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Original Research |
1 All authors: Department of Radiology and Center for Imaging Science, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Ilwon-Dong, Kangnam-Ku, Seoul 135-710, Republic of Korea.
Received October 10, 2007;
accepted after revision January 19, 2008.
Address correspondence to D. Choi.
Abstract
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MATERIALS AND METHODS. Sixty-two new HCCs appearing after percutaneous radiofrequency ablation in 59 patients who underwent follow-up multiphase CT were retrospectively identified. The volume of the new HCCs at follow-up CT was measured on a PACS monitor with an area measuring tool and summation-of-areas technique. We calculated tumor volume doubling time and tumor diameter doubling time. The growth rate was represented by tumor volume doubling time. We also used stepwise multiple linear regression analysis to evaluate the relation between clinical variables and tumor volume doubling time.
RESULTS. Mean baseline and follow-up tumor volumes were 580 mm3 (range, 85–13,861 mm3) and 2,072 mm3 (range, 535–35,937 mm3). Mean baseline and follow-up tumor diameters were 9.9 mm (range, 5.5–29.8 mm) and 15.0 mm (range, 10.1–40.9 mm). Mean tumor volume and tumor diameter doubling times were 75 days (range, 21–209 days) and 219 days (range, 57–897 days). Volume doubling times of baseline tumors with a diameter of 1 cm or less were significantly shorter than those of the larger baseline tumors (mean, 55 vs 88 days; p = 0.024).
CONCLUSION. The growth rate of new HCCs after percutaneous radiofrequency ablation was higher than that reported in natural outcome studies of untreated HCCs. The results of our study suggest that a shorter follow-up interval for imaging, 2.5 months (75 days), is appropriate.
Keywords: helical CT • hepatocellular carcinoma • radiofrequency ablation
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We retrospectively studied the baseline and serial follow-up CT scans of
all 223 patients with new HCC in the liver apart from the ablation zones. New
HCC was defined as typical arterial enhancement and venous washout at a
follow-up CT examination in which HCC was identified
[14,
15] or a tumor larger than 2
cm in diameter with arterial hypervascularization on a follow-up CT scan
associated with an elevated serum tumor marker level (
-fetoprotein
concentration > 400 µg/L)
[16]. When a nodular lesion
was found at the corresponding anatomic site of the new HCC on the previous
CT, it was considered the baseline tumor. If a new HCC was found on two or
more serial CT scans before additional treatment and no corresponding nodule
was found on previous CT images, the new HCC on the oldest CT scan also was
referred to as the baseline tumor. Among the 223 patients with new HCCs, 164
were excluded because the growth rates of new HCCs could not be estimated on
serial CT images. This final excluded group consisted of patients who had new
HCC at only one follow-up CT examination before additional treatment (that is,
there was no baseline tumor) (n = 109) or who had baseline tumors
that were recognized on fewer than three transverse CT scans regardless of
section thickness (n = 55).
Fifty-nine patients (47 men and 12 women; median age, 62 years; range, 39–88 years) with 62 new untreated HCCs were included in the final study population. Three patients had two new HCCs. Fifty-two (88%) of the 59 patients had liver cirrhosis as a result of hepatitis B (n = 35), hepatitis C (n = 11), alcoholism (n = 4), or an unknown cause (n = 2). Four patients had chronic hepatitis C, two had chronic hepatitis B, and one had fatty liver. At the time of the radiofrequency ablation, 29 patients had Child-Pugh class A and 13 had Child-Pugh class B cirrhosis. Before the first radiofrequency ablation, 45 patients (76%) had a single tumor, 11 (19%) had two tumors, and three (5%) had three tumors. This study was approved by our institutional review board, which waived the requirement of patient informed consent.
Radiofrequency Ablation Procedures
Our descriptions of the radiofrequency ablation procedures and data
assessment are based on the standardization of terms and reporting criteria
proposed by the Society of Interventional Radiology Technology Assessment
Committee and the International Working Group on Image-Guided Tumor Ablation
[17]. All of the radio
frequency ablation procedures were per formed per cutane ously with real-time
sonographic guidance by one of five experienced radiologists. Patients
underwent IV conscious sedation with 50 mg of pethidine hydrochloride
(Pethidine, Samsung Pharmaceutical) and local anesthesia. We selected the type
of device used on a case-by-case basis depending on the availability of the
electrodes in stock and the sizes and locations of the tumors. In 10 patients,
we used a multitined, expandable electrode system (model 500 series or model
1500 series, Radiofrequency Interstitial Thermal Ablation Medical System; RF
2000 system, RadioTherapeutics). The other 49 patients under went
radiofrequency ablation with an internally cooled electrode system (Cool-tip,
Valleylab). During radiofrequency ablation, we tried to include the entire
tumor and a peripheral margin of 0.5–1.0 cm of normal hepatic paren
chyma surrounding the tumor. For tumors larger than 2.5 cm in maximum
diameter, we performed multiple overlapping ablations (2–4 overlapping
ablations; mean, 2.3).
CT Follow-Up
For the early evaluation of technical success, the patients underwent
immediate follow-up CT. Postprocedural contrast-enhanced CT examin ations were
performed with one of five helical scanners (HiSpeed CT/i, LightSpeed QX/i,
LightSpeed Ultra, LightSpeed 16, GE Healthcare; Brilliance 40, Philips
Healthcare). A total of 120 mL of nonionic contrast material (iopromide 300 mg
I/mL, Ultravist 300, Bayer HealthCare) was administered IV with an automatic
injector at a rate of 3–4 mL/s. Images were obtained 25–35,
60–70, and 180 seconds after the initiation of the injection of contrast
material, representing the hepatic arterial, portal venous, and equilibrium
phases. Using a single-detector helical CT scanner (HiSpeed CT/i), we obtained
images in a craniocaudal direction at a 7-mm slice thickness and a 7-mm
interval. The parameters of the MDCT examinations were 5.0-mm slice thickness
and 5.0-mm interval.
All patients underwent follow-up four-phase helical CT, both unenhanced and contrast enhanced in three phases, 1 month after radiofrequency ablation. These CT scans were used as baseline images for evaluating therapeutic efficacy. Residual unablated tumors were defined as irregular peripherally enhancing foci in the ablation zones at either immediate or 1-month follow-up CT [17, 18]. When residual tumors were found, we first attempted to treat them with additional radiofrequency ablation. If additional radio frequency ablation was not feasible owing to lack of visualization of the tumor at sonography or to the presence of concurrent multiple new lesions, TACE was performed. When neither residual tumor nor new HCC in the liver were found at 1-month follow-up CT, subsequent contrast-enhanced three-phase CT examinations were performed every 3 months as a part of our strategy. However, the interval of follow-up CT examinations sometimes was changed to 2–6 months owing to suspected complications or the decision of the clinician.
Image Analysis
Two radiologists retrospectively reviewed all CT images on a PACS
workstation (PathSpeed, GE Healthcare). They first determined the presence of
new HCC by consensus. After a new HCC was identified, the radiologists
assessed the baseline tumor on previous CT scans and assessed the last
follow-up tumor before additional treatment. Disagreement between the
radiologists was resolved in conference with a third radiologist. One
radiologist used an area measuring tool and the summation-of-areas technique
on CT scans to measure the volumes of the baseline tumors and the last
follow-up tumors at the maximal magnification of a 2,000 x 2,000 PACS
monitor [19] (Fig.
2A,
2B). First, when the areas of
tumors were measured, the venous washout during the equilibrium phase was
preferred to exclude the arterial–portal venous shunt surrounding tumors
during the hepatic arterial phase (13 [21%] of 62 HCCs). If baseline tumors
were not to be differentiated during the equilibrium phase, they were measured
during the hepatic arterial phase, and follow-up tumors were measured during
the equilibrium phase (23 [37%] of 62 HCCs). In addition to the baseline
tumors, if follow-up tumors had similar attenuation to surrounding liver
during the equilibrium phase or was indistinguishable from regenerating or
dysplastic nodules despite their low attenuation, we measured both of the
areas during the hepatic arterial phase (26 [42%] of 62 HCCs). In tumors
measured during the hepatic arterial phase, we attempted to measure discrete
hypervascular nodular areas to eliminate the arterial–portal venous
shunt.
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62 years vs > 62 years), sex, presence
of hepatitis B surface antigen, ablated tumor size, ablated tumor
multiplicity, interval between new HCC and first radiofrequency ablation,
serum -fetoprotein level, locations of new HCC and ablated tumor, and
baseline size of new HCC. A value of p < 0.05 was considered to
indicate a significant difference. Data analyses were performed with
commercially available software (SPSS for Microsoft Windows, version 11.0,
SPSS). |
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The mean interval between radiofrequency ablation and baseline new HCC was 354 days (median, 332 days; range, 33–1,460 days), and the mean interval between baseline tumor and last follow-up HCC was 96 days (median, 94 days; range, 33–209 days). The mean volumes of baseline tumors and last follow-up HCC were 580 mm3 (median, 600 mm3; range, 85–13,861 mm3) and 2,072 mm3 (median, 2,065 mm3; range, 535–35,937 mm3). Mean baseline and follow-up tumor diameters were 9.9 mm (median, 10.5 mm; range, 5.5–29.8 mm) and 15.0 mm (median, 15.8 mm; range, 10.1–40.9 mm) (Fig. 3A, 3B, 3C, 3D). Mean tumor volume and tumor diameter doubling times were 75 days (median, 61 days; range, 21–209 days) and 219 days (median, 182 days; range, 57–897 days).
Table 1 shows the relation between tumor volume doubling time and nine clinical variables. Tumor volume doubling times were significantly shorter for baseline tumors with a diameter of 1 cm or less compared with those of larger baseline tumors (mean, 55 vs 88 days; p = 0.024) (Fig. 4). There were no significant differences in subgroups for the other eight variables.
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In the results of our study, tumor volume doubling time ranged from 21 to 209 days with a mean of 75 days. In the literature on the tumor volume doubling time (growth rate) of primary HCC [7, 8, 10–12], variable averages have been reported, 93.5 days at minimum and 204.2 days at maximum. Because the new HCCs in our study were recurrent tumors, including intrahepatic metastasis and multicentric HCCs, our tumor volume doubling times may have been shorter than those in the previous reports of primary HCC. Faster growth rates of new HCCs in our study can be related to short and regular follow-up intervals. Because a measurable growing tumor seen twice on serial imaging before treatment is needed to estimate the growth rate, short and regular follow-up intervals may be the reason that our study population appeared to have tumors with relatively faster growth than in previous reports of long and irregular follow-up intervals. Studies with long follow-up intervals have a slim possibility of showing very small baseline tumors at imaging.
In a report by Okada et al. [9], the mean tumor volume doubling time of new recurrent HCC after hepatic resection was 112 days (range, 39–420 days), which was longer than the results in our study. According to another study [13], however, the mean tumor volume doubling time of locally recurrent HCC after TACE was 72.9 days (median, 69.7 days; range, 18.0–412.1 days), which was similar to our finding. Because new lesions adjacent to the primary site after TACE were included, recurrent HCC represents the regrowth of residual tumors. Partial hepatectomy is associated with an increase in tumor regrowth in the residual liver probably owing to increased amounts of inflammatory cytokines. It is still being debated, however, whether other treatments, including radiofrequency ablation, increase tumor growth after treatment [23, 24].
Only the variable baseline tumor size was associated with a significant difference in tumor volume doubling time in our study. Smaller tumors tended to have faster tumor growth; this finding is in agreement with two prior reports [11, 12]. We presume that baseline tumors 1 cm or smaller included many advanced as well as early HCCs or dysplastic nodules with multistep carcinogenesis [25]. Results of other previous studies [7–10] have suggested that various factors were significantly associated with tumor volume doubling times. These factors included age, alcohol intake, serum albumin level, number of tumors, histologic type, mitotic indexes, and intrahepatic recurrence site.
Most (49 [79%] of 62) of the baseline tumors in our series became enhanced during the hepatic arterial phase of CT but were not visible during other phases, a finding similar to arterial–portal venous shunt. These lesions might have been omitted from the prospective radiologic report because they were not perceived owing to their subtle appearance or because they were ignored owing to the common presence of small arterial–portal venous shunts in cirrhotic livers (Fig. 3A). Small HCC is visualized most frequently as an enhancing lesion during the hepatic arterial phase after contrast injection, but benign lesions often have similar appearances. Even when small HCC is strongly suspected at CT, it may be difficult to confirm the diagnosis with other imaging techniques or even with biopsy [26]. Thus follow-up imaging is important to the diagnosis of small HCC.
In our study, tumor volume doubling time of new HCC after radiofrequency ablation at follow-up CT was estimated as an index of growth rate, and it was considered a proper follow-up interval for imaging. At many institutions, however, MRI also is used for assessing the therapeutic response to radiofrequency ablation of hepatic tumors. MRI with the use of 3D spoiled gradient-echo sequences and higher spatial resolution may be better than CT. The appropriate follow-up interval for MRI would be different from that for CT [27].
Our study had several limitations. First, our retrospective study design
had selection bias due to issues such as inclusion of only hypervascular HCCs.
Because CT-based diagnosis criteria were established to include HCCs
consistent with the imaging criteria, bias could have been present. However,
prospective studies of growth rates of malignant tumors are difficult to
conduct and are sometimes unethical. Almost all previous studies have been
retrospective in design and have included a small number of patients. Second,
all tumors, excluding three managed surgically, were not pathologically
proved, but they all had characteristic imaging features combined with an
elevated level of serum -fetoprotein and interval growth on serial
imaging studies
[14–16].
These criteria are considered sufficient for clinical diagnosis at many
institutions, including ours. Thus it was impractical to perform invasive
biopsy of all small tumors
[26]. Third, baseline tumors
in our series included not only small HCCs but also indeterminate nodules such
as dysplastic nodules. Because the purpose of our study was to determine a
proper followup interval, inclusion of indeterminate nodules was not a fault.
Fourth, local tumor progression after radiofrequency ablation was excluded for
the following reasons. Irregular shape and shunt of local tumor progression
can result in inaccurate estimation of growth rate. In addition, pathogenesis
of local tumor progression that arises from microscopic residual tumor can
affect homogeneity in a study population, and local tumor progression makes up
a small portion of all recurrent HCCs. Finally, we did not find an influence
on clinical outcomes, such as disease control and survival, with respect to
follow-up interval for imaging.
Our study had merits compared with previous studies. In our study, a relatively large number of patients underwent follow-up imaging at short and regular intervals. We estimated tumor volume directly and more exactly because we used an area measuring tool and the summation-of-areas technique (Fig. 2A, 2B). In other studies [7–13], tumor volume was calculated indirectly with two or three measuring diameters. Our figures are more accurate estimates of tumor volume doubling time and reliable statistical results.
The growth rate of new HCC after percutaneous radiofrequency ablation was higher than those reported in the natural outcome studies of untreated HCC. The results of our study favor a short follow-up interval of 2.5 months (75 days) for imaging after percutaneous radiofrequency ablation.
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