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Expert Opinions on Positron Emission Tomography and Computed Tomography Imaging in Lymphoma

^aVanderbilt University Medical Center, Nashville, Tennessee, USA; ^bUniversity Hospital, Gasthuisberg, Leuven, Belgium; ^cHôpital Saint-Louis, Paris, France; ^dHôpital Henri Mondor, Creteil, France; ^eUniversity of Southern California, Los Angeles, California, USA

Key Words. Positron emission tomography • Emission-computed tomography • Non-Hodgkin's lymphoma • Imaging

Correspondence: Peter S. Conti, M.D., Ph.D., Department of Radiology, University of Southern California, 1510 San Pablo Street, Room #350, Los Angeles, California 90033, USA. Telephone: 323-442-5940; Fax: 323-442-5778; e-mail: pconti{at}usc.edu

Received March 27, 2009; accepted for publication July 14, 2009.

Disclosures: Dominique Delbeke: Honoraria: GE Healthcare; Sigrid Stroobants: None; Eric de Kerviler: None; Christian Gisselbrecht: Research funding/contracted research: Bayer Schering Pharma; Michel Meignan: None: Peter S. Conti: Honoraria: Bayer Schering.

The content of this article has been reviewed by independent peer reviewers to ensure that it is balanced, objective, and free from commercial bias. No financial relationships relevant to the content of this article have been disclosed by the independent peer reviewers.

	ABSTRACT

Top Abstract Introduction Cheson Criteria to Define... Degree of FDG Avidity... Guidelines for Using FDG-PET... Procedure Guidelines for... Guidelines for PET... Conclusions Author Contributions References

 
Revised guidelines for the staging and response criteria of Hodgkin's lymphoma (HL) and non-Hodgkin's lymphoma (NHL) were recently published to include the expanding role of positron emission tomography/computed tomography (PET/CT) using ¹⁸F-fluoro-2-deoxyglucose. Here, we discuss the new guidelines and the need for standardized PET acquisition and interpretation in HL and NHL. We also discuss how the role for CT is evolving in the process of making treatment decisions and provide insight on how best to standardize the use of PET/CT for making therapeutic choices.

	INTRODUCTION

Top Abstract Introduction Cheson Criteria to Define... Degree of FDG Avidity... Guidelines for Using FDG-PET... Procedure Guidelines for... Guidelines for PET... Conclusions Author Contributions References

 
Clinical staging of both Hodgkin's lymphoma (HL) and non-Hodgkin's lymphoma (NHL) is critical for determining treatment strategy and prognosis for patients diagnosed with either of these diseases [1, 2]. Staging HL and NHL prior to therapy allows for accurate restaging of disease after therapy and can be used to identify complete remissions [1, 2]. Both HL and NHL staging is based on the Ann Arbor system, with the inclusion of a definition of bulky disease known as the Cotswold modification [3].

Staging of malignant lymphoma is usually performed using computed tomography (CT) [1]. However, the lack of functional information from CT can impede the identification of disease in normal-sized tissue [4]. An alternative to CT is ¹⁸F-fluoro-2-deoxyglucose positron emission tomography (FDG-PET), which is based on the increased glycolysis of cancer cells. This is visualized using the radioactive glucose analog FDG, which after phosphorylation is metabolically trapped within the cell [5]. Thus, in addition to CT, FDG-PET has become an established imaging modality to stage, restage, monitor therapy, and detect recurrent lymphoma. PET (metabolic information) and CT (anatomical information) are complementary, and interpretation of the PET portion of the study is more accurate when PET is correlated with CT [4, 6, 7]. Therefore, by 2000, integrated PET/CT systems were developed that are now the standard of care. Figure 1 demonstrates a typical PET/CT image that can be obtained using these devices. In the U.S., 90% of the PET systems currently in operation are integrated PET/CT systems [8].

View larger version (53K): [in this window] [in a new window]   Figure 1. A positron emission tomography (PET)/computed tomography (CT) image of a 70-year-old patient with relapsed small-cell lymphocytic lymphoma that had transformed into diffuse large B-cell lymphoma. The 18F-fluoro-2-deoxyglucose (FDG)-PET maximum-intensity projection (MIP) image demonstrates moderate FDG uptake in multiple lesions. A selected slice through the pelvis demonstrates moderate FDG uptake in the s.c. tissues of the back corresponding to stranding on the CT image.

	CHESON CRITERIA TO DEFINE TREATMENT RESPONSE IN LYMPHOMA

Top Abstract Introduction Cheson Criteria to Define... Degree of FDG Avidity... Guidelines for Using FDG-PET... Procedure Guidelines for... Guidelines for PET... Conclusions Author Contributions References

 
Prior to 1999, response criteria for malignant lymphoma varied among study groups and cancer centers. Therefore, an international working group (IWG) consisting of experts in the evaluation of NHL published a set of guidelines to standardize response criteria for NHL [9]. Despite being open to interpretation and not including PET evaluation as part of their assessment strategy, these guidelines became widely adopted by clinicians and regulatory bodies. However, an increase in the widespread use of FDG-PET for response assessment has prompted a need to re-evaluate and update the IWG criteria. To remedy this situation, an international harmonization initiative was set up to incorporate the rapid advances in FDG-PET technology that have occurred in the past 5 years into guidelines for performing and interpreting FDG-PET in both clinical trials and standard practice [10, 11].

One of the main criticisms of the 1999 guidelines related to the interpretation of an unconfirmed complete response (CRu) and one of the advantages of PET is that it can distinguish between viable tumor and necrosis or fibrosis in residual masses [10, 12]. Indeed, a retrospective study carried out by Juweid et al. [13] in 2005 demonstrated that integration of PET into the IWG criteria increased the number of confirmed complete responses (CRs), eliminating the need for the CRu category. Thus, the revised criteria state that, in routinely FDG-avid lymphomas, such as diffuse large B-cell lymphoma (DLBCL) and HL, a CR is assigned to all patients with a negative PET scan regardless of the presence of a residual mass on CT. In cases in which there is residual disease on PET (PET-positive patients), a partial response, stable disease, or progressive disease can be assigned based on the response shown by CT; the CRu category is eliminated (Table 1) [10].

	DEGREE OF FDG AVIDITY OF DIFFERENT TYPES OF LYMPHOMA

Top Abstract Introduction Cheson Criteria to Define... Degree of FDG Avidity... Guidelines for Using FDG-PET... Procedure Guidelines for... Guidelines for PET... Conclusions Author Contributions References

 
Lymphomas are classified into two main groups, NHL and HL. NHL is more common than HL and represents 85% of lymphomas [15]. NHL can also be divided into two prognostic groups: the indolent lymphomas and the aggressive lymphomas. Patients with indolent NHL subtypes have a relatively good prognosis, with a median survival duration as long as 10 years, but they are not usually curable in advanced clinical stages. DLBCL is the most common aggressive lymphoma, representing 30% of NHL cases; other relatively common aggressive lymphomas include mantle cell lymphoma (MCL) and adult T-cell leukemia/lymphoma, representing 6% and 8% of NHL cases, respectively [15]. Follicular lymphoma (FL) is the most common type of indolent lymphoma, representing 22% of NHL cases [15]; marginal zone lymphoma (MZL) and small-cell lymphocytic lymphoma (SLL) are other types of indolent lymphoma, representing 6% and 8% of NHL cases, respectively [15].

The degree of FDG uptake can be evaluated semiquantitatively using the standardized uptake value (SUV). The SUV is the activity in the lesion in µCi/ml corrected for the weight of the patient and the dose of FDG administered, and the use of SUVs is further addressed in a later section in this manuscript. Although there is an overlap in SUV between aggressive and indolent NHL, the SUV in aggressive NHL and HL is generally significantly higher than SUVs obtained for indolent lymphomas [16]; for example, HL and aggressive NHL types such as DLBCL and grade III FL have a high uptake of FDG (mean SUVs in newly diagnosed patients of 17.1 and 16.0, respectively), whereas FDG uptake in MCL, MZL, and grade I–II FL is clearly lower (mean SUVs in newly diagnosed patients of 6.0, 9.5, and 7.0, respectively) [16] (Table 2).

Image-Guided Needle Biopsies
Image-guided needle biopsies (IGNBs) are particularly useful for the diagnosis of new patients, or patients who require restaging as a result of incomplete subtyping or progression. A needle is inserted into the abnormal region, guided by imaging techniques, and a tissue biopsy is taken for histological diagnosis. It is advantageous because it can be used with all patients of any age (including children) and all targets that are reachable (including deep lymph nodes). IGNBs can be performed on an outpatient basis under local anesthesia and allow rapid diagnosis and therapy choices to be made [22, 23]. IGNBs are not limited to CT, because PET can also be used to guide biopsies to the site of highest FDG uptake, representing the most aggressive site of lymphoma [21]. The overall diagnostic yield of IGNBs in patients with lymphoma is in the range of 90%–96% [22, 23].

	GUIDELINES FOR USING FDG-PET AND CT OR PET/CT IMAGING IN LYMPHOMA

Top Abstract Introduction Cheson Criteria to Define... Degree of FDG Avidity... Guidelines for Using FDG-PET... Procedure Guidelines for... Guidelines for PET... Conclusions Author Contributions References

 
In 2007, the following consensus recommendations regarding the use of FDG-PET for assessment response were published by the imaging subcommittee of the International Harmonization Project [11].

1. Pretherapy FDG-PET imaging is not a mandatory requirement for assessment of response after treatment of patients with HL, DLBCL, FL, or MCL because these lymphomas are routinely FDG avid. However, pretherapy FDG-PET imaging is strongly encouraged because it facilitates the interpretation of the response to therapy.
   
2. Pretherapy FDG-PET imaging is mandatory for NHL with variable FDG avidity if PET is used to assess response to treatment.
   
3. PET is essential for the post-treatment assessment of DLBCL and HL because a negative PET scan after treatment is required for a complete remission and curative outcome. In the other incurable histologies, PET is only recommended during a clinical trial in which the response rate is a primary endpoint and if the patient was PET positive before treatment.
   
4. Although numerous studies have shown that PET performed after a few cycles of chemotherapy can predict therapeutic outcome (as discussed later in this article), no definitive proof has yet emerged that altering treatment based on this information results in superior survival outcomes. Until such data exist, this indication should be restricted to clinical trials evaluating PET in this context.
   
5. Current data are inadequate to recommend routine surveillance PET scans after the restaging study.
   
6. Prior to treatment, all patients should undergo an i.v. contrast-enhanced CT (CECT) either using a stand-alone dedicated CT scanner or as part of the PET/CT study. If there is no splenic or hepatic involvement at initial staging, the use of PET/low-dose CT without i.v. contrast to assess response is satisfactory in DLBCL and HL patients, and CECT scanning is not necessary (see later section on CT protocols). Conversely, a separate CECT or PET/CECT should be performed in cases of spleen or liver involvement and in all low-grade lymphomas.
   

The guidelines regarding the use of PET/low-dose CT are based on several studies that concluded that PET/low-dose CT may be adequate for most patients and that CECT may be recommended for selected cases. For example, there is evidence to suggest that PET/CT performed without CECT is sufficient to detect peripheral lymph nodes or other extranodal lesions that may not be detected by PET [24–27]. PET/low-dose CT and PET/CECT were compared in 47 patients with lymphoma. On a region-based analysis, there was no significant difference for the detection of lymphoma. PET/CECT provided slightly fewer equivocal sites (two of 188) and allowed detection of slightly more extranodal sites (n = 4 of 188). For the purpose of staging, there was almost perfect agreement (46 of 47 patients) [28].

However, there are ongoing debates regarding when CECT should be used for the staging of lymphoma, because the number of lymphoma patients for whom potential benefits have been evaluated systematically is still too low to come to a definitive conclusion [29].

In addition, the National Comprehensive Cancer Network has incorporated FDG-PET in the evaluation and management algorithm of most HL and NHL patients [30]. The use of FDG-PET (PET/CT where available) is recommended in the following clinical scenarios: as a baseline for lymphomas that are potentially curative (HL, DLBCL), as a baseline to exclude systemic disease in clinically localized lymphoma (HL, DLBCL, FL, MCL, AIDS-related B-cell lymphoma, nodal and splenic MZL, peripheral T-cell lymphoma, mucosa-associated lymphoid tumors), to evaluate residual masses, and to monitor therapy of aggressive lymphoma (HL, DLBCL). FDG-PET is not indicated for monitoring therapy if the CT scan is normal, or for surveillance.

Guidelines for the Timing of FDG-PET Imaging After Therapy
A proposed schedule for the timing of PET scans is shown in Figure 2A and is based on the recommendations from Juweid et al. [11]. The timing of FDG-PET is critical to avoid equivocal interpretations. FDG-PET should be performed at least 3 weeks (preferably 6–8 weeks) after completion of chemotherapy and 8–12 weeks after radiation therapy because of radiation-induced inflammatory changes that can be FDG avid [31, 32]. It is also generally accepted that FDG-PET scans should be performed 2 months postsurgery. For evaluation during therapy, FDG-PET imaging should be performed as close as possible before the subsequent cycle of therapy.

View larger version (13K): [in this window] [in a new window]   Figure 2. Recommendations for the use of positron emission tomography (PET) and computed tomography (CT). (A): Algorithm for the recommended evaluation/timing of 18F-fluoro-2-deoxyglucose (FDG)-PET. (B): Schematic representation of the recommended timing for CT use. Each arrow represents one treatment cycle. The black arrow represents the cycle at which a CT evaluation should be performed. Abbreviation: CECT, contrast-enhanced computed tomography.

Most lymphoma patients will become PET negative after two to three cycles of standard chemotherapy, and response assessments based on the new Cheson criteria are proving to be robust and highly predictive of outcome [35–37]. However, false-positive lesions occur more frequently at earlier time points, particularly with intensified schedules, and preliminary results indicate that the accuracy of PET differs depending on the given treatment [38]. In addition, with the increased use of more targeted therapies (such as immunotherapy, cell cycle inhibitors, and mammalian target of rapamycin inhibitors) whose antitumor activity is more gradual than classic cytotoxic therapies, the optimal timing and interpretation have yet to be identified [39]. A recent, small retrospective study indicated that, after treatment with either yttrium-90 (⁹⁰Y)-ibritumomab tiuxetan (Zevalin®; Spectrum Pharmaceuticals, Inc., Irvine, CA; Bayer Schering Pharma AG, Berlin, Germany) or iodine-131 (¹³¹I)-tositumomab (Bexxar®; GlaxoSmithKline, Research Triangle Park, NC), response assessment should be delayed, although the authors noted that patients with the largest decrease in FDG uptake had a longer overall survival time [40].

Guidelines for the Timing of CT Post-therapy
The grade of lymphoma determines the timing of when CT is performed (Fig. 2B). Aggressive lymphomas, such as Burkitt's lymphoma or lymphoblastic lymphoma, are usually re-evaluated after one or two cycles of chemotherapy. In the case of HL and DLBCL, where recurrence is rare after 5 years, CT should be performed early (at four cycles) and frequently after treatment (for HL, this includes assessments every 6 months for 1–2 years after a CR and then every year for the next 3–5 years in favorable groups, more frequently in disseminated forms; for DLBCL,, assessment should occur every 6 months for 2 years and every year for 3 years, because recurrences are rare beyond this time scale). For patients with indolent NHL or FL who have experienced a CR, follow-up should be performed every 6 months for 1 year then every 6–12 months, because these patients are at continuous risk for relapse [11]). For patients with FL or low-grade lymphoma who are being monitored on a "watch and wait" basis, the frequency of follow-up should be specified in the protocol, because no consensus has been reached for this group [11]. Some teams also recommend clinical and biologic follow-up with a survey using ultrasound. This would be sufficient to document any bulky disease that may necessitate therapy.

	PROCEDURE GUIDELINES FOR PERFORMING AND REPORTING PET AND PET/CT

Top Abstract Introduction Cheson Criteria to Define... Degree of FDG Avidity... Guidelines for Using FDG-PET... Procedure Guidelines for... Guidelines for PET... Conclusions Author Contributions References

 
The Society of Nuclear Medicine (SNM) procedure guidelines [41] and American College of Radiology (ACR) practice guidelines [42] for tumor imaging using FDG-PET or PET/CT address evaluation of malignancies in general. These procedure/practice guidelines include recommendations regarding the preparation of patients, protocols for PET and CT, the reporting of PET/CT results, and the training of personnel who perform and interpret PET/CT scans.

PET Protocol
The National Cancer Institute has published similar recommendations [43] regarding patient preparation, uptake time, FDG dose, parameters for acquisition of images, and image analysis. For example, a patient must fast for 4 hours prior to FDG administration and have a blood glucose level <200 mg/ml. FDG should be administered at a dose of 370–740 MBq and the distribution time should be 60 ± 10 minutes. The imaging time should be performed in accordance with the manufacturer's guidelines and attenuation correction should be performed.

CT Protocol: How Much CT Should Be Used?
The recently published revised Response Evaluation Criteria in Solid Tumors (RECIST) include recommendations for the optimal anatomical assessment of lesions, with new recommendations for lymph node imaging and clarification on the definition of disease progression [44]. A diagnostic CT (whether performed alone or as part of PET/CT) should be acquired following the standard guidelines: contiguous 5-mm slices, from the lung apices to the symphysis pubis with i.v. and oral contrast obtained during a single breathhold [44]). CECT should be used for anatomically based RECIST measurements, although the CT portion of PET/CT can be used if it is of identical diagnostic quality to a diagnostic CT [44].

The rationale for not using CECT with all PET/CT studies is to minimize radiation to the patient in accordance with the "as low as reasonably achievable" principle. CT uses larger radiation doses than more common conventional x-ray imaging procedures, and the dose is dependent on a number of factors, including x-ray beam energy, tube current, rotation or exposure time, section and object thickness, and dose-reduction techniques [45]. The typical radiation dose of a chest/abdomen/pelvis CT using an optimized protocol for diagnostic CT is in the 25-mSv range, compared with an 8-mSv range for a low-dose CT with 80 mAs.

At these doses, the most likely risk is for radiation-induced carcinogenesis, although no large-scale epidemiologic studies of these risks have been reported [46]. Most risk assessments are based on extrapolation of the data collected from atomic bomb survivors. Although there is no consensus regarding the validity of extrapolation, these data suggest a statistically significant increase in the risk for cancer at radiation doses similar to those received by patients undergoing CT [47]. It has been estimated, using data from 1991–1996 on CT usage, that 0.4% of all cancers in the U.S. may be attributable to the radiation from CT [48]. Guidelines to optimize the protection of patients during CT procedures have been provided by various international organizations. These guidelines are described as diagnostic reference levels and are based on the weighted CT dose index and the distance length product that are now displayed on the console of every CT scanner [49].

Because most systems in operation are PET/CT systems, CT can be used at the very least to perform attenuation correction of the PET images. Such attenuation correction can be performed using low-dose CT (<30 mAs). A growing body of evidence has demonstrated that fusion PET/CT images provided by integrated PET/CT systems can improve lesion detection, lesion characterization as benign or malignant, and lesion localization [6, 7, 11], such that the CT portion of the study is now commonly performed without i.v. contrast and with a low-dose CT component (40–80 mAs) to reduce the radiation dose to the patient. However, the CT component can be performed using a diagnostic CT protocol with oral contrast and CECT as part of the PET/CT protocol rather than being performed separately. Recommendations regarding the necessity of CECT in the guidelines were addressed in an earlier section of this manuscript.

	GUIDELINES FOR PET INTERPRETATION FOR RESPONSE ASSESSMENT IN LYMPHOMA

Top Abstract Introduction Cheson Criteria to Define... Degree of FDG Avidity... Guidelines for Using FDG-PET... Procedure Guidelines for... Guidelines for PET... Conclusions Author Contributions References

 
Interpretation of PET is subject to a number of variables, including the experience of the interpreter. A study performed by Zijlstra et al. [50] looked at the scoring of 11 nuclear medicine physicians and compared them with those of an expert interpreter; it identified a concordance of 82%–94% for the correct identification of PET-positive scans, but a concordance of only 45% for PET-negative scans. Furthermore, Zijlstra et al. [50] were able to show that more experienced interpreters tended to have fewer false positives, demonstrating the need to standardize PET interpretation procedures.

Recommendation on Visual Assessment Versus SUV
Consensus recommendations for the interpretation of FDG-PET for response assessment have been published by the imaging subcommittee of the International Harmonization Project. After completion of therapy, visual assessment alone is adequate for interpreting PET findings as positive or negative [11]. Mediastinal blood pool activity is used as a reference for the assessment of residual masses >2 cm. Specific criteria for defining PET positivity in the liver, spleen, lung, and bone marrow have been recommended.

Any diffuse or focal uptake in a location that is incompatible with normal anatomy/physiology should be considered as PET positive. The exception to this occurs when the residual mass is >2 cm in diameter and FDG uptake is lower than or equal to mediastinal blood pool structures; in these cases the PET status should be considered as negative [11].

If residual lesions are found in the spleen, liver, or bone marrow, other considerations need to be taken into account. Hepatic or splenic lesions >1.5 cm on CT should be considered as positive for lymphoma if their uptake is higher than or equal to that of the liver or spleen, and negative if their uptake is lower than that of the liver and spleen. If the lesion is <1.5 cm in diameter, the patient is considered as PET positive only if FDG uptake is greater than that of the liver or spleen.

Lung nodules 1.5 cm in patients should be considered as positive for lymphoma if FDG uptake is greater than the mediastinal blood pool. Lymphoma cannot be excluded in lung nodules <1.5 cm. New nodules in patients without established pulmonary lymphoma at baseline and who have evidence of a CR should be considered as negative for lymphoma, regardless of size and uptake, because they typically represent inflammatory lesions.

If there is a clearly multifocal increase in FDG uptake in the bone marrow, the patient can be considered as PET positive. The diffuse pattern of uptake of reactive bone marrow hyperplasia after chemotherapy, and especially after concurrent administration of bone marrow stimulants, can mimic or mask diffuse bone marrow involvement; therefore, appropriate history is critical. A delay of 3–4 weeks after completion of therapy permits the physiologic marrow activity to abate. Therefore, diffusely increased bone marrow uptake should not be misinterpreted as diffuse lymphomatous marrow involvement. A meta-analysis of PET for the evaluation of bone marrow infiltration demonstrated that PET had a good but not excellent correlation with bone marrow biopsies for the staging of HL and NHL [51]. The authors concluded that PET may complement the results of bone marrow biopsies and the diagnostic performance of PET may vary depending on the type of lymphoma; a more accurate result is obtained with HL and aggressive NHL than with indolent NHL [50]. Thus, a negative PET scan in the bone marrow does not exclude mild or moderate bone marrow involvement and bone marrow biopsy remains the standard of care.

Semiquantitative Analysis of PET Using SUV
The role of semiquantitative analysis of PET has not been fully determined. The SUV is the activity in the lesion in µCi/ml corrected for the weight of the patient and the dose of FDG administered. The SUV may be more accurate when measured relative to body surface area or lean body mass than to body weight. The average SUV of the normal liver parenchyma and blood pool is 2.0 and can be used as a visual reference. The SUV depends on accurate calibration of the PET system, accurate soft tissue attenuation correction, and reconstruction algorithms, among other factors. As CT transmission maps are acquired just before the acquisition of the emission data, attenuation correction can be compromised by imperfect registration of the transmission and emission images resulting from patient motion.

The SUV is also dependent on factors that are difficult to control in the clinical environment, such as the patient's plasma glucose and insulin levels, fasting state, dose infiltration, recent physical activity, and uptake time of FDG. In addition, there is inter- and intraobserver variability in identification of the lesion and slice with highest uptake and in drawing contours around the regions of interest. Thus, for the assessment of responses in a patient population, a comparison of SUVs between two studies requires rigorous quality control, especially if performed on different PET systems or using different protocols, and because of variation among institutions.

Therefore, current guidelines suggest that a visual assessment of PET status is adequate and sufficient for a positive or negative decision after completion of therapy; however, during treatment or in clinical trials, some form of semiquantitation may be helpful [11, 43, 52]. Cut-off levels of SUV to determine response to therapy are also likely to be dependent on tumor and treatment type and so need to be evaluated in further clinical trials.

Recommendations for Avoiding False Positives/Negatives
A list of etiologies for false-positive and false-negative interpretations is provided in both the SNM and the ACR guidelines for PET/CT in oncology [41, 42]; for example, physiologic uptake in response to therapy can occasionally confuse interpretation. Reactive diffuse bone marrow hyperplasia and splenic uptake occur typically for 2–4 weeks after chemotherapy and can be intense after administration of marrow-stimulating factors such as filgrastim. Thymic hyperplasia is common in children and young adults, with an incidence of 16%. It typically occurs 2–6 months after completion of therapy and may persist for 12–24 months. The pattern of moderate FDG uptake and the inverted V-shape are typical for thymic hyperplasia. FDG-avid inflammatory changes are usually seen matching radiation ports, for example, in radiation pneumonitis.

False-positive/negative interpretations can be avoided if FDG-PET is performed with appropriate patient preparation and interpreted with the knowledge of the type of lymphoma, clinical history, history of treatment, and correlative imaging studies. Therefore, published societal guidelines suggest that PET/CT should be interpreted by board-certified nuclear physicians or radiologists with the additional training and expertise in PET/CT recommended by professional societies, to minimize the occurrence of these false-positive/negative interpretations [41]. Alternatively, a central PET review network, such as the multisite online PET interpretations (IMOTEP) network in France, could be used to standardize interpretation.

Central Review of Groupe d'Etude des Lymphomes de l'Adulte (GELA) Within the Intergroup European Organization for Research and Treatment of Cancer/GELA-ILL H10 Protocol
IMOTEP was developed to use a reading procedure that can include the opinions of various experts in order to evaluate the results of early PET in clinical trials. This was deemed necessary because there are no consensus criteria for interpreting early PET scans [53]. The cornerstone of this network is the positoscope workstation, which allows side-by-side display of pre- and post-treatment PET/CT as well as complete image processing. The workstation can be used to send these files to the workstations of six experts located in France and Belgium, who can evaluate the scans independently and send their results to a centralized server where the results are integrated. The final results are then sent to the coordinating center and verified by the coordinating nuclear medicine physicist before being sent back to the investigator. All communication is carried out by mail and short message service, and the whole procedure can be carried out in <72 hours. The IMOTEP system was used extensively for the H10 protocol to standardize the early PET readings during that trial.

The H10 protocol is investigating the use of PET scans after two cycles of ABVD to modulate treatment strategies for patients with stage I/II HL [54]. Patients were initially randomized to the standard or investigational arm. In the standard arm, patients receive three cycles of ABVD plus involved-field radiotherapy in the favorable group or four cycles of ABVD plus radiotherapy in the unfavorable group, regardless of the PET result after two cycles. Patients in the experimental arm receive two cycles of ABVD followed by a PET scan to decide on a further treatment strategy. Patients who are PET negative continue with either two or four further cycles of ABVD without radiotherapy for favorable and unfavorable patients, respectively. Patients who are PET positive are switched to a salvage therapy with two cycles of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (escalated BEACOPP) plus involved-field radiotherapy. This study is ongoing and has recruited almost 800 patients as of January 2009.

All PET scans of the GELA group were interpreted using the IMOTEP network and the Juweid and Cheson published criteria. During an interim analysis of 148 patient scans that were submitted to the IMOTEP network, 10% of the final interpretations differed from the investigating center and 85% of these were changed from negative to positive results.

This trial and others have demonstrated the distinct advantages of central review: similar PET processing and analysis independent of which PET device is used, independent and online reading by any number of experts including those at the investigating center, fast transfer of PET images, compatibility with routine practice, security, and a fast turnaround for final results.

	CONCLUSIONS

Top Abstract Introduction Cheson Criteria to Define... Degree of FDG Avidity... Guidelines for Using FDG-PET... Procedure Guidelines for... Guidelines for PET... Conclusions Author Contributions References

 
The increased use of PET required revision of the lymphoma clinical staging guidelines published in 1999 to standardize CT and PET protocols. The integration of PET has eliminated the need for CRu; however, PET does not replace the need for biopsy. There are still questions that need to be addressed relating to the use of PET in indolent lymphoma, and further trials are necessary to fully evaluate the role of PET in indolent lymphoma. The need also remains to standardize PET/CT protocols in order to improve compatibility among and within centers. Despite these new guidelines simplifying the management of lymphoma patients, there are still limitations to these guidelines that need to be addressed. For instance, the role of the protocol for the CT portion of PET/CT has not been fully determined and continues to evolve, and PET during treatment still requires semiquantitative measurements that are still under investigation. Finally, because these guidelines are based on the authors' expertise and the literature currently available, they remain limited and indicate a need for further research and validation.

	AUTHOR CONTRIBUTIONS

Top Abstract Introduction Cheson Criteria to Define... Degree of FDG Avidity... Guidelines for Using FDG-PET... Procedure Guidelines for... Guidelines for PET... Conclusions Author Contributions References

 
Conception/design: Dominique Delbeke, Sigrid Stroobants, Christian Gisselbrecht, Peter S. Conti

Provision of study materials or patients: Eric de Kerviler, Christian Gisselbrecht

Collection/assembly of data: Eric de Kerviler, Michel Meignan, Peter S. Conti

Data analysis and interpretation: Christian Gisselbrecht, Peter S. Conti

Manuscript writing: Dominique Delbeke, Sigrid Stroobants, Michel Meignan, Peter S. Conti

Final approval of manuscript: Dominique Delbeke, Sigrid Stroobants, Michel Meignan, Peter S. Conti

The authors take full responsibility for the scope, direction, and content of the manuscript and have approved the submitted manuscript. They would like to thank Lynda Chang, Ph.D., at Complete HealthVizion for her assistance in the preparation and revision of the draft manuscript, based on detailed discussion and feedback from all the authors. Editorial assistance was supported by a grant from Bayer HealthCare Pharmaceuticals.

	ACKNOWLEDGMENTS

Top Abstract Introduction Cheson Criteria to Define... Degree of FDG Avidity... Guidelines for Using FDG-PET... Procedure Guidelines for... Guidelines for PET... Conclusions Author Contributions References

 
Dominique Delbeke and Sigrid Stroobants contributed equally to this article and share first authorship.

	REFERENCES

Top Abstract Introduction Cheson Criteria to Define... Degree of FDG Avidity... Guidelines for Using FDG-PET... Procedure Guidelines for... Guidelines for PET... Conclusions Author Contributions References

 

1. Armitage JO. Staging non-Hodgkin lymphoma. CA Cancer J Clin 2005;55:368–376.[Abstract/Free Full Text]
2. Connors JM. State-of-the-art therapeutics: Hodgkin's lymphoma. J Clin Oncol 2005;23:6400–6408.[Abstract/Free Full Text]
3. Lister TA, Crowther D, Sutcliffe SB et al. Report of a committee convened to discuss the evaluation and staging of patients with Hodgkin's disease: Cotswolds meeting. J Clin Oncol 1989;7:1630–1636.[Abstract]
4. Kwee TC, Kwee RM, Nievelstein RA. Imaging in staging of malignant lymphoma: A systematic review. Blood 2008;111:504–516.[Abstract/Free Full Text]
5. Rohren EM, Turkington TG, Coleman RE. Clinical applications of PET in oncology. Radiology 2004;231:305–332.[Abstract/Free Full Text]
6. Blodgett TM, Meltzer CC, Townsend DW. PET/CT: Form and function. Radiology 2007;242:360–385.[Abstract/Free Full Text]
7. von Schulthess GK, Steinert HC, Hany TF. Integrated PET/CT: Current applications and future directions. Radiology 2006;238:405–422.[Abstract/Free Full Text]
8. Hillner BE, Siegel BA, Liu D et al. Impact of positron emission tomography/computed tomography and positron emission tomography (PET) alone on expected management of patients with cancer: Initial results from the National Oncologic PET Registry. J Clin Oncol 2008;26:2155–2161.[Abstract/Free Full Text]
9. Cheson BD, Horning SJ, Coiffier B et al. Report of an international workshop to standardize response criteria for non-Hodgkin's lymphomas. NCI Sponsored International Working Group. J Clin Oncol 1999;17:1244.[Abstract/Free Full Text]
10. Cheson BD, Pfistner B, Juweid ME et al. Revised response criteria for malignant lymphoma. J Clin Oncol 2007;25:579–586.[Abstract/Free Full Text]
11. Juweid ME, Stroobants S, Hoekstra OS et al. Use of positron emission tomography for response assessment of lymphoma: Consensus of the Imaging Subcommittee of International Harmonization Project in Lymphoma. J Clin Oncol 2007;25:571–578.[Abstract/Free Full Text]
12. Zinzani PL, Fanti S, Battista G et al. Predictive role of positron emission tomography (PET) in the outcome of lymphoma patients. Br J Cancer 2004;91:850–854.[Medline]
13. Juweid ME, Wiseman GA, Vose JM et al. Response assessment of aggressive non-Hodgkin's lymphoma by integrated International Workshop Criteria and fluorine-18-fluorodeoxyglucose positron emission tomography. J Clin Oncol 2005;23:4652–4661.[Abstract/Free Full Text]
14. Hillner BE, Siegel BA, Shields AF et al. Relationship between cancer type and impact of PET and PET/CT on intended management: Findings of the National Oncologic PET Registry. J Nucl Med 2008;49:1928–1935.[Abstract/Free Full Text]
15. Lu P. Staging and classification of lymphoma. Semin Nucl Med 2005;35:160–164.[CrossRef][Medline]
16. Schöder H, Noy A, Gönen M et al. Intensity of ¹⁸fluorodeoxyglucose uptake in positron emission tomography distinguishes between indolent and aggressive non-Hodgkin's lymphoma. J Clin Oncol 2005;23:4643–4651.[Abstract/Free Full Text]
17. Elstrom R, Guan L, Baker G et al. Utility of FDG-PET scanning in lymphoma by WHO classification. Blood 2003;101:3875–3876.[Abstract/Free Full Text]
18. Tsukamoto N, Kojima M, Hasegawa M et al. The usefulness of ¹⁸F-fluorodeoxyglucose positron emission tomography (¹⁸F-FDG-PET) and a comparison of ¹⁸F-FDG-PET with ⁶⁷gallium scintigraphy in the evaluation of lymphoma: Relation to histologic subtypes based on the World Health Organization classification. Cancer 2007;110:652–659.[CrossRef][Medline]
19. Bruzzi JF, Macapinlac H, Tsimberidou AM et al. Detection of Richter's transformation of chronic lymphocytic leukemia by PET/CT. J Nucl Med 2006;47:1267–1273.[Abstract/Free Full Text]
20. Karam M, Novak L, Cyriac J et al. Role of fluorine-18 fluoro-deoxyglucose positron emission tomography scan in the evaluation and follow-up of patients with low-grade lymphomas. Cancer 2006;107:175–183.[CrossRef][Medline]
21. Bodet-Milin C, Kraeber-Bodéré F, Moreau P et al. Investigation of FDG-PET/CT imaging to guide biopsies in the detection of histological transformation of indolent lymphoma. Haematologica 2008;93:471–472.[Abstract/Free Full Text]
22. de Kerviler E, Guermazi A, Zagdanski AM et al. Image-guided core-needle biopsy in patients with suspected or recurrent lymphomas. Cancer 2000;89:647–652.[CrossRef][Medline]
23. de Kerviler E, de Bazelaire C, Mounier N et al. Image-guided core-needle biopsy of peripheral lymph nodes allows the diagnosis of lymphomas. Eur Radiol 2007;17:843–849.[CrossRef][Medline]
24. Freudenberg LS, Antoch G, Scht P et al. FDG-PET/CT in re-staging of patients with lymphoma. Eur J Nucl Med Mol Imaging 2004;31:325–329.[CrossRef][Medline]
25. Schaefer NG, Hany TF, Taverna C et al. Non-Hodgkin lymphoma and Hodgkin disease: Coregistered FDG PET and CT at staging and restaging—do we need contrast-enhanced CT? Radiology 2004;232:823–829.[Abstract/Free Full Text]
26. Allen-Auerbach M, Quon A, Weber WA et al. Comparison between 2-deoxy-2-[¹⁸F]fluoro-D-glucose positron emission tomography and positron emission tomography/computed tomography hardware fusion for staging of patients with lymphoma. Mol Imaging Biol 2004;6:411–416.[CrossRef][Medline]
27. Antoch G, Freudenberg LS, Beyer T et al. To enhance or not to enhance? ¹⁸F-FDG and CT contrast agents in dual-modality ¹⁸F-FDG PET/CT. J Nucl Med 2004;45(suppl 1):56S–65S.[Abstract/Free Full Text]
28. Rodríguez-Vigil B, Gómez-León N, Pinilla I et al. PET/CT in lymphoma: Prospective study of enhanced full-dose PET/CT versus unenhanced low-dose PET/CT. J Nucl Med 2006;47:1643–1648.[Abstract/Free Full Text]
29. Allen-Auerbach M, de Vos S, Czernin J. The impact of fluorodeoxyglucose-positron emission tomography in primary staging and patient management in lymphoma patients. Radiol Clin North Am 2008;46:199–211, vii.[CrossRef][Medline]
30. Podoloff DA, Advani RH, Allred C et al. NCCN task force report: Positron emission tomography (PET)/computed tomography (CT) scanning in cancer. J Natl Compr Canc Netw 2007;5(suppl 1):S1–S22.
31. Naumann R, Vaic A, Beuthien-Baumann B et al. Prognostic value of positron emission tomography in the evaluation of post-treatment residual mass in patients with Hodgkin's disease and non-Hodgkin's lymphoma. Br J Haematol 2001;115:793–800.[CrossRef][Medline]
32. Weihrauch MR, Re D, Scheidhauer K et al. Thoracic positron emission tomography using ¹⁸F-fluorodeoxyglucose for the evaluation of residual mediastinal Hodgkin disease. Blood 2001;98:2930–2934.[Abstract/Free Full Text]
33. Terasawa T, Lau J, Bardet S et al. Fluorine-18-fluorodeoxyglucose positron emission tomography for interim response assessment of advanced-stage Hodgkin's lymphoma and diffuse large B-cell lymphoma: A systematic review. J Clin Oncol 2009;27:1906–1914.[Abstract/Free Full Text]
34. Römer W, Schwaiger M. Positron emission tomography in diagnosis and therapy monitoring of patients with lymphoma. Clin Positron Imaging 1998;1:101–110.[CrossRef][Medline]
35. Gallamini A, Hutchings M, Rigacci L et al. Early interim 2-[¹⁸F]fluoro-2-deoxy-D-glucose positron emission tomography is prognostically superior to International Prognostic Score in advanced-stage Hodgkin's lymphoma: A report from a joint Italian-Danish study. J Clin Oncol 2007;25:3746–3752.[Abstract/Free Full Text]
36. Brepoels L, Stroobants S. Is [¹⁸F]fluorodeoxyglucose positron emission tomography the ultimate tool for response and prognosis assessment? Hematol Oncol Clin North Am 2007;21:855–869.[CrossRef][Medline]
37. Brepoels L, Stroobants S, De Wever W et al. Aggressive and indolent non-Hodgkin's lymphoma: Response assessment by integrated international workshop criteria. Leuk Lymphoma 2007;48:1522–1530.[CrossRef][Medline]
38. Haioun C, Itti E, Rahmouni A et al. [¹⁸F]fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) in aggressive lymphoma: An early prognostic tool for predicting patient outcome. Blood 2005;106:1376–1381.[Abstract/Free Full Text]
39. Ulaner GA, Colletti PM, Conti PS. B-cell non-Hodgkin lymphoma: PET/CT evaluation after ⁹⁰Y-ibritumomab tiuxetan radioimmunotherapy—initial experience. Radiology 2008;246:895–902.[Abstract/Free Full Text]
40. Jacene HA, Filice R, Kasecamp W et al. ¹⁸F-FDG PET/CT for monitoring the response of lymphoma to radioimmunotherapy. J Nucl Med 2009;50:8–17.[Abstract/Free Full Text]
41. Delbeke D, Coleman RE, Guiberteau MJ et al. Procedure guideline for tumor imaging with ¹⁸F-FDG PET/CT 1.0. J Nucl Med 2006;47:885–895.[Free Full Text]
42. American College of Radiology. ACR Practice Guideline for Performing FDG PET/CT in Oncology. Available at http://www.acr.org/SecondaryMainMenuCategories/quality_safety/guidelines/nuc_med/fdg_pet_ct.aspx. accessed January 16, 2009.
43. Shankar LK, Hoffman JM, Bacharach S et al. Consensus recommendations for the use of ¹⁸F-FDG PET as an indicator of therapeutic response in patients in National Cancer Institute trials. J Nucl Med 2006;47:1059–1066.[Free Full Text]
44. Eisenhauer EA, Therasse P, Bogaerts J et al. New response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1). Eur J Cancer 2009;45:228–247.[CrossRef][Medline]
45. NcNitt-Gray MF. AAPM/RSNA physics tutorial for residents: Topics in CT. Radiation dose in CT. Radiographics 2002;22:1541–1553.[Abstract/Free Full Text]
46. Brenner DJ, Hall EJ. Computed tomography—an increasing source of radiation exposure. N Engl J Med 2007;357:2277–2284.[Free Full Text]
47. Preston DL, Pierce DA, Shimizu Y et al. Effect of recent changes in atomic bomb survivor dosimetry on cancer mortality risk estimates. Radiat Res 2004;162:377–389.[CrossRef][Medline]
48. Berrington de González A, Darby S. Risk of cancer from diagnostic x-rays: Estimates for the UK and 14 other countries. Lancet 2004;363:345–351.[CrossRef][Medline]
49. Tsapaki V, Aldrich JE, Sharma R et al. Dose reduction in CT while maintaining diagnostic confidence: Diagnostic reference levels at routine head, chest, and abdominal CT—IAEA-coordinated research project. Radiology 2006;240:828–834.[Abstract/Free Full Text]
50. Zijlstra JM, Comans EF, van Lingen A et al. FDG PET in lymphoma: The need for standardization of interpretation. An observer variation study. Nucl Med Commun 2007;28:798–803.[CrossRef][Medline]
51. Pakos EE, Fotopoulos AD, Ioannidis JP. ¹⁸F-FDG PET for evaluation of bone marrow infiltration in staging of lymphoma: A meta-analysis. J Nucl Med 2005;46:958–963.[Abstract/Free Full Text]
52. Lin C, Itti E, Haioun C et al. Early ¹⁸F-FDG PET for prediction of prognosis in patients with diffuse large B-cell lymphoma: SUV-based assessment versus visual analysis. J Nucl Med 2007;48:1626–1632.[Abstract/Free Full Text]
53. Meignan M. Advantages and disadvantages of central PET review. A new approach to PET interpretation. Presented at the Sixth Meeting of the International Workshop on Nuclear Oncology; April 17–19, 2008; Madrid, Spain.
54. Gisselbrecht C. Central review of PET scans in the GELA. Risk adjusted therapy in Hodgkin's lymphoma and aggressive lymphoma. Presented at the Sixth Meeting of the International Workshop on Nuclear Oncology; April 17–19, 2008; Madrid, Spain.

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