PET alone for the staging of patients with nonsmall cell lung cancer. Ann Thorac Surg 2004;78:1017– 23 [discussion: 1017–23]. Asamura H, Suzuki K, Kondo H, et al. Where is the boundary between N1 and N2 stations in lung cancer? Ann Thorac Surg 2000;70:1839–45 [discussion: 1845–6]. Oturai PS, Mortensen J, Enevoldsen H, et al. Gamma-camera 18F-FDG PET in diagnosis and staging of patients presenting with suspected lung cancer and comparison with dedicated PET. J Nucl Med 2004;45(8):1351–7. Lardinois D, Weder W, Hany TF, et al. Staging of non-small-cell lung cancer with integrated positron-emission tomography and computed tomography. N Engl J Med 2003;348(25):2500–7. Halpern BS, Schiepers C, Weber WA, et al. Presurgical staging of non-small cell lung cancer: positron emission tomography, integrated positron emission tomography/CT, and software image fusion. Chest 2005;128(4):2289–97. Graeter TP, Hellwig D, Hoffmann K, et al. Mediastinal lymph node staging in suspected lung cancer: comparison of positron emission tomography with F-18fluorodeoxyglucose and mediastinoscopy. Ann Thorac Surg 2003;75:231–5 [discussion: 235–6]. Bille´ A, Pelosi E, Skanjeti A, et al. Preoperative intrathoracic lymph node staging in patients with non-small-cell lung cancer: accuracy of integrated positron emission tomography and computed tomography. Eur J Cardiothorac Surg 2009;36(3):440–5. Ung YC, Maziak DE, Vanderveen JA, et al. 18Fluorodeoxyglucose positron emission tomography in the diagnosis and staging of lung cancer: a systematic review. J Natl Cancer Inst 2007;99(23):1753–67. Kru¨ger S, Buck AK, Mottaghy FM, et al. Detection of bone metastases in patients with lung cancer: 99mTc-MDP planar bone scintigraphy, 18F-fluoride PET or 18F-FDG PET/CT. Eur J Nucl Med Mol Imaging 2009;36(11):1807–12.

18. Ak _I, Sivrikoz MC, Entok E, et al. Discordant findings in patients with non-small-cell lung cancer: absolutely normal bone scans versus disseminated bone metastases on positron-emission tomography/computed tomography. Eur J Cardiothorac Surg 2010;37(4):792–6. 19. Min JW, Um SW, Yim JJ, et al. The role of wholebody FDG PET/CT, Tc 99m MDP bone scintigraphy, and serum alkaline phosphatase in detecting bone metastasis in patients with newly diagnosed lung cancer. J Korean Med Sci 2009;24(2):275–80. 20. Song JW, Oh YM, Shim TS, et al. Efficacy comparison between (18)F-FDG PET/CT and bone scintigraphy in detecting bony metastases of non-small-cell lung cancer. Lung Cancer 2009; 65(3):333–8. 21. Paesmans M, Berghmans T, Dusart M, et al. Primary tumor standardized uptake value measured on fluorodeoxyglucose positron emission tomography is of prognostic value for survival in non-small cell lung cancer: update of a systematic review and meta-analysis by the European Lung Cancer Working Party for the International Association for the Study of Lung Cancer Staging Project. J Thorac Oncol 2010;5:612–9. 22. Machtay M, Duan F, Siegel BA, et al. Prediction of survival by [18F]fluorodeoxyglucose positron emission tomography in patients with locally advanced nonsmall-cell lung cancer undergoing definitive chemoradiation therapy: results of the ACRIN 6668/RTOG 0235 trial. J Clin Oncol 2013;31(30):3823–30. 23. Markovina S, Duan F, Snyder BS, et al. Residual post-treatment FDG avidity in regional lymph nodes impacts local-regional control in patients receiving definitive chemoradiation for non-small cell lung cancer; a secondary analysis of ACRIN 6668/RTOG 0235. ASTRO 2014 Annu Meet Abstr. September 16, 2014. San Francisco, CA. 24. Al-Sarraf N, Gately K, Lucey J, et al. Clinical implication and prognostic significance of standardised uptake value of primary non-small cell lung cancer on positron emission tomography: analysis of 176 cases. Eur J Cardiothorac Surg 2008;34:892–7. 25. Hanin FX, Lonneux M, Cornet J, et al. Prognostic value of FDG uptake in early stage non-small cell lung cancer. Eur J Cardiothorac Surg 2008;33(5):819–23. 26. Davies A, Tan C, Paschalides C, et al. FDG-PET maximum standardised uptake value is associated with variation in survival: analysis of 498 lung cancer patients. Lung Cancer 2007;55(1):75–8. 27. Goodgame B, Pillot GA, Yang Z, et al. Prognostic value of preoperative positron emission tomography in resected stage I non-small cell lung cancer. J Thorac Oncol 2008;3(2):130–4. 28. Agarwal M, Brahmanday G, Bajaj SK, et al. Revisiting the prognostic value of preoperative (18)F-fluoro-2-deoxyglucose ( (18)F-FDG) positron

PET-Based Radiation Therapy Planning

29.

30.

31.

32.

33.

34.

35.

36.

37.

38.

39.

emission tomography (PET) in early-stage (I & II) non-small cell lung cancers (NSCLC). Eur J Nucl Med Mol Imaging 2010;37(4):691–8. Bradley J, Thorstad WL, Mutic S, et al. Impact of FDG-PET on radiation therapy volume delineation in non-small-cell lung cancer. Int J Radiat Oncol Biol Phys 2004;59:78–86. Mac Manus MP, Everitt S, Bayne M, et al. The use of fused PET/CT images for patient selection and radical radiotherapy target volume definition in patients with non-small cell lung cancer: results of a prospective study with mature survival data. Radiother Oncol 2013;106(3):292–8. Caldwell CB, Mah K, Ung YC, et al. Observer variation in contouring gross tumor volume in patients with poorly defined non-small-cell lung tumors on CT: the impact of 18FDG-hybrid PET fusion. Int J Radiat Oncol Biol Phys 2001;51:923–31. Paulino AC, Koshy M, Howell R, et al. Comparison of CT- and FDG-PET-defined gross tumor volume in intensity-modulated radiotherapy for head-andneck cancer. Int J Radiat Oncol Biol Phys 2005; 61(5):1385–92. Biehl KJ, Kong FM, Dehdashti F, et al. 18F-FDG PET definition of gross tumor volume for radiotherapy of non-small cell lung cancer: is a single standardized uptake value threshold approach appropriate? J Nucl Med 2006;47:1808–12. Nestle U, Kremp S, Schaefer-Schuler A, et al. Comparison of different methods for delineation of 18FFDG PET-positive tissue for target volume definition in radiotherapy of patients with non-small cell lung cancer. J Nucl Med 2005;46:1342–8. Hoetjes NJ, van Velden FH, Hoekstra OS, et al. Partial volume correction strategies for quantitative FDG PET in oncology. Eur J Nucl Med Mol Imaging 2010;37:1679–87. 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):e99–105. Lamb JM, Robinson C, Bradley J, et al. Generating lung tumor internal target volumes from 4D-PET maximum intensity projections. Med Phys 2011; 38(10):5732–7. Lamb JM, Robinson CG, Bradley JD, et al. Motion-specific internal target volumes for FDGavid mediastinal and hilar lymph nodes. Radiother Oncol J Eur Soc Ther Radiol Oncol 2013;109(1): 112–6. Bradley JD, Paulus R, Komaki R, et al. A randomized phase III comparison of standarddose (60 Gy) versus high-dose (74 Gy) conformal chemoradiotherapy with or without cetuximab for stage III non-small cell lung cancer: results on radiation dose in RTOG 0617. J Clin Oncol 2013; 31(Suppl) [abstract: 7501].

40. Owonikoko TK, Ragin CC, Belani CP, et al. Lung cancer in elderly patients: an analysis of the surveillance, epidemiology, and end results database. J Clin Oncol 2007;25(35):5570–7. 41. Bradley JD, Dehdashti F, Mintun MA, et al. Positron emission tomography in limited-stage small-cell lung cancer: a prospective study. J Clin Oncol 2004;22(16):3248–54. 42. Hauber HP, Bohuslavizki KH, Lund CH, et al. Positron emission tomography in the staging of smallcell lung cancer: a preliminary study. Chest 2001; 119(3):950–4. 43. Kamel EM, Zwahlen D, Wyss MT, et al. Whole-body 18F-FDG PET improves the management of patients with small cell lung cancer. J Nucl Med 2003;44(12):1911–7. 44. Brink I, Schumacher T, Mix M, et al. Impact of [18F] FDG-PET on the primary staging of small-cell lung cancer. Eur J Nucl Med Mol Imaging 2004;31(12): 1614–20. 45. Turrisi AT 3rd, Kim K, Blum R, et al. Twice-daily compared with once-daily thoracic radiotherapy in limited small-cell lung cancer treated concurrently with cisplatin and etoposide. N Engl J Med 1999;340(4):265–71. 46. Van Loon J, De Ruysscher D, Wanders R, et al. Selective nodal irradiation on basis of (18)FDG-PET scans in limited-disease small-cell lung cancer: a prospective study. Int J Radiat Oncol Biol Phys 2010;77(2):329–36. 47. De Ruysscher D, Bremer RH, Koppe F, et al. Omission of elective node irradiation on basis of CTscans in patients with limited disease small cell lung cancer: a phase II trial. Radiother Oncol J Eur Soc Ther Radiol Oncol 2006;80(3):307–12. 48. Baas P, Belderbos JS, Senan S, et al. Concurrent chemotherapy (carboplatin, paclitaxel, etoposide) and involved-field radiotherapy in limited stage small cell lung cancer: a Dutch multicenter phase II study. Br J Cancer 2006;94(5):625–30. 49. Van Loon J, Offermann C, Ollers M, et al. Early CT and FDG-metabolic tumour volume changes show a significant correlation with survival in stage I-III small cell lung cancer: a hypothesis generating study. Radiother Oncol J Eur Soc Ther Radiol Oncol 2011;99(2):172–5. 50. Grigsby PW. PET/CT imaging to guide cervical cancer therapy. Future Oncol 2009;5(7):953–8. 51. Wright JD, Dehdashti F, Herzog TJ, et al. Preoperative lymph node staging of early-stage cervical carcinoma by [18F]-fluoro-2-deoxy-D-glucosepositron emission tomography. Cancer 2005; 104(11):2484–91. 52. Yen TC, Ng KK, Ma SY, et al. Value of dual-phase 2fluoro-2-deoxy-d-glucose positron emission tomography in cervical cancer. J Clin Oncol 2003;21(19): 3651–8.

41

42

Speirs et al 53. Rose PG, Adler LP, Rodriguez M, et al. Positron emission tomography for evaluating para-aortic nodal metastasis in locally advanced cervical cancer before surgical staging: a surgicopathologic study. J Clin Oncol 1999;17(1):41–5. 54. Reinhardt MJ, Ehritt-Braun C, Vogelgesang D, et al. Metastatic lymph nodes in patients with cervical cancer: detection with MR imaging and FDG PET. Radiology 2001;218(3):776–82. 55. Narayan K, Hicks RJ, Jobling T, et al. A comparison of MRI and PET scanning in surgically staged locoregionally advanced cervical cancer: potential impact on treatment. Int J Gynecol Cancer 2001; 11(4):263–71. 56. Lin WC, Hung YC, Yeh LS, et al. Usefulness of (18) F-fluorodeoxyglucose positron emission tomography to detect para-aortic lymph nodal metastasis in advanced cervical cancer with negative computed tomography findings. Gynecol Oncol 2003;89(1):73–6. 57. Kidd EA, El Naqa I, Siegel BA, et al. FDG-PETbased prognostic nomograms for locally advanced cervical cancer. Gynecol Oncol 2012;127(1): 136–40. 58. Kidd EA, Siegel BA, Dehdashti F, et al. Clinical outcomes of definitive intensity-modulated radiation therapy with fluorodeoxyglucose-positron emission tomography simulation in patients with locally advanced cervical cancer. Int J Radiat Oncol Biol Phys 2010;77(4):1085–91. 59. Miller TR, Grigsby PW. Measurement of tumor volume by PET to evaluate prognosis in patients with advanced cervical cancer treated by radiation therapy. Int J Radiat Oncol Biol Phys 2002;53(2):353–9. 60. Macdonald DM, Lin LL, Biehl K, et al. Combined intensity-modulated radiation therapy and brachytherapy in the treatment of cervical cancer. Int J Radiat Oncol Biol Phys 2008;71(2):618–24. 61. Kidd EA, Siegel BA, Dehdashti F, et al. The standardized uptake value for F-18 fluorodeoxyglucose is a sensitive predictive biomarker for cervical cancer treatment response and survival. Cancer 2007; 110(8):1738–44. 62. Zhang Y, Hu J, Li J, et al. Comparison of imagingbased gross tumor volume and pathological volume determined by whole-mount serial sections in primary cervical cancer. Onco Targets Ther 2013;6:917–23. 63. Zhang Y, Hu J, Lu HJ, et al. Determination of an optimal standardized uptake value of fluorodeoxyglucose for positron emission tomography imaging to assess pathological volumes of cervical cancer: a prospective study. PLoS One 2013;8(11):e75159. 64. Kidd EA, Spencer CR, Huettner PC, et al. Cervical cancer histology and tumor differentiation affect 18F-fluorodeoxyglucose uptake. Cancer 2009; 115(15):3548–54.

65. Gouy S, Morice P, Narducci F, et al. Prospective multicenter study evaluating the survival of patients with locally advanced cervical cancer undergoing laparoscopic para-aortic lymphadenectomy before chemoradiotherapy in the era of positron emission tomography imaging. J Clin Oncol 2013;31(24): 3026–33. 66. Lamoreaux WT, Grigsby PW, Dehdashti F, et al. FDG-PET evaluation of vaginal carcinoma. Int J Radiat Oncol Biol Phys 2005;62(3):733–7. 67. Cohn DE, Dehdashti F, Gibb RK, et al. Prospective evaluation of positron emission tomography for the detection of groin node metastases from vulvar cancer. Gynecol Oncol 2002;85(1):179–84. 68. Kitajima K, Murakami K, Yamasaki E, et al. Diagnostic accuracy of integrated FDG-PET/ contrast-enhanced CT in staging ovarian cancer: comparison with enhanced CT. Eur J Nucl Med Mol Imaging 2008;35(10):1912–20. 69. Horowitz NS, Dehdashti F, Herzog TJ, et al. Prospective evaluation of FDG-PET for detecting pelvic and para-aortic lymph node metastasis in uterine corpus cancer. Gynecol Oncol 2004;95(3): 546–51. 70. Umesaki N, Tanaka T, Miyama M, et al. Positron emission tomography with (18)F-fluorodeoxyglucose of uterine sarcoma: a comparison with magnetic resonance imaging and power Doppler imaging. Gynecol Oncol 2001;80(3):372–7. 71. Ho KC, Lai CH, Wu TI, et al. 18F-fluorodeoxyglucose positron emission tomography in uterine carcinosarcoma. Eur J Nucl Med Mol Imaging 2008; 35(3):484–92. 72. Schwarz JK, Grigsby PW, Dehdashti F, et al. The role of 18F-FDG PET in assessing therapy response in cancer of the cervix and ovaries. J Nucl Med 2009;50(Suppl 1):64S–73S. 73. Kidd EA, Grigsby PW. Intratumoral metabolic heterogeneity of cervical cancer. Clin Cancer Res 2008;14(16):5236–41. 74. Yang F, Thomas MA, Dehdashti F, et al. Temporal analysis of intratumoral metabolic heterogeneity characterized by textural features in cervical cancer. Eur J Nucl Med Mol Imaging 2013;40(5): 716–27. 75. Schwarz JK, Lewis JS Jr, Pfeifer J, et al. Prognostic significance of p16 expression in advanced cervical cancer treated with definitive radiotherapy. Int J Radiat Oncol Biol Phys 2012;84(1):153–7. 76. Kitajima K, Suenaga Y, Ueno Y, et al. Value of fusion of PET and MRI in the detection of intra-pelvic recurrence of gynecological tumor: comparison with (18)F-FDG contrast-enhanced PET/CT and pelvic MRI. Ann Nucl Med 2014;28(1):25–32. 77. Fletcher JW, Djulbegovic B, Soares HP, et al. Recommendations on the use of 18F-FDG PET in oncology. J Nucl Med 2008;49(3):480–508.

PET-Based Radiation Therapy Planning 78. Rege S, Maass A, Chaiken L, et al. Use of positron emission tomography with fluorodeoxyglucose in patients with extracranial head and neck cancers. Cancer 1994;73(12):3047–58. 79. Karni RJ, Rich JT, Sinha P, et al. Transoral laser microsurgery: a new approach for unknown primaries of the head and neck. Laryngoscope 2011;121(6):1194–201. 80. Kyzas PA, Evangelou E, Denaxa-Kyza D, et al. 18Ffluorodeoxyglucose positron emission tomography to evaluate cervical node metastases in patients with head and neck squamous cell carcinoma: a meta-analysis. J Natl Cancer Inst 2008;100(10): 712–20. 81. Schwartz DL, Ford E, Rajendran J, et al. FDG-PET/ CT imaging for preradiotherapy staging of headand-neck squamous cell carcinoma. Int J Radiat Oncol Biol Phys 2005;61(1):129–36. 82. Koshy M, Paulino AC, Howell R, et al. F-18 FDG PET-CT fusion in radiotherapy treatment planning for head and neck cancer. Head Neck 2005; 27(6):494–502. 83. Schmid DT, Stoeckli SJ, Bandhauer F, et al. Impact of positron emission tomography on the initial staging and therapy in locoregional advanced squamous cell carcinoma of the head and neck. Laryngoscope 2003;113(5):888–91. 84. Nishioka T, Shiga T, Shirato H, et al. Image fusion between 18FDG-PET and MRI/CT for radiotherapy planning of oropharyngeal and nasopharyngeal carcinomas. Int J Radiat Oncol Biol Phys 2002; 53(4):1051–7. 85. Schinagl DA, Vogel WV, Hoffmann AL, et al. Comparison of five segmentation tools for 18F-fluoro-deoxy-glucose-positron emission tomographybased target volume definition in head and neck cancer. Int J Radiat Oncol Biol Phys 2007;69(4): 1282–9. 86. Riegel AC, Berson AM, Destian S, et al. Variability of gross tumor volume delineation in head-andneck cancer using CT and PET/CT fusion. Int J Radiat Oncol Biol Phys 2006;65(3):726–32. 87. Ciernik IF, Dizendorf E, Baumert BG, et al. Radiation treatment planning with an integrated positron emission and computer tomography (PET/CT): a feasibility study. Int J Radiat Oncol Biol Phys 2003;57(3):853–63. 88. Scarfone C, Lavely WC, Cmelak AJ, et al. Prospective feasibility trial of radiotherapy target definition for head and neck cancer using 3-dimensional PET and CT imaging. J Nucl Med 2004;45(4):543–52. 89. Ford EC, Kinahan PE, Hanlon L, et al. Tumor delineation using PET in head and neck cancers: threshold contouring and lesion volumes. Med Phys 2006;33(11):4280–8. 90. Schinagl DA, Hoffmann AL, Vogel WV, et al. Can FDG-PET assist in radiotherapy target volume

91.

92.

93.

94.

95.

96.

97.

98.

99.

100.

101.

102.

103.

definition of metastatic lymph nodes in head-andneck cancer? Radiother Oncol J Eur Soc Ther Radiol Oncol 2009;91(1):95–100. Garsa AA, Chang AJ, DeWees T, et al. Prognostic value of 18F-FDG PET metabolic parameters in oropharyngeal squamous cell carcinoma. J Radiat Oncol 2013;2(1):27–34. Murphy JD, La TH, Chu K, et al. Postradiation metabolic tumor volume predicts outcome in head-and-neck cancer. Int J Radiat Oncol Biol Phys 2011;80(2):514–21. Tang C, Murphy JD, Khong B, et al. Validation that metabolic tumor volume predicts outcome in headand-neck cancer. Int J Radiat Oncol Biol Phys 2012;83(5):1514–20. Chu KP, Murphy JD, La TH, et al. Prognostic value of metabolic tumor volume and velocity in predicting head-and-neck cancer outcomes. Int J Radiat Oncol Biol Phys 2012;83(5):1521–7. Daisne JF, Duprez T, Weynand B, et al. Tumor volume in pharyngolaryngeal squamous cell carcinoma: comparison at CT, MR imaging, and FDG PET and validation with surgical specimen. Radiology 2004;233(1):93–100. Murphy JD, Chisholm KM, Daly ME, et al. Correlation between metabolic tumor volume and pathologic tumor volume in squamous cell carcinoma of the oral cavity. Radiother Oncol J Eur Soc Ther Radiol Oncol 2011;101(3):356–61. Schwartz DL, Ford EC, Rajendran J, et al. FDGPET/CT-guided intensity modulated head and neck radiotherapy: a pilot investigation. Head Neck 2005;27(6):478–87. Madani I, Duthoy W, Derie C, et al. Positron emission tomography-guided, focal-dose escalation using intensity-modulated radiotherapy for head and neck cancer. Int J Radiat Oncol Biol Phys 2007; 68(1):126–35. Wang D, Schultz CJ, Jursinic PA, et al. Initial experience of FDG-PET/CT guided IMRT of head-andneck carcinoma. Int J Radiat Oncol Biol Phys 2006;65(1):143–51. Arens AI, Troost EG, Schinagl D, et al. FDG-PET/CT in radiation treatment planning of head and neck squamous cell carcinoma. Q J Nucl Med Mol Imaging 2011;55(5):521–8. Troost EG, Schinagl DA, Bussink J, et al. Clinical evidence on PET-CT for radiation therapy planning in head and neck tumours. Radiother Oncol J Eur Soc Ther Radiol Oncol 2010;96(3):328–34. Ley J, Mehan P, Wildes TM, et al. Cisplatin versus cetuximab given concurrently with definitive radiation therapy for locally advanced head and neck squamous cell carcinoma. Oncology 2013;85(5):290–6. Due AK, Vogelius IR, Aznar MC, et al. Recurrences after intensity modulated radiotherapy for head and neck squamous cell carcinoma more likely to

43

Speirs et al

44

104.

105.

106.

107.

108.

109.

110.

111.

originate from regions with high baseline [18F]FDG uptake. Radiother Oncol 2014;111:360–5. Due AK, Korreman S, Bentzen SM, et al. Methodologies for localizing loco-regional hypopharyngeal carcinoma recurrences in relation to FDG-PET positive and clinical radiation therapy target volumes. Acta Oncol 2010;49(7):984–90. Leong T, Everitt C, Yuen K, et al. A prospective study to evaluate the impact of FDG-PET on CT-based radiotherapy treatment planning for oesophageal cancer. Radiother Oncol 2006;78(3):254–61. Moureau-Zabotto L, Touboul E, Lerouge D, et al. Impact of CT and 18F-deoxyglucose positron emission tomography image fusion for conformal radiotherapy in esophageal carcinoma. Int J Radiat Oncol Biol Phys 2005;63(2):340–5. Choi JY, Lee KH, Shim YM, et al. Improved detection of individual nodal involvement in squamous cell carcinoma of the esophagus by FDG PET. J Nucl Med 2000;41(5):808–15. Van Westreenen HL, Westerterp M, Bossuyt PM, et al. Systematic review of the staging performance of 18F-fluorodeoxyglucose positron emission tomography in esophageal cancer. J Clin Oncol 2004;22(18):3805–12. Duong CP, Hicks RJ, Weih L, et al. FDG-PET status following chemoradiotherapy provides high management impact and powerful prognostic stratification in oesophageal cancer. Eur J Nucl Med Mol Imaging 2006;33(7):770–8. Mistrangelo M, Pelosi E, Bello` M, et al. Role of positron emission tomography-computed tomography in the management of anal cancer. Int J Radiat Oncol Biol Phys 2012;84(1):66–72. Sveistrup J, Loft A, Berthelsen AK, et al. Positron emission tomography/computed tomography in the staging and treatment of anal cancer. Int J Radiat Oncol Biol Phys 2012;83(1):134–41.

112. Kachnic LA, Winter K, Myerson RJ, et al. RTOG 0529: a phase 2 evaluation of dose-painted intensity modulated radiation therapy in combination with 5-fluorouracil and mitomycin-C for the reduction of acute morbidity in carcinoma of the anal canal. Int J Radiat Oncol Biol Phys 2013;86(1): 27–33. 113. Myerson RJ, Garofalo MC, El Naqa I, et al. Elective clinical target volumes for conformal therapy in anorectal cancer: a Radiation Therapy Oncology Group consensus panel contouring atlas. Int J Radiat Oncol Biol Phys 2009;74(3):824–30. 114. Schwarz JK, Siegel BA, Dehdashti F, et al. Tumor response and survival predicted by post-therapy FDG-PET/CT in anal cancer. Int J Radiat Oncol Biol Phys 2008;71(1):180–6. 115. Saxena A, Chua TC, Chu FC, et al. Impact of treatment modality and number of lesions on recurrence and survival outcomes after treatment of colorectal cancer liver metastases. J Gastrointest Oncol 2014;5(1):46–56. 116. Ramanathan R, Sharma A, Lee DD, et al. Multimodality therapy and liver transplantation for hepatocellular carcinoma: a 14-year prospective analysis of outcomes. Transplantation 2014;98:100–6. 117. Salem ME, Jain N, Dyson G, et al. Radiographic parameters in predicting outcome of patients with hepatocellular carcinoma treated with yttrium-90 microsphere radioembolization. ISRN Oncol 2013; 2013:538376. 118. Gates VL, Esmail AA, Marshall K, et al. Internal pair production of 90Y permits hepatic localization of microspheres using routine PET: proof of concept. J Nucl Med 2011;52(1):72–6. 119. Gates VL, Salem R, Lewandowski RJ. Positron emission tomography/CT after yttrium-90 radioembolization: current and future applications. J Vasc Interv Radiol 2013;24(8):1153–5.