The Role of 18F-FDG-PET and PET/CT in Patients with Colorectal Liver Metastases Undergoing Selective Internal Radiation Therapy with Yttrium-90: A First Evidence-Based Review

Purpose. To provide a first evidence-based review of the literature on the role of fluorine-18-fluorodeoxyglucose positron emission tomography and positron emission tomography/computed tomography (FDG-PET and PET/CT) in patients with colorectal liver metastases (CRLM) undergoing selective internal radiation therapy (SIRT) with yttrium-90 (90Y) microspheres. Methods. A comprehensive computer literature search was conducted to find relevant published articles on whole-body FDG-PET or PET/CT in patients with CRLM undergoing SIRT. Results. We identified 19 studies including 833 patients with CRLM undergoing SIRT. The role of FDG-PET or PET/CT was analysed in treatment planning, treatment response evaluation, and as prognostic tool. Conclusion. FDG-PET and PET/CT provide additional information in treatment evaluation of CRLM patients treated with SIRT and may have a role in treatment planning and patient selection. FDG-PET/CT is emerging as good prognostic tool in these patients.


Introduction
Liver is the most frequent site of metastases in patients with colorectal cancer [1]. In the past, only 10% of patients with CRLM were eligible to surgery. New chemotherapy schemes and improvement in surgical techniques allow to treat surgically patients with CRLM in advanced stages of illness [1]. Radioembolization (RE) using yttrium-90 ( 90 Y) resin or glass microspheres, also known as selective internal radiation therapy (SIRT), is a palliative treatment [2] which reduces the liver tumour mass, eventually permitting surgical resection.
Clinical evaluation of patients with CRLM needs many different diagnostic tools. Morphological imaging procedures like computed tomography (CT), contrast enhanced CT (CECT), and magnetic resonance imaging (MRI) are useful techniques in staging and treatment evaluation of patients with CRLM, referring to the Response Evaluation Criteria In Solid Tumours (RECIST) [3]. Angiography allows the evaluation of vascular anatomy of the liver before SIRT. Singlephoton emission computed tomography (SPECT) with Technetium 99m Tc albumin aggregated ( 99m Tc-MAA) is used to calculate hepatic shunts to other organs (as lungs) before or after SIRT [4].
Fluorine-18-fluorodeoxyglucose positron emission tomography and positron emission tomography/computed tomography (FDG-PET and PET/CT) are noninvasive functional imaging techniques which have become well established tools in an oncology setting [5]. FDG is a glucose analogue that identifies areas of high-glucose metabolism. Recently published PET response criteria (PERCIST) assessed the usefulness of FDG-PET and PET/CT in treatment evaluation of cancer patients [6]. 2 The Scientific World Journal Until now, several studies have shown the potential role of whole-body FDG-PET or PET/CT in patients with CRLM undergoing SIRT [7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25]. Therefore, the aim of our evidencebased paper is to provide a first evidence-based review of the literature on this topic to confirm known evidence data and to eventually investigate new emerging roles of FDG-PET or PET/CT in patients with CRLM undergoing SIRT.

Search Strategy.
A comprehensive computer literature search of the PubMed/MEDLINE, Scopus, and Embase databases was conducted to find relevant published articles on whole-body FDG-PET or PET/CT in patients with CRLM undergoing SIRT with 90 Y microspheres.
We used a search algorithm that was based on a combination of the terms (a) "SIRT" or "radioembolization" or "yttrium" and (b) "positron emission tomography" or "PET. " No beginning date limit was used; the search was updated until June 18, 2013. To expand our search, references of the retrieved articles were also screened for additional studies.

Study Selection.
Studies or subsets in studies investigating the role of whole-body FDG-PET or PET/CT in patients with CRLM undergoing SIRT with 90 Y were eligible for inclusion. Review articles, editorials or letters, comments, conference proceedings, case reports, and preclinical studies were excluded from this review.
Only those studies or subsets in studies that satisfied all of the following criteria were included: (a) FDG-PET and SIRT with 90 Y performed in patients with CRLM, (b) sample size of at least ten patients with CRLM, and (c) only patients with histologically confirmed CRLM.
The exclusion criteria were (a) FDG-PET or SIRT with 90 Y not performed in patients with CRLM, (b) sample size of less than ten patients with CRLM, and (c) studies with no histologically confirmed CRLM. The studies including patients with both liver metastases from colon-rectum cancer and different primary tumours (or with primary liver cancer) were excluded from this review, if data about CRLM could not be retrieved, to avoid bias in the literature data discussion.
Two researchers (S. Annunziata and G. Treglia) independently reviewed titles and abstracts of the retrieved articles, applying the inclusion and exclusion criteria mentioned above. Articles were rejected if they were clearly ineligible. The same two researchers then independently reviewed the full-text versions of the remaining articles to determine their eligibility for inclusion. Disagreements were resolved in a consensus meeting.

Data Abstraction.
For each included study, information was collected concerning basic study (authors, journal, year of publication, country of origin, and type of study), patient characteristics (number of patients with MLT treated with SIRT, sex, mean age, and number of patients performing PET), and technical aspects (PET device, PET tracers, injected FDG activity, acquisition time, type of image analysis, 90 Y device, and injected 90 Y activity). Finally, the main findings of the articles included in this review have been reported and discussed.

Results
The comprehensive computer literature search from the PubMed/MEDLINE, Embase, and Scopus databases revealed 268 articles.
The 19 included studies were retrieved in their full-text version and included in this review. No additional studies were found after screening the references ( Figure 1). The basic and technical characteristics of the studies included are shown in Tables 1 and 2.

Role of FDG-PET and PET/CT in Treatment Planning of
Patients with CRLM Undergoing SIRT. FDG-PET or PET/CT may be used to stage patients with CRLM [46]. Until now, the role of these diagnostic tools in treatment planning of patients with CRLM undergoing SIRT is controversial [11,12,19,23].
About the use of FDG-PET or PET/CT before SIRT, Denecke et al. [11] evaluated a standardized diagnostic approach using different radiological and nuclear medicine imaging procedures. All patients initially underwent chest and abdominal CT. Patients in whom CT revealed no contraindications against RE entered the next diagnostic step, which consisted of MRI of the liver and FDG-PET or PET-CT. This sequential diagnostic algorithm allowed an appropriate patient selection for RE of CRLM and reduced the number of unnecessary examinations and treatments. A recent study [23] included a total of 42 patients planned for SIRT. Patients who underwent both CT and FDG-PET in the diagnostic workup were selected. Findings on CT and FDG-PET matched in 20 patients. In 4 patients, lesions detected on CT were not FDG-avid, and in 18 patients FDG-PET showed significantly more lesions than CT. The same study [23] assessed the value of FDG-PET for preprocedural workup of patients with CRLM referred for RE and found that the use of FDG-PET changed patients' management in 7 out of 42 patients (17%). Six patients were not treated with RE because of extensive extrahepatic lesions that were only detected with FDG-PET. In one patient, abdominal CT had shown only one liver lesion that would have been treated with SIRT if it had not been for FDG-PET imaging which showed a second lesion in another segment.
In two recent studies FDG-PET or PET/CT was firstly used to validate other triage methods of patients planned for SIRT (as different formula of absorbed dose [12] or 90 Y-PET imaging [19]). An American study group [12] evaluated a patient-specific SPECT-based method of dose calculation for treatment planning of SIRT. Absorbed dose to tumour and normal liver tissue was calculated by partition methods with two different tumour/normal liver vascularity ratios: The Scientific World Journal 3 268 records identified through database using the terms (("SIRT" or "radioembolization" or " yttrium") and ("positron emission tomography" or "PET")) 268 records screened 229 records excluded (reviews, editorial or letters; case report or case series; no direct link with the main subject) 20 articles excluded due to different primary tumors in the same study  an average 3 : 1 and a patient-specific ratio derived from pretreatment 99m Tc-MAA SPECT. Tumour dose calculated with the patient-specific method was more predictive of response 90 Y SIRT. Differently, Bagni et al. [19] demonstrated the feasibility of 90 Y-PET imaging for biodistribution assessment after SIRT. CRLM detected with 90 Y-PET and 99m Tc-MAA were assessed and compared with FDG-PET obtained before treatment. 90 Y-PET images were more accurate than 99m Tc-MAA SPECT, which is now considered the gold standard reference for biodistribution assessment.
Finally, FDG-PET or PET/CT before SIRT in patients with CRLM may have a role in staging of these patients and as baseline scan to further evaluate response to treatment. Further studies are needed to assess the role of FDG-PET or PET/CT in treatment planning and patients' selection before SIRT in patients with CRLM.

Role of FDG-PET and PET/CT in Treatment Evaluation of
Patients with CRLM Treated with SIRT. Six studies included in this review analysed the role of FDG-PET and PET/CT in treatment evaluation of patients with CRLM treated with SIRT [7-10, 13, 14].
Firstly, FDG-PET or PET/CT was included in a diagnostic algorithm to evaluate feasibility, safety, and tumour response of patients with CRLM undergoing SIRT. These outcomes were investigated in glass microspheres labelled with 90 Y [7,8] and in different countries (as USA [9,14] and Europe [10,13]).
Recently, six studies mainly analysed the diagnostic performance of FDG-PET or PET/CT in treatment evaluation of patients with CRLM treated with SIRT [7-9, 13, 14, 22]. Several studies have shown that FDG-PET/CT imaging in liver metastases from different primary tumours performs better than anatomical imaging in evaluating the early tumour response to SIRT [25]. Wong et al. [7] assessed the feasibility of using FDG-PET for quantifying metabolic response of SIRT for CRLM by comparing visual estimates with hepatic lesions standardized uptake values (SUVs). SUVs of the entire axial slices of liver agree well with subjective visual evaluations, so quantitative FDG-PET is a useful technique in the treatment response evaluation of these patients. Lewandowski et al. [8] treated 27 patients with unresectable CRLM at a targeted absorbed dose of 135-150 Gy. Tumor response measured by FDG-PET imaging exceeded that measured by CT imaging for the first (88% versus 35%) and second (73% versus 36%) treated lobes. Another group [14] performed a baseline CT scan within 4 weeks of treatment. Baseline FDG-PET imaging was encouraged but not mandatory. Improvement was noted in 30 of 39 patients (77%) who had pretreatment and posttreatment FDG-PET studies available. Kennedy et al. [9] performed salvage SIRT for 4 The Scientific World Journal  [13] evaluated the effectiveness of CRLM RE with 90 Y. A CT scan and a FDG-PET were performed to assess liver disease and to evaluate extrahepatic metastatic disease. According to RECIST, a complete response was observed in 2 patients, a partial response in 17 patients, stable disease in 14 patients, and progressive disease in 8 patients. Zerizer et al. [22] evaluated the ability of FDG-PET/CT imaging to predict early response to 90 Y-RE in comparison with CECT using RECIST and lesion density criteria. The patients response to treatment were categorized using PET criteria, tumour density criteria, and RECIST. Early response assessment to 90 Y-RE using FDG-PET/CT was superior to RECIST and tumour density.
In two different studies [16,21], Tochetto et al. concluded that changes in CT attenuation of CRLM treated with 90 Y-RE correlated highly with metabolic activity at FDG-PET and might be useful as an early surrogate marker for assessing treatment response. In the first study [16], for an attenuation reduction level of 15% or greater, attenuation showed 84% sensitivity and 83% specificity in predicting response at FDG-PET evaluation. In the second study [21], a similar strong association was found between FDG-PET response at 3 months and response based on attenuation criteria.
In another study [18], FDG-PET/CT was used to analyse patients treated with SIRT, in combination with contemporary systemic chemotherapy. Systemic chemotherapy was supplied to both liver lobes, whereas SIRT was administered selectively to the target liver lobe only. Response to treatment was evaluated by serial FDG-PET/CT performed at 4 weeks, 2 to 4 months, and 6 to 8 months. The chemo-SIRT combination produced greater objective responses as compared with chemo-only therapy in a front-line treatment in patients with CRLM.
Finally, in the past FDG-PET and PET/CT helped to assess that SIRT is a safe and feasible treatment for patients with CRLM. Recent studies confirmed that FDG-PET and PET/CT are useful to evaluate treatment response in these patients, in both early and long-term follow-up.

Prognostic Value of FDG-PET/CT in Patients with CRLM Undergoing SIRT.
Five recent studies mainly focused on the prognostic value of FDG-PET/CT in patients with CRLM treated with SIRT [15,17,20,22,24].
In 2011 Gulec et al. [17] investigated the relationship between functional tumour volume (FTV), total lesion glycolysis (TLG), and clinical outcomes. FTV and TLG seemed to be predictive of clinical outcomes and useful criteria for patient selection and disease prognostication. In a recent study, authors of [25] evaluated tumour response using FDG-PET/CT in similar patients. Calculation of SUV, FTV, and TLG before and at the sixth week after SIRT seemed to play an important role in evaluating early tumour response and survival expectancy in these patients and to decide whether these patients should be referred to other treatment modalities or to follow-up. Another study [15] analysed 48 patients with The Scientific World Journal 5  [20] demonstrated that patients with CRLM treated with SIRT developed a greater proportion of extrahepatic failure, and tumour volumes >300 mL were predictive for hepatic recurrence.
To date, FDG-PET/CT is an emerging prognostic tool in patients with CRLM undergoing SIRT. Semiquantitative factors (as FTV and TLG) seem to correlate with outcome and survival in these patients better than RECIST criteria. 6 The Scientific World Journal However, further prospective studies are needed to confirm this indication of FDG-PET/CT in patients with CRLM treated with SIRT.

Limitations of the Studies
Included. Some limitations of the included studies in our evidence-based review should be underlined. The most significant ones are the heterogeneity of the patients enrolled, the variability in the sample analysed, the different devices used (PET or PET/CT, resin or glass 90 Ylabelled microspheres), the methodology used to perform the scans (and lack of technical data in some papers), and the frequent retrospective nature of the studies. The most important limitation of this review is the exclusion of the studies including patients with both liver metastases from colon-rectum cancer and different primary tumours, to avoid possible biases in the literature data discussion.

Conclusion
From this first evidence-based review of the literature about the role of FDG-PET and PET/CT in patients with CRLM undergoing SIRT we conclude the following.
(1) FDG-PET and PET/CT seem to be useful molecular imaging methods in evaluating treatment response of patients with CRLM treated with SIRT.
(2) FDG-PET or PET/CT may have a role in treatment planning and patient selection for SIRT, but more studies are needed to confirm this indication.
(3) FDG-PET/CT is emerging as an important prognostic tool in patients with CRLM undergoing SIRT, especially referring to PET semiquantitative analysis factors (as FTV and TLG).
Further studies are needed to evaluate the impact of FDG-PET and PET/CT on clinical management of these patients.