Radiol med (2014) 119:215–221 DOI 10.1007/s11547-013-0332-5
ABDOMINAL RADIOLOGY
Hepatocellular carcinoma enhancement on contrast-enhanced CT and MR imaging: response assessment after treatment with sorafenib: preliminary results Giuseppe Salvaggio • Alessandro Furlan • Francesco Agnello • Giuseppe Cabibbo Daniele Marin • Lydia Giannitrapani • Chiara Genco • Massimo Midiri • Roberto Lagalla • Giuseppe Brancatelli
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Received: 28 December 2012 / Accepted: 23 April 2013 / Published online: 3 December 2013 Ó Italian Society of Medical Radiology 2013
Abstract Purpose This study was undertaken to compare response evaluation criteria in solid tumours (RECIST) 1.1 and modified RECIST (mRECIST) in patients with unresectable hepatocellular carcinoma (HCC) on sorafenib, and to describe HCC enhancement changes before and after sorafenib treatment. Methods and materials Seventeen patients (12 men, 5 women; mean age 69 years; age range 58–79 years) were included. Tumour response was assessed according to RECIST and mRECIST. Two readers placed a region of interest (ROI) within each target lesion, on the portion showing enhancement during the arterial phase. The lesion attenuation values measured within the ROIs on computed tomography or the signal intensity measured on magnetic
G. Salvaggio F. Agnello M. Midiri R. Lagalla G. Brancatelli (&) Dipartimento di Biotecnologie Mediche e Forensi, Sezione di Scienze Radiologiche, Universita` di Palermo, Via del Vespro 127, 90127 Palermo, Italy e-mail:
[email protected] A. Furlan Department of Radiology, University of Pittsburgh Medical Center, 200 Lothrop Street, Pittsburgh, PA 15213, USA G. Cabibbo C. Genco Department of Gastroenterology, DIBIMIS, University of Palermo, Via del Vespro 127, 90127 Palermo, Italy D. Marin Department of Radiology, Duke University Medical Center, Box 3808, Durham, NC 27710, USA L. Giannitrapani Department of Clinical Medicine and Emerging Pathologies, University of Palermo, Via del Vespro 127, 90147 Palermo, Italy
resonance imaging, during the unenhanced phase, hepatic arterial phase and venous phase were recorded. Changes in arterial and venous contrast enhancement before and after treatment were compared among the mRECIST groups using Mann–Whitney U test. Results Agreement between mRECIST and RECIST was good (Cohen’s k coefficient, 0.791). Patients with partial response had a greater decrease in arterial enhancement (-79.8 %) than did patients with stable disease (SD) (-24.8 %; p = 0.011) or progressive disease (PD) (-32.9 %; p = 0.034). No statistically significant difference in arterial enhancement variation was found among patients with SD and PD. No statistically significant difference in venous enhancement was found among the mRECIST groups. Conclusions mRECIST showed a more favourable response compared to RECIST 1.1 in patients with unresectable HCC receiving sorafenib. Keywords
Liver CT MR HCC Sorafenib
Introduction Hepatocellular carcinoma (HCC) is a major health problem worldwide and the main cause of death among cirrhotic patients [1]. At the time of initial diagnosis, only 10–30 % of patients have early stage, curable HCC [2]. Sorafenib is an oral multikinase inhibitor with anti-angiogenic effect that blocks tumour cell proliferation [3]. Sorafenib has been shown to improve survival in patients with advanced-stage HCC [3, 4]. The introduction of this new therapy has led to search for new radiological endpoints/biomarkers able to measure and predict tumour response to treatment [3, 5–11]. Response evaluation criteria in solid tumours (RECIST) are typically used to assess response to cytotoxic therapy.
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However, these criteria may not adequately reflect tumour response to sorafenib, because changes in tumour vascularity and necrosis may occur without major changes in tumour size [6, 8, 11–15]. Therefore, modified RECIST (mRECIST) have been developed which differ from RECIST in that the target lesion measured is not the whole lesion but only the viable tumour, defined as the contrast-enhanced portion of the tumour on hepatic arterial phase images [9, 12, 16, 17]. We hypothesised that the anti-angiogenic effect of sorafenib could be measured on contrast-enhanced computed tomography (CT) and magnetic resonance (MR) imaging as changes in tumour enhancement. Therefore, the purpose of our study was to compare tumour response according to RECIST and mRECIST and to describe changes in HCC enhancement before and after sorafenib treatment.
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Imaging studies Baseline examinations were performed at a median of 30 days (range 28–36 days) before the start of treatment. Thirteen (76 %) patients had one follow-up imaging study available, two (12 %) patients had two follow-up imaging studies available, and two (12 %) patients had three followup imaging studies available. The latest follow-up imaging study available was performed after a median of 103 days (range 55–617 days) after the treatment starting date. The CT and MR imaging protocol was the same for the baseline and follow-up examinations. The baseline examination was performed with either CT (n = 10) or MR imaging (n = 7). Computed tomography
Patients and methods Study population Review board approval was obtained, with a waiver for informed patient consent. Through a computerised search of our Gastroenterology Department database from December 2007 to January 2010, a study coordinator identified 40 patients who received anti-angiogenic treatment with sorafenib (Nexavar, Bayer Healthcare, Germany) in a standard dose of 800 mg daily for unresectable HCC. These patients were deemed inoperable or untransplantable either because tumour burden exceeded the United Network of Organ Sharing (UNOS) or University of California Sans Francisco (UCSF) criteria or because of comorbidities. Patients with previous locoregional treatment (n = 15) and patients without available baseline or follow-up contrast-enhanced CT/MR imaging studies (n = 4) were excluded. Of 21 patients available for imaging analysis, two were excluded because of artefacts compromising lesion measurement and two because the criteria for target lesion could not be fulfilled. Therefore, the final study population consisted of 17 cirrhotic patients with 27 HCCs. There were 12 men (mean age 68 years; range 58–79 years) and five women (mean age 73 years; range 67–78 years) with an overall mean age of 69 years (range 58–79 years). The underlying cause of cirrhosis was hepatitis C in 11 (64 %) patients, hepatitis B in three (18 %) patients and ethanol in three (18 %) patients. Seven (41 %) patients had one measurable lesion and 10 (59 %) patients had multiple measurable lesions. The study coordinator noted the following clinical data for each patient: alphafetoprotein level, performance status, Child-Pugh class, Barcelona Clinic Liver Cancer (BCLC) stage, treatment starting date and duration, previous vascular surgery and association with other vascular hepatic diseases.
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CT imaging was performed using a 64-section scanner (Philips Brilliance, Royal Philips Electronics, Eindhoven, the Netherlands). The following CT parameters were used: detector configuration, 64 9 0.625 mm; peak, 120 KVp; scan time, 4 s; mAs, 250–300; section thickness, 3 mm; no section overlap. Multidetector (MD) CT was performed before contrast medium administration and during the hepatic arterial, hepatic venous and delayed phases. All patients received 1.5 mL/kg total body weight of an intravenous nonionic contrast medium containing an iodine concentration of 400 mgI/mL (Iomeron 400; Bracco Imaging). The contrast medium was administered with a mechanical power injector (Invision CT, Medrad) at a rate of 3–5 mL/s through an 18- to 20-gauge intravenous catheter inserted into an arm vein, followed by a flush of 25 mL of saline administered at the same injection rate. Automatic bolus-tracking techniques with automated scantriggering software (Bolus Pro Ultra, Philips Medical Systems) were used. Hepatic arterial phase and venous phase scanning were started automatically 18 and 58 s, respectively, after the trigger threshold (150 HU) was reached at the level of the suprarenal abdominal aorta. The delayed phase was started 180 s after the start of contrast material injection. MR imaging MR imaging was performed using a 1.5-T scanner (Signa Excite HDXT, General Electric, Healthcare, Milwaukee, WI, USA). The imaging protocol included a T2-weighted fast-spin echo sequence (TR/TE, 4,000/76 ms; flip angle, 90°; section thickness, 6 mm; matrix size, 224 9 320; field of view, 30–50 cm); a T1-weighted in-phase and out-of-phase gradient-recalled-echo (GRE) sequence (TR/TE, 150/4.4–2.2 ms; flip angle, 80°; section thickness, 5 mm; matrix size, 256 9 256; field of view, 30–50 cm) and an axial breath-hold
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three-dimensional T1-weighted fat-suppressed spoiled gradient-recalled-echo contrast-enhanced sequence (TR/TE, 4.2/ 2.0 ms; flip angle, 12°; section thickness, 3 mm; matrix size, 196 9 320; field of view, 30–50 cm). Contrast administration consisted of 0.1 mmol/kg body weight of gadobenate dimeglumine (MultiHance; Bracco Imaging, Milan, Italy) in six patients or 0.025 mmol/kg of gadoxetate disodium (Primovist, Bayer, Berlin, Germany) in one patient, injected at 1–2 mL/s through a 20-gauge intravenous catheter with a power injector (Spectris; Medrad, Pittsburgh, PA, USA), followed by 20-mL saline flush at the same rate. Patients received the same contrast agents at baseline and follow-up examination. Images were acquired using an automated bolus-detection technique (Smartprep technique, GE Healthcare) during the arterial (14 s after bolus detection), hepatic venous and delayed phase (60 and 180 s after bolus injection, respectively). Image analysis The CT and MR imaging studies were evaluated in consensus by two experienced abdominal radiologists (G.B. and G.S. with respectively 13 and 12 years of experience in abdominal imaging) on a picture archiving and communication system (PACS) (Impax 6.4, Agfa, Mortsel, Belgium). Readers were blinded to the imaging reports. The pre-sorafenib (baseline) and post-sorafenib (follow-up) CT and MR examinations were assessed in the same session. If a patient had multiple follow-up CT or MR imaging studies, the latest was considered for analysis. Diagnosis of HCC was made using a combination of imaging and laboratory criteria (i.e., size [1 cm; enhancement during the hepatic arterial phase and washout during hepatic venous and/or delayed phase; interval growth; mild hyperintensity on T2-weighted imaging; signal loss on out-ofphase imaging due to the presence of lipids; tumour invasion of the portal vein; elevated alphafetoprotein) [1]. The diameter of the HCC lesions was measured. When multiple HCC lesions were noted at baseline CT or MR examinations, a maximum of two target lesions were selected for further analysis; a target lesion was selected if the following conditions were satisfied: (a) the lesion could be accurately measured in at least one dimension; (b) it was suitable for repeat
measurement; (c) it showed intratumoural arterial enhancement on contrast-enhanced CT or MR imaging. Finally, the presence of portal vein thrombosis was noted. RECIST vs mRECIST Tumour response was evaluated according to RECIST 1.1 and mRECIST. For RECIST 1.1, the whole lesion was considered as the target lesion, whereas for mRECIST the target lesion was defined as the portion of the tumour showing enhancement on hepatic arterial phase images. Patients were classified according to tumour response to treatment as follows: complete response, partial response; stable disease; progressive disease (Table 1). Tumour arterial and venous enhancement The readers manually placed largest possible circular ROIs within each target lesion, on the enhancing portion of the lesion during the arterial phase. The ROIs were then copied and pasted onto the images acquired during the unenhanced and venous phase. The ROI values of lesion attenuation measured on the CT images or the signal intensity values measured on the MR images during the unenhanced, hepatic arterial and venous phase were recorded. Enhancement values during the hepatic arterial phase and venous phase were calculated for each lesion as: hepatic arterial phase enhancement = [(attenuation/signal intensity during hepatic arterial phase - attenuation/signal intensity during unenhanced phase)/attenuation/signal intensity during unenhanced phase] 9 100; venous phase enhancement = [(attenuation/ signal intensity during venous phase - attenuation/signal intensity during unenhanced phase)/attenuation/signal intensity during unenhanced phase] 9 100. Then, changes (%) in hepatic arterial phase and venous phase tumour enhancement between baseline and follow-up were calculated as: (enhancement at follow-up - enhancement at baseline/ enhancement at baseline) 9 100. Statistical analysis The Cohen coefficient was used to determine the level of agreement between RECIST 1.1 criteria and mRECIST
Table 1 Evaluation criteria used to evaluate the treatment response of hepatocellular carcinomas Criteria
CR
PR
SD
PD
RECIST 1.1
Disappearance of all target lesions
C30 % decrease in the sum of diameters of target lesions
No criteria for other responses are met
C20 % increase in the sum of the diameters of target lesions
mRECIST
Disappearance of intratumoural HAP enhancement in all target lesions
C30 % decrease in the sum of diameters of viable target lesions
No criteria for other responses are met
C20 % increase in the sum of the diameters of viable target lesions
CR complete response, PR partial response, SD stable disease, PD progressive disease, HAP hepatic arterial phase
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criteria (0.00–0.20, poor agreement; 0.21–0.40, fair agreement; 0.41–0.60, moderate agreement; 0.61–0.80, good agreement; 0.81–1.00, excellent agreement). To assess the association between variation in hepatic arterial phase enhancement and venous phase enhancement and response to therapy according to mRECIST, variations were compared among the groups of treatment response with a pairwise method using the Mann–Whitney test. A p value \0.05 was considered to be statistically significant. Statistical analysis was performed with SPSS, version 16.0 (SPSS, Chicago, IL, USA).
Results Six of 17 patients had alphafetoprotein levels higher than 200 ng/mL (200 lg/L). Sixteen (94 %) patients were in Child-Pugh class A, and one (6 %) patient was in ChildPugh class B. The Child-Pugh score was 5 in 12 patients, 6 in four patients and 7 in one patient. Performance status was 0 in eight (47 %) patients, and 1 in nine (53 %) patients. Stage according to BCLC was A in three (18 %) patients, B in four (23 %) patients, and C in 10 (59 %) patients. No patient had been treated with transjugular intrahepatic portosystemic shunt or surgical spleno-renal shunt. RECIST vs mRECIST Response was slightly different depending on whether RECIST or mRECIST was used. According to RECIST, two of 17 (12 %) patients showed partial response, ten of 17 (59 %) patients showed stable disease and five of 17 (29 %) showed progression disease. According to mRECIST, three of 17 (18 %) patients showed partial response, ten of 17 (59 %) patients showed stable disease and four of 17 (23 %) patients showed progression disease. No patient was a complete responder according to either criteria. The comparison of RECIST 1.1 and mRECIST is detailed in
Table 2 Response evaluation according to RECIST 1.1 and mRECIST mRECIST PR RECIST1.1
SD
PD
Total
PR
2 (12)
0 (0)
0 (0)
2 (12)
SD
1 (6)
9 (53)
0 (0)
10 (59)
PD Total
0 (0) 3 (18)
1 (6) 10 (59)
4 (23) 4 (23)
5 (29) 17 (100)
Numbers are the numbers of patients; numbers in parentheses are percentages PR partial response, SD stable disease, PD progressive disease
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Table 2. Agreement between the methods was good (k value, 0.791; 95 % CI 75–90 %; p \ 0.001). Specifically, one patient was considered a partial responder with mRECIST and to have stable disease with RECIST 1.1 (Fig. 1); another patient was considered to have progressive disease by RECIST 1.1 and stable disease by mRECIST. Tumour arterial and venous phase enhancement HCC had an average size of 6 cm (range 1–11.3 cm). Median tumour arterial and venous enhancement at baseline and follow-up imaging studies is reported in Tables 3 and 4. Compared to baseline, both the arterial and venous phase enhancement showed reduction after sorafenib treatment. When we compared the variation in arterial phase enhancement among the mRECIST groups, we noticed that the lesions of patients showing partial response had a significantly greater decrease in arterial phase enhancement (-79.8 %) in comparison to those of patients with stable disease (-24.8 %; p = 0.011) or progressive disease (-32.9 %; p = 0.034) (Fig. 2; Table 4). On the other hand, there was no statistically significant difference in variation of arterial phase enhancement among lesions belonging to patients with stable disease and patients with progressive disease (p = 0.888). Similarly, patients with partial response had a greater decrease in venous phase enhancement than did those with stable disease or progressive disease, but the differences were not statistically significant. Four patiens had tumor invasion of the portal vein and one patient had bland portal vein thrombosis.
Discussion In this study, we compared RECIST and mRECIST in assessing response in 17 patients with unresectable HCCs treated with sorafenib. Our results showed disagreement between these evaluation criteria in two of 17 (12 %) patients. Specifically, mRECIST showed a more favourable response in comparison to RECIST 1.1. Since mRECIST measures only the viable (i.e., the enhancing) portion of the tumour, as opposed to RECIST 1.1, which measures the whole tumour regardless of the enhancing components, the results of our study are not surprising, because sorafenib acts as a cytostatic drug causing a reduction in tumour vascularity rather than in tumour size. Moreover, our findings are in agreement with those of a recent study by Edeline et al. [9] based on CT measurements. Those authors compared RECIST and mRECIST in 70 patients with unresectable HCCs treated with sorafenib and found a good agreement between the two methods (Pearson’s coefficient r = 0.818), whereas ten of 70 patients (18 %)
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Fig. 1 Transverse unenhanced (a, d) and contrast-enhanced fatsuppressed three-dimensional gradient-echo images acquired in the hepatic arterial phase (b, e) and venous phase (c, f) in a 61-year-old man with hepatitis C virus (HCV)-related cirrhosis and multiple hepatocellular carcinomas. A target lesion in liver segment IV is shown before (a–c) and 180 days after anti-angiogenic treatment (d–e). Thick lines indicate mRECIST evaluation (b, e). Thin lines indicate RECIST 1.1 evaluation (b, e). The viable portion of the lesion decreased after treatment without any significant decrease in lesion size. Stability in lesion size and partial decrease of viable portion was defined as stable disease according to RECIST 1.1 and partial response according to mRECIST. Variation in hepatic arterial phase enhancement was -37.61 %, and variation in venous phase enhancement was -25.75 %. This case represents an example of discordance between mRECIST and RECIST criteria and demonstrates that arterial enhancement variation after sorafenib is a useful marker of therapy response
who had stable disease according to RECIST had partial response according to mRECIST [9]. In our study, no patient showed complete response according to either RECIST and mRECIST, possibly as a result of the relatively small size of our study population. The second purpose of our study was to describe changes in HCC enhancement before and after sorafenib treatment. We measured the degree of tumour enhancement in the hepatic arterial phase and venous phase before and after sorafenib treatment and we compared enhancement variations among the mRECIST groups. In our series,
patients with partial response had a statistically significant decrease in hepatic arterial phase enhancement at followup in comparison to patients with stable disease and progressive disease. Our preliminary data might indicate criteria to select patients for a prospective study. Our results are, however, preliminary and should be analysed with caution because the low number of subjects included in this study prevents any definitive conclusion. We also compared venous phase enhancement among the mRECIST groups. We noted that patients with partial response also presented a greater decrease in venous phase
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Table 3 Hepatic arterial and portal venous tumour enhancement at baseline and follow-up imaging studies Tumour enhancement at baseline (%)
Tumour enhancement at follow-up (%)
Arterial
Venous
Arterial
PRa
101.2
113.8
(n = 3)
(78.4–244.6)
(69.1–120.2)
SDa
118.8
135.9
30.5 (20.5–30.6) 92.4
Venous 45.9 (40.3–120.9) 106.7
(n = 10)
(33.8–211.5)
(63.8–186.3)
(58.4–201.0)
(63.4–233.2)
PDa
190.5
187.9
178.9
207.1
(n = 4)
(82.5–463.7)
(108.8–470.9)
(99.9–264.8)
(121.8–301.6)
Values are median of enhancement expressed as percentages; values in parentheses are range PR partial response, SD stable disease, PD progressive disease a
According to mRECIST
Table 4 Change in tumour enhancement between baseline and follow-up imaging studies Change (%) in tumour enhancement Arterial
Venous
PRa
-79.8
-32.3
(n = 3)
(-87.5 to -61.0)
(-61.7 to 6.3)
SDa (n = 10)
-24.8 (-60.7 to 350.4)
-20.9 (-54.3 to 256.6)
PDa
-32.9
-16.9
(n = 4)
(-55.2 to 220.9)
(-35.9 to 101.8)
Values are median of enhancement expressed as percentage; values in parentheses are range PR partial response, SD stable disease, PD progressive disease a
According to mRECIST
Fig. 2 Box and whisker plot of arterial phase enhancement variation in mRECIST groups. In box is median enhancement value with upper and lower margins of box denoting 25th and 75th percentile of values, respectively. Whiskers give ranges of values. Asterisk indicates outlier for standard deviation (SD)
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enhancement in comparison to patients with stable disease or progressive disease, but the differences were not statistically significant. One explanation for this finding might be that during the venous phase one measures the ‘‘washout’’ and not the ‘‘arterial’’ enhancement, which is directly proportional to neoangiogenesis. However, this is only speculation. Some investigators have shown the potential of changes in intensity/attenuation for evaluating response to antiangiogenic therapies. Choi et al. [16, 17] reported that changes in tumour vascularity were the most specific indicators of treatment response in patients with gastrointestinal stromal tumours (GIST) on imatinib and proposed new criteria based on evaluation of either tumour size or tumour attenuation after contrast enhancement. Smith et al. [10] proposed similar criteria for metastatic renal cell carcinomas on sorafenib or sunitinib [SACT (size and attenuation on CT) criteria] and demonstrated that these criteria were more accurate than conventional RECIST for the assessment of tumour response. Faivre et al. [6] reported that tumour density assessment on contrastenhanced CT (CECT) may be considered in addition to RECIST to evaluate sunitinib activity in HCC. These and our results suggest that a different method for measuring HCC response after cytostatic therapy, taking into account the changes in enhancement and not only the size of the viable tumour portion, should be incorporated into clinical practice. Our results cautiously support the hypothesis that measurement of tumour enhancement may be useful for the evaluation of treatment response. However, this procedure is more time consuming in comparison to RECIST and mRECIST, because three ROIs within each target lesion need to be recorded on nonenhanced and postcontrast images and compared at baseline and follow-up. Furthermore, ROI placement can be more prone to bias than a single tumour dimension measurement. Some authors have reported the potential of perfusion CT and MR imaging examinations as an emerging tool for the evaluation of tumour response to anti-angiogenic
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therapies [18–20]. However, the high radiation dose delivered by CT, breathing and cardiac motion, long postprocessing time required to obtain perfusion parameters [19] and measurement variability are all limitations to the dissemination of this technique. One additional means for monitoring the effects of targeted therapy agents on HCC with MR imaging is diffusion-weighted imaging, whose potential, however, has still to be further investigated [8]. There are several limitations to our study. First, followup imaging studies were not performed at regular intervals, and therefore standard endpoints such as time to tumour progression could not be calculated. Second, the study design was retrospective and therefore not all patients were studied with the same imaging modality at baseline and follow-up. Moreover, contrast media were administered at different rates for CT (3–5 mL/s) and MR (1–2 mL/s) imaging, and different MR contrast agents with different doses of gadolinium were also administered. Nevertheless, our population was similar to patients who are treated in routine clinical practice. Third, although our results were not pathologically confirmed, we relied on widely accepted imaging criteria for the diagnosis. Fourth, we did not conduct a multivariate analysis, so we did not ‘‘correct’’ our results for other variables. Fifth, the clinical importance of these findings is limited owing to the small study population, and further prospective studies would require a more systematic design and a precise timing to evaluate response to treatment using mRECIST criteria on the basis of CT or MR changes in tumour density or intensity, respectively. In conclusion, our preliminary results suggest that, in comparison to RECIST 1.1, mRECIST may show a more favourable treatment response in patients with unresectable HCCs treated with sorafenib. Sorafenib administration causes a decrease in the arterial enhancement of unresectable HCC.
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Conflict of interest Giuseppe Salvaggio, Alessandro Furlan, Francesco Agnello, Giuseppe Cabibbo, Daniele Marin, Lydia Giannitrapani, Chiara Genco, Massimo Midiri, Roberto Lagalla, Giuseppe Brancatelli declare no conflict of interest.
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