Scarlett Lewitschnig • Saabry Osmany • Imene Zerizer • Gary Cook
A wide range of clinical investigations are available to assess benign and malignant liver lesions. Contrast-enhanced CT, US, and MRI are all of considerable importance in the evaluation of liver lesions but SPECT and PET nuclear medicine techniques frequently allow additional or complementary information to be collected that help direct patient management. Nuclear medicine has an increasing role in the management of primary liver tumors including hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA). Liver metastases are a more frequent clinical problem than HCC or CCA and nuclear medicine has an important role in this application also. On occasion, benign lesions such as focal nodular hyperplasia (FNH) and hemangiomas can be difficult to assess with other imaging techniques and nuclear medicine imaging can improve specificity.
BENIGN LIVER LESIONS
Benign focal liver lesions are common and include cysts, FNH, hepatic adenomas, cavernous hemangiomas, and abscesses (Table 10.1). US and CT play an important role in characterizing liver lesions but MRI can often add sensitivity and specificity in problematic cases and is probably the most accurate imaging modality for hepatic adenomas and FNH.
FNH is believed to be a hyperplastic response to an anomalous artery with no malignant potential. Since FNH contains hepatic cells, it can be imaged with 99mTc-iminodiacetic acid (HIDA) and its derivatives as well as with 99mTc sulfur colloid. HIDA is taken up by hepatocytes and the typical appearance of FNH with HIDA is increased flow followed by prompt uptake and delayed clearance compared to the surrounding normal liver tissue. This characteristic pattern is seen in 90% of cases and is, therefore, more accurate than 99mTc sulfur colloid imaging, which has a sensitivity of around 40% to 70%.1–3 FNH shows equal or greater colloid uptake compared to the surrounding liver, where the mechanism of uptake is via the Kupffer cells. A recent report suggests a possible role of 18F-fluorormethylcholine PET/CT in differentiating FNH from hepatocellular adenoma where FNH has been reported as more avid.4
Hepatic adenomas are benign epithelial liver tumors with the rare potential to rupture and cause bleeding or to transform to HCC. Hepatic adenomas contain only hepatocytes, but do not take up HIDA but show normal blood flow on early imaging. 99mTc sulfur colloid imaging is not helpful in the diagnosis of hepatic adenomas as most of these tumors do not take up colloid (although some do). Therefore, neither 99mTc sulfur colloid imaging nor HIDA scans are helpful in distinguishing adenomas from other intrahepatic lesions.
Hepatic hemangiomas can be accurately assessed with 99mTc-labeled red blood cell scanning using SPECT with a reported sensitivity of 81% and a specificity of 97%.5 The typical appearance is of increased activity compared to the background on 1 to 2 hours delayed imaging (Fig. 10.1). Giant cavernous hemangiomas can demonstrate heterogeneous uptake, with areas of increased and decreased activities.
SOME BENIGN LIVER LESIONS WHERE RADIONUCLIDE IMAGING MAY CONTRIBUTE TO MANAGEMENT
MALIGNANT LIVER LESIONS
Malignant liver lesions include CCA, HCC, and liver metastases from other primary tumors which are particularly common in primary gastrointestinal malignancies and neuroendocrine tumors (Table 10.2).
Cholangiocarcinomas arise from the epithelial cells of the bile ducts and are associated with poor prognosis. The overall median survival of patients with unresectable disease is 6 to 12 months.6 Approximately 60% occur at the hepatic duct bifurcation and only 5% to 15% within the liver. The best treatment option remains surgical excision as the response rate for chemo- or radiotherapy is limited.7 Accurate preoperative staging is essential to detect early metastatic disease. MRI is the gold standard to evaluate the extent of local disease.
Conventional Nuclear Medicine Imaging
99mTc sulfur colloid can be used to demonstrate CCAs. Approximately 85% of intravenously injected 99mTc sulfur colloid accumulates in the liver because of reticuloendothelial cell uptake. Intrahepatic CCAs are seen as cold lesions. Specificity is low as reduced uptake is seen in most benign and malignant liver lesions including abscesses. This technique helps in localizing the lesions when they are larger than 2 cm but is now rarely used since the advent of MRI.
18F-FDG PET and PET/CT
The literature on 18F-FDG PET and PET/CT to image CCA is sparse with small numbers of patients in most series. The largest prospective study was conducted by Kim et al.8 who reviewed 123 patients with suspected CCA. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy of 18F-FDG PET/CT in primary tumor detection were 84%, 79.3%, 92.9%, 60.5%, and 82.9%, respectively. It was concluded that 18F-FDG PET/CT demonstrated no statistically significant advantage over CT and MRI/MRCP in the diagnosis of primary liver tumors. According to different morphologic characteristics of CCA, 18F-FDG PET/CT showed no significant difference in detecting the mass-forming, periductal-infiltrating, and intraductal-growing types.
SOME MALIGNANT LIVER LESIONS WHERE RADIONUCLIDE IMAGING MAY CONTRIBUTE TO MANAGEMENT
FIGURE 10.1. A 99mTc-labeled red blood cell scan showing a hypoperfused area in the dome of the liver on the 5-minute images (left), which “fills in” on the 2-hour images (right) in keeping with a hepatic hemangioma.
Petrowsky et al.9 found a sensitivity of 93% to detect intrahepatic CCA with a specificity of 80%. Sensitivity and specificity to detect distant metastases, however, were 100%.9,10 18F-FDG PET appeared to be very poor to accurately determine local lymph node metastases, with a reported sensitivity of 12%, but a specificity of 96%. Breitenstein et al.10 also confirms a higher sensitivity for intrahepatic CCA compared to extrahepatic CCA where the sensitivity drops to 60%.
Kim found conflicting results in the lymph node assessment compared to previous studies. He described a significantly higher accuracy over CT in the diagnosis of regional lymph node metastases (75.9% versus 60.9%, p = 0.004) and distant metastases (88.3% versus 78.7%, p = 0.004). Jadvar et al.11 focused on tumor recurrence and confirmed the high detection rate for distant CCA metastases, with a sensitivity of 94% and a specificity of 100%.
Kluge et al.12 directly compared the accuracy of 18F-FDG PET/CT against MRI in detecting CCA in 26 known cases and found a sensitivity of 92.3% for 18F-FDG PET/CT. Poor sensitivity for detection of lymph node involvement was reported, with positive lymph nodes detected in 2 out of 15 patients.
This primary liver tumor usually develops in a background of chronic liver disease, most commonly caused by hepatitis B or C. Therefore, its global distribution is related to the prevalence of these infections. In Southeast Asia and Africa, hepatitis B virus infections are common, whereas in the Western world, hepatitis C infections and alcoholic liver disease lead to liver cirrhosis and HCC. It is thought that the incorporation of viral DNA into the HCC genome results in the transformation into HCC. The prognosis of HCC is poor. Early detection and correct staging, therefore, is crucial for successful management.
Imaging in Hepatocellular Carcinoma
US is used to screen patients with chronic liver disease for HCC as it is readily available. However, US cannot reliably distinguish HCC from other solid tumors.
Contrast-enhanced CT examinations have a high sensitivity and allow the detection of hypervascular HCCs as small as 3 mm.13 Triple phase CT can visualize tumors that are isoattenuated on the arterial and portal phases, increasing the sensitivity.14 Triple phase CT scans of the liver during contrast injection, include an arterial phase shortly after injection, a portal phase, and a delayed phase. The arterial phase will highlight arterial lesions whereas the portal phase will show lesions that primarily enhance from the portal vein. The portal phase shows the liver during higher parenchymal enhancement and allows depiction of most lesions with a greater lesion to liver ratio. The delayed phase of helical CT is performed 5 to 10 minutes post contrast and has been reported to show higher liver HCC contrast than does the portal venous phase, thus improving the rate of detection of well-differentiated hypovascular HCCs.14
The sensitivity of MRI to detect HCC is similar to helical CT; however, it is more sensitive and specific in differentiating regenerative nodules from HCC in the cirrhotic liver.15,16
Limitations of Conventional Imaging for Response Assessment
The current standard method to assess response of unresectable primary and metastatic HCC is by contrast-enhanced CT using response evaluation criteria in solid tumors (RECIST) criteria17 but it is recognized that this is a relatively insensitive and nonspecific method. In a Phase III study of sorafenib in HCC, only 2% of subjects demonstrated an RECIST response to the drug, despite an improvement in overall survival.18 As a consequence, a beneficial tumor effect may be unrecognized in some patients who do not show a reduction in tumor volume and, in contrast, some patients may continue to receive treatment that is not beneficial until there is unequivocal evidence of progression. This may result in unnecessary treatment-related toxicity.
Given the limitations of RECIST size change criteria for monitoring HCC, alternative methods to assess response have been proposed.19,20 With CT, this has depended on the measurement of viable enhancing parenchyma which provides a better correlation with survival.21,22 but still suffers from some of the same limitations as RECIST criteria for response assessment in that these criteria still rely on the measurement of size change, albeit of lesions identified as visible in the arterial phase of contrast-enhanced imaging.
Conventional Nuclear Medicine Imaging of Hepatocellular Carcinoma
Imaging with HIDA shows characteristic findings for HCCs. There is reduced flow on initial imaging. Two to four hours delayed imaging shows “filling in” within the HCC with further tracer washout by the normal liver tissue. The pattern is very specific; however, poorly differentiated HCC may not demonstrate filling in on delayed imaging.
Functional Imaging Biomarkers
To meet the clinical need to be able to predict response and stratify patients at an early stage of treatment, functional imaging biomarkers have been of considerable interest. Potential methods include PET tracers such as 18F-FDG, 18F-Fluorodeoxygalactose (18F-FDGal), 11C-acetate (11C-Act), 11C or 18F-choline (11C-Cho, 18F-Cho), and 18F-Fluorothymidine (18F-FLT) to assess metabolism, lipogenesis, cellular membrane metabolism, and proliferation, respectively.23
Most of the existing literature comes to the conclusion that the uptake of 18F-FDG in HCC is variable, with more uptake demonstrated in poorly differentiated carcinomas. The false-negative rate is high in well-differentiated HCCs.24Wu et al.25 showed sensitivity for 18F-FDG in well and moderately differentiated HCCs is as low as 35%, but 83.3% in poorly differentiated HCC. The high level of FDG-6-phosphatase activity in well-differentiated HCCs appears to be responsible for the high false-negative rate as FDG-6-phosphate is not trapped in the cell.25
Despite these limitations 18F-FDG PET has proven to be useful to detect postoperative tumor recurrence, response to liver-directed therapy, including radiofrequency ablation and to predict tumor recurrence post liver transplant for HCC (Fig. 10.2).26
FIGURE 10.2. The liver lesions of a 69-year-old man with a history of hepatocellular carcinoma post transarterial chemoembolization and radiofrequency ablation, with a rising alpha feto protein (AFP). The peripheral portion of the mass in segment II/III of the liver is both 18F-FDG (top) and 11C-acetate-avid (bottom). This is indicative of a recurrent metabolically active disease.
11C-Choline [11C-Cho] and 18F-Fluorocholine [18F-Cho]
Choline is one of the components of phosphatidylcholine, a phospholipid found in cell membranes. In carcinoma, rapid cell duplication results in active uptake of choline.27
11C-Cho is more sensitive than 18F-FDG in the detection of well-differentiated HCC. Wu et al.25 investigated the advantage of combined 18F-FDG and 11C-Cho imaging in 76 patients diagnosed with HCC. 11C-Cho scans were positive in 71.4% (20/28) of patients who had a negative 18F-FDG PET scan. Similar results were found in a small study by Yamamoto et al.,28 reviewing 12 patients that showed a sensitivity of 75% for 11C-Cho versus 42% for 18F-FDG in the detection of moderately differentiated HCC lesions. In well-differentiated HCC lesions, 11C-Cho PET showed a sensitivity of 66.7% versus 35.7% for 18F-FDG. None of these comparisons reached statistical significance, most likely because of small numbers reviewed (12 patients with 16 lesions). The same study also found a poor sensitivity for 11C-Cho to detect poorly differentiated HCC.
11C-Cho has several disadvantages: High background standardised uptake value (SUV) (approximately 13) within the normal liver parenchyma and a short half-life (20 minutes) limit its use to institutions with an on-site cyclotron. 18F-Cho has a longer physical half-life of 110 minutes and appears, therefore, to be a more convenient alternative to 11C-Cho. Direct comparison of 18F-Cho and 11C-Cho by Kolthammer et al.29 in a woodchuck model found that they perform similarly. The Eastern woodchuck in the US harbors a DNA virus, the woodchuck hepatitis virus (WHV), that is similar in structure and life cycle to the HBV (human hepatitis B virus). WHV infects the liver causing acute and chronic hepatitis and leads to the development of HCC.
Talbot et al.27 compared 18F-Cho with 18F-FDG and found that 18F-Cho is more sensitive to detect well-differentiated HCCs than 18F-FDG, 94% versus 59%, respectively.
At this stage, 18F-FDG PET/CT in combination with 11C-Cho or 18F-Cho PET/CT seems to be the most effective approach to detect HCC. A negative study, however, should still be interpreted with caution.
11C-Acetate [11C-Act] PET
In the woodchuck HCC model, 11C-Act uptake is associated with de novo tumoral lipogenesis and fatty acid synthase activity. The sensitivity of 11C-Act to detect HCC has also been shown previously in the woodchuck HCC model.30 11C-Cho and 11C-Act detected 17/17 and 16/17 tumors compared to 7/13 with 18F-FDG. The same study showed that lipid-related genes were upregulated. In man, previous studies have established the value of 11C-Act PET to detect primary and metastatic HCC31–35 with sensitivities up to 87% in the liver and 77% for a metastatic disease.
Although 11C-Act PET appears to be one of the most sensitive modalities to detect HCC and its metastases, studies have observed a complementary relationship between 18F-FDG and 11C-Act imaging in HCC whereby 18F-FDG PET is often positive in the few patients who are 11C-Act negative with 83% of primary tumors and 86% of metastases being detected in one study by the dual tracer technique.32 In another study, 98% of metastatic lesions were detected by the dual tracer technique (Fig. 10.2).33
18-Fluoro-3 ′-Deoxy-3′-L-Fluorothymidine (18F-FLT PET)
18F-FLT uptake has also been investigated as a proliferation marker and although the degree of uptake seemed to predict overall survival, only 69% of primary lesions were detectable.36
In a feasibility study, 18F-FDGal showed promising results with 22 of 23 tumors showing uptake before treatment, including nine patients with extrahepatic disease and no uptake in seven patients without HCC.37
Metastases are the most common malignant liver lesions and account for 95% of all liver lesions seen in clinical practice. Metastases can result from various tumors; however, the most common are colorectal, breast, melanoma, and lung.38
Comparative studies between CT, MRI, and US without contrast demonstrate a high specificity but a low sensitivity of 55% for ultrasound.39,40 Intraoperative ultrasound is the most accurate imaging technique to detect liver metastases at the time of primary tumor resection.39,41
CT and MRI
MRI imaging techniques include T1, T2, and diffusion-weighted imaging (DWI) and post-contrast acquisitions. Contrast agents used include gadolinium and tissue-specific MR contrast agents, such as mangafodipir (Mn-DPDP), a hepatocyte-specific agent, and iron oxide particles.42 Mn-DPDP is taken up by hepatocytes but not metastases, which therefore appear hypo-intense on T1W images. Iron oxide particles are taken up by Kupffer cells within the normal liver parenchyma and not by metastases and therefore iron oxides increase the liver-to-lesion ratio and can improve detection.43
Motosugi et al.44 reviewed 94 patients with colorectal cancer using contrast-enhanced MRI and triple-phase CT for the evaluation of small hepatic metastases below 2 cm.
The same sensitivity of 61% was found for both CT and MRI. The mean positive predictive value of triple phase CT was inferior to that of MRI (82% versus 91%, respectively).44 Helical CT has a reported sensitivity of 64.7% to detect liver metastases regardless of size and 1.5-T MRI has a sensitivity of 75.8%.40
99mTc Sulfur Colloid Imaging
As with most other benign and malignant liver lesions, metastatic deposits present as a photopenic defect on 99mTc sulfur colloid imaging. With SPECT, the sensitivity and specificity to detect liver metastatic disease is 90%. Although this was a common method to assess and monitor metastases in the past, it has no routine role in modern imaging.
Two large meta-analyses found 18F-FDG PET to be the most sensitive imaging modality for liver metastases assessment in patients with colorectal, gastric, and esophageal cancer.40,45 Lai et al.46 also found a high sensitivity of 94% of 18F-FDG PET to detect liver metastases. Similar results were found by D’Souza et al.,47 who evaluated 45 patients with suspected hepatic metastases in a prospective study. The authors reported a sensitivity and specificity of 97% and 75%, respectively for 18F-FDG PET.
Most of the published data evaluating the benefit of 18F-FDG PET for the assessment of liver metastases are studies from staging colorectal carcinoma; since 50% of patients with CRC develop liver metastases (Fig. 10.3).38Patients with solitary liver metastases are amendable for surgical intervention. If there are extrahepatic involvement or disseminated liver metastases, however, palliative chemotherapy is frequently the more appropriate management.48,49
Accurate preoperative staging is essential to reduce the number of futile operations. The ability of 18F-FDG PET to detect occult metastatic disease has been demonstrated in multiple studies. In 150 preoperative patients, Ruers et al.50 found that CT staging alone resulted in 45% futile operations, (defined as any laparotomy that did not result in complete tumor treatment, revealed benign disease, or did not result in a disease-free survival period longer than 6 months), whereas only 28% of 18F-FDG PET-staged patients had a futile operation. The relative risk reduction of futile operations, therefore, was 38% with 18F-FDG PET staging. Grassetto et al.51 evaluated 43 patients with known solitary liver metastases prior to surgical intervention with 18F-FDG PET/CT. In 28% of patients (12/43), 18F-FDG PET/CT resulted in restaging and change of management. The authors concluded that 18F-FDG PET/CT can have a significant impact on staging and selecting patients for surgical intervention.
FIGURE 10.3. Multiple 18F-FDG avid liver metastases in a patient with disseminated malignancy.
A meta-analysis by Patel et al.,52 reviewing the diagnostic accuracy of 18F-FDG PET/CT for colorectal liver metastases, found that PET/CT is more sensitive than CT alone to detect extrahepatic disease (75% to 89% versus 58% to 64%) with a similar specificity (95% to 96% versus 87% to 97%). 18F-FDG PET/CT was also more sensitive and specific for detecting hepatic disease: 91% to100% versus 78% to 94% and 75% to 100% versus 25% to 99%, respectively. 18F-FDG PET/CT also was found to have a high sensitivity and specificity to detect local recurrence when compared to CT: 93% to 100% versus 0% to 100% and 97% to 98% specificity for both modalities.
Problems arise following treatment with neo-adjuvant chemotherapy. The sensitivity of 18F-FDG PET was reduced to 49% following neo-adjuvant chemotherapy.53 This is not only because of reduced metabolic activity, but also reduction in tumor size below PET resolution. Although sensitivity may be impaired to detect small volume residual but viable metastases following chemotherapy, 18F-FDG PET has been shown to be helpful to assess treatment response of liver metastases. Findlay et al.54 used 18F-FDG PET to evaluate tumor response to fluorouracil and found responsive lesions had a lower tumor-to-liver ratio after 4 to 5 weeks of treatment.
After radiofrequency ablation (RFA) therapy of hepatic lesions, surveillance with conventional CT may be difficult, as a contrast-enhancing rim is often demonstrated on contrast CT.55 Veit et al.56 showed that 18F-FDG PET/CT is more accurate than contrast-enhanced CT to detect recurrence after RFA (65% versus 22%). Choi evaluated treatment response to RFA with 18F-FDG PET/CT and found that within 3 weeks of therapy, most lesions became photopenic on 18F-FDG PET. Those lesions demonstrating persistent 18F-FDG uptake after 3 weeks were associated with local recurrence. The 18F-FDG negative lesions did not recur during 18 months of follow-up.57
These groups of tumors, deriving from endocrine cells, have the capacity to produce biogenic amines and polypeptides and frequently spread to the liver.
In conventional nuclear medicine, In-111-labeled pentetreotide (OctreoScan) is used for the diagnosis and staging of neuroendocrine tumors. It was found to be the single most sensitive imaging method compared to CT, MRI, and US.58
In terms of PET/CT imaging, 18F-FDG can be used; however, it is not taken up by indolent well-differentiated neuroendocrine tumors with a low metabolic turnover but 18F-FDG may be taken up by poorly differentiated tumors. Scans using alternate tracers such as 11C-hydroxytryptophane (HT), 18F-dihydroxyphenylalanine (DOPA), or 18F-fluorodopamine in PET imaging are being utilized.59 Kayani et al. 60 found that 18F-FDG and 68Ga-DOTA-tate combined, increases sensitivity in accurate tumor staging (66% 18F-FDG alone, 82% 68Ga-DOTA-tate alone, and 92% combined, respectively) (Fig. 10.4).
FIGURE 10.4. Multiple 68Ga-DOTATATE avid hepatic lesions in a patient with a metastatic neuroendocrine tumor with no significant interval change demonstrated over an 5-month period.
RADIONUCLIDE THERAPY OF LIVER TUMORS
Intra-arterial radionuclide treatment is becoming a well-established treatment modality in the management of unresectable liver tumors. Since normal liver parenchyma receives the majority of its blood supply from the portal vein and malignant liver tumors derive 95% of their blood supply from the hepatic arteries,61 it has become evident that targeted therapies delivered directly into the hepatic artery can selectively treat tumors sparing healthy liver tissue.
Intra-Arterial Radiolabeled Lipiodol (131I-Lipiodol) Therapy
131I-Lipiodol (Lipiocis®, IBA, Brussels, Belgium) is the oldest radionuclide compound used for the treatment of unresectable HCC.62 It is prepared from ethiodized oil which is a 38% iodine-rich fatty acid ethyl ester derived from poppy seed oil. Its stable 127I is substituted with 131I using a simple exchange reaction. 131I is a β-emitting radionuclide with a physical half-life of 8.04 days and a maximum and mean soft tissue range of 2.4 and 0.9 mm, respectively. 131I also emits a γ-photon of 364 keV which can be used for imaging.
131I-Lipiodol is supplied in a solution for use at room temperature. Its viscous properties offer high resistance to syringe dispensing and catheter injection.63
The treatment is administered via the hepatic artery using an implanted catheter with a port or through a femoral catheter under fluoroscopy guidance which is the preferred method of administration. Administration of a fixed activity of 2.22 GBq (60 mCi) leads to a mean dose in the liver of approximately 50 Gy.62 Once in the hepatic circulation, 131I-Lipiodol migrates toward liver tumors because of increased vessel permeability and has slow clearance because of the lack of lymphatic vessels and Kupffer cells.63–65 Twenty-four hours post administration, 75% to 90% of the administered activity is trapped in liver tumors and a proportion remains in normal liver tissue.63–65 Major arteriovenous shunts are a contraindication to treatment.62 Slight pulmonary uptake is possible as a result of arteriovenous shunting in the liver after release of 131I-Lipiodol bound to nontumoral liver. Other possible complications include gastrointestinal uptake when 131I-Lipiodol is administered into arteries supplying the gastrointestinal tract or because of reflux.
Side effects are rare and the treatment can be repeated 2, 5, 8, and 12 months after the first administration.62
Intra-Arterial Radiolabeled Microsphere Therapy
Because of the undesirable properties of 131I and its increased radiation burden to healthy tissues, other treatment options have been developed. This includes Y-90 radioembolization which is increasingly becoming a well-established treatment for HCC and liver metastases. It involves the administration of radiolabeled microspheres which are available in two forms for commercial use. The microspheres are either made of glass beads (TheraSpheres) or resin beads (SIR-Spheres), with a mean diameter of 20 to 30 and 30 to 40 microns respectively.66 They are usually labeled with Yttrium-90 (90Y), which emits β-radiation with a maximum range of 11 mm (mean range: 2.5 mm) inducing damage to the nearby tumor cells.37 The half-life of 90Y is 64.2 hours providing effective treatment duration of 92.3 hours. 90Y also produces x-rays (Bremsstrahlung) and has positron emission that can be utilized to image the distribution of the delivered therapy dose using a standard γ-camera for Bremsstrahlung imaging and a PET/CT scanner for positron emission.
The delivery of 90Y-microspheres into the hepatic artery and the liver is done angiographically in two interventional sessions. The first is for initial assessment of hepatic as well as gastrointestinal arterial circulation and calculation of hepatic–pulmonary shunt. Angiography of the abdominal aorta and its branches is performed and any vessels that can potentially deliver microspheres to nontarget organs leading to complications are embolized. During this procedure, the hepatic to pulmonary shunt is also calculated which is used to adjust the activity delivered to avoid radiation pneumonitis.
The second angiographic procedure is usually undertaken 1 to 2 weeks afterward to deliver 90Y-microspheres. Patients are usually discharged the following day. The treatment is generally well tolerated in experienced centers with limited side effects, the majority of which are treated conservatively such as transient radiation fever and pain.
Role of PET/CT in Y-90 Radioembolization
It has recently been shown that a minor branching fraction in the decay chain of 90Y results in the emission of a positron (+β).67 This has opened new frontiers in imaging the distribution of 90Y-microspheres in the liver using PET/CT. Lhommel et al.68 evaluated the feasibility of imaging the positron emissions of 90Y with a PET/CT scanner in the preclinical setting and in a patient following Y-90 radioembolization using a high-end time-of-flight (TOF) PET/CT. The study showed that PET images correlated reasonably well with the baseline pretherapy 18FDG PET images despite the differences in the mechanism of uptake and reflected more accurately the tumor heterogeneity compared with the traditional Bremsstrahlung imaging using single photon emission tomography. Initial results in clinical practice also demonstrated a high-resolution absorbed dose distribution and showed that 90Y dosimetry correlated very well with tumor response.68 The authors also used a copper filter (2.5 mm) to prevent saturation and dead time losses of the detector because of the effect of other energy interactions such as the Bremsstrahlung. However, subsequent work conducted by Werner et al.69 suggested that good quality 90Y PET/CT can be obtained without the need for additional copper ring or advanced TOF. More recently, a study by D’Arienzo et al.70 has shown that 90Y-PET provided very good quality images of liver tumors 2 hours after Y-90 radioembolization which correlated with 18F-FDG uptake in the target lesions on the pretreatment PET/CT. The Y-90 PET/CT images were used to calculate the target dose using voxel-based dosimetry. More importantly, the authors have shown that the calculated dose to target lesions on the Y-90 PET/CT predicted response to treatment on the 6-month follow-up PET/CT.
18F-FDG PET/CT is also rapidly gaining an important role in the assessment of response to Y-90 radioembolization. As previously mentioned, RECIST criteria are insensitive in assessing response to interventional treatments which include Y-90 radioembolization. This is because the effects of these treatments can take several months before producing a measurable change on contrast-enhanced CT (CECT) using RECIST which relies on measurements of the longest diameter of the lesions. Therefore, metabolic response may be more accurate in assessing response to these therapies.
A study that described early experience of the authors in using 90Y-radioembolization in 23 patients with nonresectable liver disease not responding to chemotherapy or local treatments used a 3-month 18F-FDG PET follow-up for response assessment.71 Data available in 13 patients showed a marked decrease in 18F-FDG uptake of liver metastases in 10 out of 13 patients, reaching even normal hepatic 18F-FDG uptake in three out of 10 patients. This decline paralleled a decrease in tumor markers (carcinoembryonic antigen [CEA], CA19-9, CA 15-3, and special markers for neuroendocrine tumors [Cyfra 21-1, ProGRP, NSE]) which also decreased in all 10 patients, reaching normal levels approximately 3 months after 90Y-radioembolization in 5 out of 10 patients. A recently published study in 58 patients with breast cancer liver metastases treated with 90Y-radioembolization has shown that 18F-FDG PET/CT performed 3 months after treatment was the strongest predictor of overall survival (67 weeks in responders versus 43 weeks in nonresponders) whereas response on CT/MRI could not predict survival.72 The authors also found that a pretreatment SUVmax > 20 was a poor prognostic indicator (overall survival [OS] 20 weeks versus 57 weeks in patients with SUV < 20). The above studies have assessed response at 3 months but there has been an interest in predicting response earlier at 6 to 8 weeks so that a different treatment approach can be adopted. A study by Szyszko et al.73 evaluated the role of 18F-FDG PET in comparison to RECIST in early response assessment post 90Y-radioembolization in 21 patients. The authors demonstrated that an early 18F-FDG PET performed at 6 weeks showed a decline in SUV in 86% of patients whereas CT demonstrated a decline in size in only 13% of patients. In one patient, the decline in 18F-FDG uptake was significant to downstage the patient and as a consequence underwent surgical resection. Recently, Zerizer et al.74 evaluated the role of early 18F-FDG PET/CT performed at 6 to 8 weeks in predicting a progression-free survival after 90Y-radioembolization of colorectal liver metastases in comparison to RECIST and tumor density criteria (CHOI criteria). The authors found that patients with a metabolic partial response on PET/CT had longer progression free survival (PFS) compared to nonresponders (12 months versus 5 months, respectively). RECIST and tumor density criteria assessed on contrast-enhanced CT at 6 to 8 weeks failed to demonstrate treatment response and did not predict PFS. Response on PET/CT also highly correlated with response in tumor markers (CEA and Ca 19-9).
18F-FDG PET /CT is a more accurate imaging biomarker of treatment response to 90Y-radioembolization and is a prognostic indicator.
Despite increased usefulness of CT and MRI, there remain a number of situations where functional imaging with SPECT or PET tracers can be complementary to, or can add to, diagnostic accuracy. The ability to image several aspects of liver physiology and tumor biology with nuclear medicine techniques means that these will remain part of the required imaging algorithms for both benign and malignant tumors of the liver.
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