Gastrointestinal Imaging • Original Research Sanuki et al. CT of Hepatocellular Carcinoma Treated With Stereotactic Ablative Body Radiotherapy
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Gastrointestinal Imaging Original Research
Naoko Sanuki1,2 Atsuya Takeda1,2 Tomikazu Mizuno 3 Yohei Oku1 Takahisa Eriguchi1 Shogo Iwabuchi2 Etsuo Kunieda4 Sanuki N, Takeda A, Mizuno T, et al.
Keywords: hepatocellular carcinoma, modified Response Evaluation Criteria in Solid Tumors, stereotactic ablative body radiotherapy, tumor marker
Tumor Response on CT Following Hypofractionated Stereotactic Ablative Body Radiotherapy for Small Hypervascular Hepatocellular Carcinoma With Cirrhosis OBJECTIVE. The purpose of this study is to evaluate the CT appearances of tumor responses following hypofractionated stereotactic ablative body radiotherapy for small hypervascular hepatocellular carcinomas (HCCs) and to assess the relationship between tumor responses and local control. MATERIALS AND METHODS. Among 277 HCC tumors treated with stereotactic ablative body radiotherapy (35 or 40 Gy per five fractions), we selected enhanced lesions on arterial phase CT performed before stereotactic ablative body radiotherapy. Radiographic findings after stereotactic ablative body radiotherapy were evaluated during a 2-year followup period with the modified Response Evaluation Criteria in Solid Tumors. Local control and survival rates were calculated with the Kaplan-Meier method. RESULTS. Forty-two tumors with a median size of 2.1 cm (range, 1.0–3.8 cm) were selected with a median follow-up of 23.3 months (range, 9–56 months). Local recurrence was observed in two tumors after achieving a complete response (CR). The 2-year local control rate was 97%, and the overall survival rate was 81%. CR increased from 10 (24%) to 28 (67%) to 30 (71%) tumors at 3, 6, and 12 months after stereotactic ablative body radiotherapy. Overall CR at maximum follow-up was 39 tumors (93%), yet three enhanced tumors persisted for more than 2 years. The median time to achieve CR was 5.9 months (range, 1.2–34.2 months). CONCLUSION. The CR rate in hypervascular HCCs after hypofractionated stereotactic ablative body radiotherapy increased during the 2-year follow-up period. Cautious and continuous observation until tumor regrowth is considered relevant to evaluate a true effect of this treatment. Further studies for the optimal evaluation of treatment outcome after stereotactic ablative body radiotherapy are warranted.
DOI:10.2214/AJR.12.10169 Received October 18, 2012; accepted after revision March 11, 2013. 1 Radiation Oncology Center, Ofuna Chuo Hospital, Ofuna, Kamakura-shi, Kanagawa, Japan. 2 Department of Hepatology and Gastroenterology, Ofuna Chuo Hospital, Ofuna, Kamakura-shi, Kanagawa, Japan. 3 Department of Radiology, Ofuna Chuo Hospital, Ofuna, Kamakura-shi, Kanagawa, Japan. 4
Department of Radiation Oncology, Tokai University, 143 Shimokasuya, Isehara, Kanagawa 259-1193, Japan. Address correspondence to E. Kunieda ([email protected]).
WEB This is a web exclusive article. AJR 2013; 201:W812–W820 0361–803X/13/2016–W812 © American Roentgen Ray Society
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C
urrently, the incidence of hepatocellular carcinoma (HCC) is rising as a result of an increased incidence of viral hepatitis infections [1]. Because of underlying cirrhosis and the presence of multiple simultaneous lesions, some patients are not eligible for curative treatments, such as surgery or percutaneous ablation, or such treatments may not be feasible. These patients can benefit only from options like transarterial chemoembolization (TACE). Although conventional radiotherapy historically has not been considered to be a definitive treatment of liver tumors because of the low radiation tolerance of the liver, recent developments in advanced radiotherapy techniques and hypofractionated stereotactic ablative body radiotherapy have enabled accurate delivery of much higher doses of radi-
ation to a confined target [2]. Excellent local control rates of over 90% have been reported with stereotactic ablative body radiotherapy [3–10]. However, little evidence exists for optimal evaluation of treatment response for this new modality. On the basis of our experience with stereotactic ablative body radiotherapy, especially for HCC with vascularity, we have found that the tumor enhancement remains for a long time in a substantial portion of patients and that the objective treatment response effect could vary depending on duration of follow-up after stereotactic ablative body radiotherapy. The purpose of our study was to describe the long-term imaging appearance of small hypervascular HCC following stereotactic ablative body radiotherapy using modified Response Evaluation Criteria in Solid Tumors (RECIST).
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CT of Hepatocellular Carcinoma Treated With Stereotactic Ablative Body Radiotherapy
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Materials and Methods Patients Patients were required to meet all of the following criteria: single HCC (either solitary or recurrent), inoperable tumor or one for which surgery would be difficult, ineligible for percutaneous ablative therapies, liver function with Child-Pugh class A or B, tumors 4 cm or smaller in diameter, target located at a distance so that the dose to the bowels did not exceed 25 Gy per five fractions, curative intent, and informed consent. The diagnosis was established according to the results of imaging studies and was based on the international guidelines for the management of HCC [11], because candidates for stereotactic ablative body radiotherapy were usually not eligible for pathologic confirmation procedures. The imaging studies included a combination of sonography, CT, MRI, and angiography studies. The following patients were included: those with typical hypervascular HCC tumors that showed enhancement on either early or late arterial phase dynamic CT, as well as washout in delayed phase, and those who were monitored with dynamic CT scans on our follow-up protocol for more than 6 months after the treatment. All pretreatment images were read by a diagnostic radiologist. Cases with enhanced tumors were identified by a radiation oncologist who reviewed all applicable pretreatment images. The review board of our institution approved this study (protocol number 2012–007).
Treatment Stereotactic ablative body radiotherapy was performed with dynamic conformal multiple arc irradiation. Details of the treatment procedures have been described elsewhere [12, 13]. In brief, planning CT to determine the internal target volume was performed using a slow scan. For the planning target volume (PTV), individualized treatment margins of 5–8 mm were applied around the internal target volume. A stereotactic multiarc dynamic conformal radiation planned by a radiation treatment planning system (FOCUS XiO version 4.2.0–4.3.3, Computerized Medical Systems) was performed using x-ray beams from a 6-MV linear accelerator (Clinac 2100 C, Varian Medical Systems). A total dose of 35–40 Gy was delivered in five fractions over 5–9 days, depending on liver function or the dose to the normal liver (40 Gy for Child-Pugh class A and 35 Gy for Child-Pugh class B). Treatment was planned to enclose the PTV by the 70–80% isodose line of the maximum dose equated to the prescribed dose. With this method, a prescribed dose to the PTV periphery essentially corresponds to the minimal dose delivered to 95% of the target volume. A superposition algorithm was used for dose calculations.
Before stereotactic ablative body radiotherapy, TACE was performed for some patients to obtain a synergistic local treatment effect, as well as to visualize the position of the target with unenhanced CT by the deposition of lipiodol. Tumors treated with TACE in this study had insufficient lipiodol accumulation and were partially left to be hypervascular; therefore, they showed tumor enhancement on dynamic CT before and after stereotactic ablative body radiotherapy.
Patient Follow-Up The patients were seen monthly. Laboratory tests were done to evaluate liver function and blood cell counts. Treatment responses and local recurrences were evaluated with dynamic CT at 1 month and every 3 months after treatment. The CT technique at follow-up was identical to that at diagnosis. Laboratory tests included aspartate aminotransferase, total bilirubin, platelet count, and albumin. Toxicity was evaluated by the Common Terminology Criteria for Adverse Events (version 4) occurring within 3 months after stereotactic ablative body radiotherapy.
Imaging Evaluation A CT examination was performed with a 16MDCT scanner (Bright Speed, GE Healthcare) with a reconstructed slice width of 5 mm and a slice interval of 5 mm for both unenhanced and enhanced phases. Scanning parameters were 120 kV, 440 mA, 5-mm section thickness, 22 helical pitch (1.375 beam pitch), and 0.5-second rotation speed.
Dynamic CT scans were done over the range of the diaphragmatic dome to the inferior edge of the liver. Images were obtained before contrast enhancement and at 25 seconds (early arterial phase), 40 seconds (late arterial phase), and 63 seconds (portal venous phase) after injection of 100 mL of nonionic contrast medium at a rate of 4 mL/s. Treatment response was first reported by a diagnostic radiologist who made diagnostic reports. Then, images were reviewed by two radiation oncologists for the current analysis. If there was a discrepancy between reports and review, the final response evaluation was made on the basis of a consensus decision between the radiologist and radiation oncologists. Unenhanced images were compared with enhanced images to measure the longest viable tumor diameter; enhancement on either early or late arterial phase dynamic CT as well as washout in delayed phase was observed on follow-up CT scans. Reactions of the normal liver tissue surrounding a tumor were defined as sharply demarcated regions fitting to a high-dose area. They often presented as enhanced lesions in the portal venous phases, began at a median of 3 months, and peaked at 6 months [12–14]. According to the modified RECIST [15], a complete response (CR) was defined as the disappearance of contrast enhancement in the tumor for the arterial phase. At least 30% volume reduction of an enhanced area in the arterial phase, taking as reference the baseline diameter of the tumor, was judged to be a partial response (PR). Tumors without any of these changes or an increase in volume were judged
TABLE 1: Patient and Tumor Characteristics Characteristic
Value
No. of lesions
42
No. of patients
38
Sex (no. of patients) Male Female
22 16
Patient age (y), median (range)
75 (52–86)
Tumor size (cm), median (range)
2.1 (1.0–3.8)
Child-Pugh class (no. of lesions) A
38
B
4
Type of chronic hepatitis (no. of lesions) Hepatitis B virus infection
32
Hepatitis C virus infection
5
Alcoholic
4
Nonalcoholic steatohepatitis
1
Total dose (no. of lesions) 35 Gy
9
40 Gy
33
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Sanuki et al. as stable disease. An increase of at least 20% of the diameter of a viable (enhancing) lesion, taking as reference the smallest diameter of the viable lesion, was judged as progressive disease (PD). In this study, PD was counted when it occurred before CR to distinguish it from local recurrence following CR. A local recurrence was defined as the new appearance of an enhanced lesion within the site of the PTV after CR. Conversely, a new appearance of a tumor outside the PTV was judged to be an intrahepatic recurrence. Local control and survival rates were calculated with the Kaplan-Meier method using SPSS software (version 20.0, IBM).
Results Eligible Patients Between March 2005 and July 2012, 277 HCC tumors in 232 patients underwent stereotactic ablative body radiotherapy. Among these, 38 patients with 42 tumors that enhanced on CT were eligible for this study. Baseline characteristics of the eligible patients are listed in Table 1. There were 22 men and 16 women with a median age of 75 years (range, 52–86 years). All patients had underlying liver cirrhosis with Child-Pugh class A or B. The median tumor size was 2.1 cm (range, 1.0–3.8 cm). The prescribed doses were 35 Gy in nine lesions and 40 Gy in 33 lesions, in five fractions. Twenty-five tumors (60%) underwent TACE before stereotactic ablative body radiotherapy. Among them, patterns of lipiodol deposit were partial (n = 3), inhomogeneous (n = 3), and no or slight accumulation (n = 19). For those treated with TACE, the median time between TACE and stereotactic ablative body radiotherapy was 1.1 months (range, 0.5–2.8 months). Treatment Outcomes and Objective Responses During the follow-up period (median, 23.3 months; range, 9–56 months), all lesions but two maintained CR. The two local relapses occurred 12.3 and 43.2 months after treatment. Both cases had achieved CR previously (6.2 and 21.1 months after treatment, respectively) and then presented with a new arterial enhancement and delayed washout lesion on dynamic CT. The local recurrence in the first case arose from the edge of the PTV (Fig. 1), whereas it emerged within the gross tumor volume in the second case. Intrahepatic recurrences outside the treated volumes developed in 22 (58%) patients during follow-up. Distant metastases were observed in three patients (all three had preceding intrahepatic recurrences). Thirteen patients (34%) died as a result of either progression of HCC (n = 6), liver failure with W814
hepatic decompensation (n = 4), or a nonhepatic cause (n = 3). The 2-year local control rate was 97%, and the 2-year overall survival rate was 81% for all patients (100% for previously untreated tumors and 67% for recurrent tumors) (Figs. 2A and 2B). CR increased over time; it was 10 (24%), 28 (67%), and 30 (71%) at 3, 6, and 12 months after stereotactic ablative body radiotherapy, respectively, with a maximum overall CR of 39 tumors (93%). However, there were three enhanced tumors that persisted for more than 2 years (24, 29, and 34 months, respectively). In contrast, there was no PD before CR. Figure 3 shows response rates by duration after treatment. To distinguish PD (before CR) from relapse (after CR), the two locally relapsed tumors were censored at the time of their CR and were included in CR group because both had achieved CR before relapse. In contrast, there was no PD. Four tumors showed continuous vascularity after 12 months, and CR was achieved at 15, 16, 21, and 43 months after treatment. Figure 4 shows the images of a tumor with persistent vascularity for 34 months after stereotactic ablative body radiotherapy. Overall, the median time to reach CR was 5.9 months (range, 1.2–34.2 months). Treatment-Related Toxicity All scheduled treatments were completed without manifestations of toxicity. There were five patients with grade 3 laboratory abnormalities in pretreatment data. All of these recovered from grade 3 to grades 1 and 2. Excluding the five patients, acute grade 3 or higher toxicities were observed in two patients. Among them, one persistent toxicity resulted in hepatic decompensation. Other laboratory toxicities were transient and resolved to baseline levels. Discussion Recently, high local control rates after stereotactic ablative body radiotherapy for HCC have been reported, although little evidence exists for the optimal evaluation of treatment response. In this study, we attempted to describe the long-term imaging appearance after stereotactic ablative body radiotherapy for HCC with enhancement on arterial phase CT. With regard to the optimal time for tumor response assessment, we evaluated objective response rates at 3, 6, and 12 months after treatment as well as at the maximum followup time, which varied significantly over time. Measurement of response rate in HCC is challenging, because HCC can be treated with
several modalities, including surgery, TACE, radiofrequency ablation, and radiotherapy. Guidelines for treatment evaluation are proposed as methods for measuring treatment response on the basis of tumor shrinkage; however, tumor response metrics are mainly useful for chemotherapy and can be misleading, particularly following local ablation or chemoembolization treatments [15–17]. Recently, groups of experts developed a guideline taking into account treatment-induced tumor necrosis and the concept of viable tumor showing uptake in the arterial phase of contrast-enhanced radiologic imaging [15]. Response rate can also be used in evaluating the effect of conventionally fractionated radiotherapy. However, with regard to the time of evaluation, reports on treatment response following conventional radiotherapy for HCC vary significantly. Park et al. [18] evaluated the maximum tumor size on serial CT scans 4–8 weeks after completion of radiotherapy and reported CR and PR in five (8%) and 34 (58%) patients, respectively. Kim et al. [19] evaluated the imaging change in contrast enhancement in 50 patients with HCC after local radiotherapy. According to their final response evaluation on 6–12 months after treatment, a CR was observed in 11 (22%) patients, and a PR was observed in 16 (32%) patients. Compared with nonresponsive patients on 1-month follow-up CT, responsive patients showed a significant decrease in tumor enhancement. Those authors concluded that the change in contrast enhancement of HCC seen on 1-month follow-up CT in patients after local radiotherapy may be used as an early predictor of final treatment response. Information on optimal response evaluation of stereotactic ablative body radiotherapy is also limited. Controversies in HCC response assessment exist because of variability in response rates among published HCC stereotactic ablative body radiotherapy studies [3–9, 20–22] (Table 2). Although the majority of the studies took more than 12 months to evaluate response, evaluation criteria, time of evaluation, and definition of local recurrence were different across studies. It seems that the longer the time to evaluation, the better the response, which means that the results can change significantly over time. Price et al. [22] evaluated radiologic response by RECIST [23] in 26 patients with HCC treated with stereotactic ablative body radiotherapy. Mean tumor dimension decreased by 35%, 37%, 48%, and 55% at 3, 6, 9, and 12 months, respectively, compared with pretreatment size. They also compared RECIST [23] and European AJR:201, December 2013
0 0 7 93 At 23 months
Note—CR = complete response, EASL = European Association for the Study of the Liver, PD = progressive disease, PR = partial response, PTV = planning target volume, RECIST = Response Evaluation Criteria in Solid Tumors, SD = stable disease.
0
0 0
0 71
29
67
At 12 months
43 Current study
35–40
5
Modified RECIST
2.1 cm(1.0–3.8 cm)
23 (9–56)
At 6 months
33
Not mentioned
New appearance of an enhanced lesion within the PTV 0
0 27
24 52
58 15
24 At 3 months
26 Price et al. [22] (2012)
24–48
3–5
RECIST
13 (3–42)
Maximum response
Progression of the targeted lesion 42 32 16 10 13 (0.5–54)
33.9 cm3 (2.0–95 cm3)
21 Ibarra et al. [21] (2012)
18–50
1–10
RECIST
4.1 cm3 (11–464 cm3)
Maximum response
Not mentioned 0 78 22 0 At 3 months 19 (1–39) 4 cm (1.2–6.5 cm) RECIST 10 50 18 (21 lesions) Katz et al. [20] (2012)
Not mentioned 7 56 7 30 At 3 months 22 (2–48) 2.0 cm (0.8 cm) Modified RECIST 2–4 39 Facciuto et al. [6] (2012)
24–36
Not mentioned 2 21 38 38 Best response within 6 months 17 (6–38) 2.9 cm (1.3–0.8 cm) Modified RECIST 3 47 Kang et al. [4] (2012)
42–60
Recurrence within the PTV
Recurrence within the PTV 5
2 39
25 40
37 22
30 Maximum response
Maximum response 14 (2–35)
27 (2–52) 3.2 cm
4.4 cm (1.1–12.3 cm) RECIST
RECIST 3–5
4–5 42
24–48 60 Andolino et al. [9] (2011)
Huang et al. [5] (2012)
25–48
Any progression of the target lesion within the irradiated field
Not mentioned 7
29 0
7 29
12 60
57 Maximum response
Maximum reduction within 12 months
13 (1–24)
29 (8–49)
4.5 cm (1.8–10 cm)
15.4 cm3 (3.0–81.8 cm3)
EASL criteria
Modified RECIST 3
3 45
Kwon et al. [8] (2010)
30–39
14
42
Louis et al. [7] (2010)
Recurrence within the high-dose region (> 80% isodose volume) 9 42 44 5 18 (11–39) RECIST 6 24–54 31
No. of Patients Study (Year)
Tse et al. [3] (2008)
No. of Fractions
Evaluation Criteria
173 cm3 (9–1913 cm3)
Maximum response
Definition of Local (or In-Field) Recurrence CR PR SD PD Time of Evaluation
Response (%)
Duration of Follow-Up (mos), Median (Range) Tumor Size, Median (Range or SD) Total Doses (Gy)
TABLE 2: Reports on Treatment Response After Stereotactic Ablative Body Radiotherapy for Hepatocellular Carcinoma
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CT of Hepatocellular Carcinoma Treated With Stereotactic Ablative Body Radiotherapy Association for the Study of the Liver criteria [16] and concluded that reduced vascularity or nonenhancement as tumor necrosis might be a more useful indicator than size reduction in evaluating HCC response to stereotactic ablative body radiotherapy in the first 6–12 months [22]. In the current study, the size reduction or disappearance of hypervascularity of the nodule also took considerable time in some cases, and treatment response varied depending on duration after treatment (Fig. 3). In fact, there were tumors that finally achieved CR but had presented long-lasting vascularity for more than 12 months after stereotactic ablative body radiotherapy. In the current study, two local recurrences were observed in spite of initial CR. However, there is substantial ambiguity in the definition of local recurrence (or in-field recurrence) across studies (Table 2). It is critical but difficult to define local recurrence or in-field recurrence clearly, because the mode of local recurrence can reflect the reason for treatment failure. If a recurrent tumor arises from the gross tumor volume, it implies an inadequate dose for control. On the other hand, if a recurrence is observed around the border of the high-dose region with a steep dose gradient, it may be due to insufficient subclinical margins around the tumor volume or excessive respiratory movements or uncertainties in patient positioning during therapy. It is known that HCC bears satellite lesions around a nodule, and it is possible that growth of a satellite lesion arises as a new tumor within the relatively high-dose area adjacent to the PTV. In the current study, the first local recurrence (Fig. 1) arose from the high-dose area peripheral to the PTV in the diaphragmatic dome 1 year after stereotactic ablative body radiotherapy. By our definition, local recurrence should have arisen within the PTV; however, the main location of the recurrent tumor was so close to the PTV that we could not eliminate it from an event as a local recurrence. In contrast, the second case recurred within the gross tumor volume 3.6 years later. Although the true reason for local recurrence could not be revealed, the first case may have suffered from insufficient subclinical margins or geometric uncertainties, and the second case may have been radioresistant. Reactions of the normal liver tissue surrounding a tumor after stereotactic ablative body radiotherapy present unique and distinctive pathophysiologic features, in both the normally functioning liver and the cirrhotic liver, and their imaging appearances on CT have
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Sanuki et al. been described elsewhere [12, 14]. These reactions typically present as areas that are sharply demarcated from the surrounding liver tissue and that presents, often enhanced, in the portal venous or late phases. Previously, we reported that radiation-induced focal liver reactions in the cirrhotic liver began at a median of 3 months, peaked at 6 months, and disappeared about 9 months later, and these appearances remained for more than 12 months in at least one third of the patients [12]. This reaction following stereotactic ablative body radiotherapy to the liver has to be recognized, and it should not be misinterpreted as local recurrence, because the duration with tumor viability after stereotactic ablative body radiotherapy overlaps with this time. Fortunately, this focal liver reaction with contrast enhancement can be distinguished from recurrence by noticing that the enhanced lesion corresponds to the highdose area with a certain threshold [13, 14] and is not washed out in the portal venous phase. Our study has several limitations. First, we studied only hypervascular HCCs. In addition, we did not provide a pathologic correlation in any of the cases. Moreover, the influence of preceding TACE on outcome is unclear because of the low incidence of local recurrence in this study. In contrast, the strength of our report is that it probed deeply into the issue of changes after stereotactic ablative body radiotherapy and provided an extensive literature review. In conclusion, the response rate to hypofractionated stereotactic ablative body radiotherapy in hypervascular HCC increased over time during a 2-year follow-up period. Despite a remarkably high local control rate, it took considerable time to show disappearance of tumor enhancement. Therefore, cautious and continuous observation until tumor regrowth is relevant to evaluate a true effect of this treatment. Further studies regarding the optimal evaluation of treatment outcome after use of this new treatment modality are warranted. References 1. El-Serag HB, Mason AC. Rising incidence of hepatocellular carcinoma in the United States. N Engl J Med 1999; 340:745–750 2. Dawson LA, McGinn CJ, Normolle D, et al. Esca-
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lated focal liver radiation and concurrent hepatic artery fluorodeoxyuridine for unresectable intrahepatic malignancies. J Clin Oncol 2000; 18: 2210–2218 3. Tse RV, Hawkins M, Lockwood G, et al. Phase I study of individualized stereotactic body radiotherapy for hepatocellular carcinoma and intrahepatic cholangiocarcinoma. J Clin Oncol 2008; 26:657–664 4. Kang JK, Kim MS, Cho CK, et al. Stereotactic body radiation therapy for inoperable hepatocellular carcinoma as a local salvage treatment after incomplete transarterial chemoembolization. Cancer 2012; 118:5424–5231 5. Huang WY, Jen YM, Lee MS, et al. Stereotactic body radiation therapy in recurrent hepatocellular carcinoma. Int J Radiat Oncol Biol Phys 2012; 84:355–361 6. Facciuto ME, Singh MK, Rochon C, et al. Stereotactic body radiation therapy in hepatocellular carcinoma and cirrhosis: evaluation of radiological and pathological response. J Surg Oncol 2012; 105:692–698 7. Louis C, Dewas S, Mirabel X, et al. Stereotactic radiotherapy of hepatocellular carcinoma: preliminary results. Technol Cancer Res Treat 2010; 9:479–487 8. Kwon JH, Bae SH, Kim JY, et al. Long-term effect of stereotactic body radiation therapy for primary hepatocellular carcinoma ineligible for local ablation therapy or surgical resection: stereotactic radiotherapy for liver cancer. BMC Cancer 2010; 10:475 9. Andolino DL, Johnson CS, Maluccio M, et al. Stereotactic body radiotherapy for primary hepatocellular carcinoma. Int J Radiat Oncol Biol Phys 2011; 81:e447–e453 10. Dewas S, Bibault JE, Mirabel X, et al. Prognostic factors affecting local control of hepatic tumors treated by stereotactic body radiation therapy. Radiat Oncol 2012; 7:166 11. European Association for the Study of the Liver; European Organisation for Research and Treatment of Cancer. EASL-EORTC clinical practice guidelines: management of hepatocellular carcinoma. J Hepatol 2012; 56:908–943 12. Sanuki-Fujimoto N, Takeda A, Ohashi T, et al. CT evaluations of focal liver reactions following stereotactic body radiotherapy for small hepatocellular carcinoma with cirrhosis: relationship between imaging appearance and baseline liver function. Br J Radiol 2010; 83:1063–1071
13. Takeda A, Oku Y, Sanuki N, et al. Dose volume histogram analysis of focal liver reaction in follow-up multiphasic CT following stereotactic body radiotherapy for small hepatocellular carcinoma. Radiother Oncol 2012; 104:374–378 14. Herfarth KK, Hof H, Bahner ML, et al. Assessment of focal liver reaction by multiphasic CT after stereotactic single-dose radiotherapy of liver tumors. Int J Radiat Oncol Biol Phys 2003; 57:444–451 15. Lencioni R, Llovet JM. Modified RECIST (mRECIST) assessment for hepatocellular carcinoma. Semin Liver Dis 2010; 30:52–60 16. Bruix J, Sherman M, Llovet JM, et al. Clinical management of hepatocellular carcinoma: conclusions of the Barcelona-2000 EASL conference. European Association for the Study of the Liver. J Hepatol 2001; 35:421–430 17. Therasse P, Arbuck SG, Eisenhauer EA, et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 2000; 92:205–216 18. Park W, Lim DH, Paik SW, et al. Local radiotherapy for patients with unresectable hepatocellular carcinoma. Int J Radiat Oncol Biol Phys 2005; 61:1143–1150 19. Kim EY, Choi D, Lim do H, Lee WJ, Yoo BC, Paik SW. Change in contrast enhancement of HCC on 1-month follow-up CT after local radiotherapy: an early predictor of final treatment response. Eur J Radiol 2009; 72:440–446 20. Katz AW, Chawla S, Qu Z, Kashyap R, Milano MT, Hezel AF. Stereotactic hypofractionated radiation therapy as a bridge to transplantation for hepatocellular carcinoma: clinical outcome and pathologic correlation. Int J Radiat Oncol Biol Phys 2012; 83:895–900 21. Ibarra RA, Rojas D, Snyder L, et al. Multicenter results of stereotactic body radiotherapy (SBRT) for non-resectable primary liver tumors. Acta Oncol 2012; 51:575–583 22. Price TR, Perkins SM, Sandrasegaran K, et al. Evaluation of response after stereotactic body radiotherapy for hepatocellular carcinoma. Cancer 2012; 118:3191–3198 23. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 2009; 45:228–247 (Figures appear on next page)
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CT of Hepatocellular Carcinoma Treated With Stereotactic Ablative Body Radiotherapy
A
B
D
C
E
Fig. 1—83-year-old man with local recurrence of hepatocellular carcinoma after stereotactic ablative body radiation therapy. A, Dose distribution. Bold lines from center to outer curve are 80%, 60%, 40%, and 20% isodose lines, respectively. B–E Tumor enhancement (arrow, B–D), shown before treatment (B) and 1 month (C) and 3 months (D) after treatment, gradually shrank and disappeared 6 months after stereotactic ablative body radiotherapy (E). In contrast, focal liver reaction in surrounding normal liver (arrowheads, C–E) appeared after 1 month and remained after disappearance of tumor enhancement. (Fig. 1 continues on next page)
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F
G
H
Fig. 1 (continued)—83-year-old man with local recurrence of hepatocellular carcinoma after stereotactic ablative body radiation therapy. F, Dose distribution. Bold lines from center to outer curve are 80%, 60%, 40%, and 20% isodose lines, respectively. G and H, Local recurrence arose from high-dose area. Twelve months after treatment, enhanced nodule (arrow, G) appeared at edge of focal liver reaction cranial to first tumor volume, suggesting local recurrence. Three months later (H), follow-up CT scan revealed increased tumor enhancement.
100
100
90
90
Overall Survival Rate (%)
Local Control Rate (%)
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Sanuki et al.
80 70 60 50 40 30 20 10 0
0
10
20
30
40 Months After Treatment
50
80 70 60 50 40 30 20 10 0
60
0
10
20 30 40 Months After Treatment
A
50
60
B
Fig. 2—Control and survival rates. A and B, Graphs show local control (A) and overall survival (B) rates. Vertical hash marks indicate where data were censored.
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CT of Hepatocellular Carcinoma Treated With Stereotactic Ablative Body Radiotherapy Fig. 3—Response rates by duration after treatment. To distinguish progressive disease (PD) (before complete response [CR]) from relapse (after CR), two locally relapsed tumors were censored at time of their CR and were included in CR group because both had achieved CR before relapse. SD = stable disease.
100 Percentage of Patients
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90 80 70
SD
60
PR
50
CR
40 30 20 10 0
3 Months
6 Months
12 Months
A
D
Maximum
B
E
C
Fig. 4—68-year-old man with gradually decreased but persistent tumor enhancement of hepatocellular carcinoma after stereotactic ablative body radiation therapy. A, Dose distribution. Bold lines from center to outer curve are 80%, 60%, 40%, and 20% isodose lines, respectively. B–E, Pretreatment images at unenhanced with slight lipiodol deposit (B), early arterial (at 25 seconds) (C), late arterial (at 40 seconds) (D), and portal venous (at 63 seconds) (E) phases show that tumor enhancement peaked in late arterial phase and was washed out in portal venous phase. (Fig. 4 continues on next page)
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Sanuki et al.
F
I
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J
H
Fig. 4 (continued)—68-year-old man with gradually decreased but persistent tumor enhancement of hepatocellular carcinoma after stereotactic ablative body radiation therapy. F–J, Size of tumor enhancement (arrow, F–I) in segment 4 gradually decreased at 1 (F), 6 (G), 12 (H), and 24 (I) months; however, vascularity remained for more than 2 years and disappeared 35 months after treatment (J). This patient had new intrahepatic recurrence in segment 4/8 at 31 months after first stereotactic ablative body radiotherapy, and recurrence was treated with second stereotactic ablative body radiotherapy.
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Gastrointestinal Imaging Original Research
Naoko Sanuki1,2 Atsuya Takeda1,2 Tomikazu Mizuno 3 Yohei Oku1 Takahisa Eriguchi1 Shogo Iwabuchi2 Etsuo Kunieda4 Sanuki N, Takeda A, Mizuno T, et al.
Keywords: hepatocellular carcinoma, modified Response Evaluation Criteria in Solid Tumors, stereotactic ablative body radiotherapy, tumor marker
Tumor Response on CT Following Hypofractionated Stereotactic Ablative Body Radiotherapy for Small Hypervascular Hepatocellular Carcinoma With Cirrhosis OBJECTIVE. The purpose of this study is to evaluate the CT appearances of tumor responses following hypofractionated stereotactic ablative body radiotherapy for small hypervascular hepatocellular carcinomas (HCCs) and to assess the relationship between tumor responses and local control. MATERIALS AND METHODS. Among 277 HCC tumors treated with stereotactic ablative body radiotherapy (35 or 40 Gy per five fractions), we selected enhanced lesions on arterial phase CT performed before stereotactic ablative body radiotherapy. Radiographic findings after stereotactic ablative body radiotherapy were evaluated during a 2-year followup period with the modified Response Evaluation Criteria in Solid Tumors. Local control and survival rates were calculated with the Kaplan-Meier method. RESULTS. Forty-two tumors with a median size of 2.1 cm (range, 1.0–3.8 cm) were selected with a median follow-up of 23.3 months (range, 9–56 months). Local recurrence was observed in two tumors after achieving a complete response (CR). The 2-year local control rate was 97%, and the overall survival rate was 81%. CR increased from 10 (24%) to 28 (67%) to 30 (71%) tumors at 3, 6, and 12 months after stereotactic ablative body radiotherapy. Overall CR at maximum follow-up was 39 tumors (93%), yet three enhanced tumors persisted for more than 2 years. The median time to achieve CR was 5.9 months (range, 1.2–34.2 months). CONCLUSION. The CR rate in hypervascular HCCs after hypofractionated stereotactic ablative body radiotherapy increased during the 2-year follow-up period. Cautious and continuous observation until tumor regrowth is considered relevant to evaluate a true effect of this treatment. Further studies for the optimal evaluation of treatment outcome after stereotactic ablative body radiotherapy are warranted.
DOI:10.2214/AJR.12.10169 Received October 18, 2012; accepted after revision March 11, 2013. 1 Radiation Oncology Center, Ofuna Chuo Hospital, Ofuna, Kamakura-shi, Kanagawa, Japan. 2 Department of Hepatology and Gastroenterology, Ofuna Chuo Hospital, Ofuna, Kamakura-shi, Kanagawa, Japan. 3 Department of Radiology, Ofuna Chuo Hospital, Ofuna, Kamakura-shi, Kanagawa, Japan. 4
Department of Radiation Oncology, Tokai University, 143 Shimokasuya, Isehara, Kanagawa 259-1193, Japan. Address correspondence to E. Kunieda ([email protected]).
WEB This is a web exclusive article. AJR 2013; 201:W812–W820 0361–803X/13/2016–W812 © American Roentgen Ray Society
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urrently, the incidence of hepatocellular carcinoma (HCC) is rising as a result of an increased incidence of viral hepatitis infections [1]. Because of underlying cirrhosis and the presence of multiple simultaneous lesions, some patients are not eligible for curative treatments, such as surgery or percutaneous ablation, or such treatments may not be feasible. These patients can benefit only from options like transarterial chemoembolization (TACE). Although conventional radiotherapy historically has not been considered to be a definitive treatment of liver tumors because of the low radiation tolerance of the liver, recent developments in advanced radiotherapy techniques and hypofractionated stereotactic ablative body radiotherapy have enabled accurate delivery of much higher doses of radi-
ation to a confined target [2]. Excellent local control rates of over 90% have been reported with stereotactic ablative body radiotherapy [3–10]. However, little evidence exists for optimal evaluation of treatment response for this new modality. On the basis of our experience with stereotactic ablative body radiotherapy, especially for HCC with vascularity, we have found that the tumor enhancement remains for a long time in a substantial portion of patients and that the objective treatment response effect could vary depending on duration of follow-up after stereotactic ablative body radiotherapy. The purpose of our study was to describe the long-term imaging appearance of small hypervascular HCC following stereotactic ablative body radiotherapy using modified Response Evaluation Criteria in Solid Tumors (RECIST).
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CT of Hepatocellular Carcinoma Treated With Stereotactic Ablative Body Radiotherapy
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Materials and Methods Patients Patients were required to meet all of the following criteria: single HCC (either solitary or recurrent), inoperable tumor or one for which surgery would be difficult, ineligible for percutaneous ablative therapies, liver function with Child-Pugh class A or B, tumors 4 cm or smaller in diameter, target located at a distance so that the dose to the bowels did not exceed 25 Gy per five fractions, curative intent, and informed consent. The diagnosis was established according to the results of imaging studies and was based on the international guidelines for the management of HCC [11], because candidates for stereotactic ablative body radiotherapy were usually not eligible for pathologic confirmation procedures. The imaging studies included a combination of sonography, CT, MRI, and angiography studies. The following patients were included: those with typical hypervascular HCC tumors that showed enhancement on either early or late arterial phase dynamic CT, as well as washout in delayed phase, and those who were monitored with dynamic CT scans on our follow-up protocol for more than 6 months after the treatment. All pretreatment images were read by a diagnostic radiologist. Cases with enhanced tumors were identified by a radiation oncologist who reviewed all applicable pretreatment images. The review board of our institution approved this study (protocol number 2012–007).
Treatment Stereotactic ablative body radiotherapy was performed with dynamic conformal multiple arc irradiation. Details of the treatment procedures have been described elsewhere [12, 13]. In brief, planning CT to determine the internal target volume was performed using a slow scan. For the planning target volume (PTV), individualized treatment margins of 5–8 mm were applied around the internal target volume. A stereotactic multiarc dynamic conformal radiation planned by a radiation treatment planning system (FOCUS XiO version 4.2.0–4.3.3, Computerized Medical Systems) was performed using x-ray beams from a 6-MV linear accelerator (Clinac 2100 C, Varian Medical Systems). A total dose of 35–40 Gy was delivered in five fractions over 5–9 days, depending on liver function or the dose to the normal liver (40 Gy for Child-Pugh class A and 35 Gy for Child-Pugh class B). Treatment was planned to enclose the PTV by the 70–80% isodose line of the maximum dose equated to the prescribed dose. With this method, a prescribed dose to the PTV periphery essentially corresponds to the minimal dose delivered to 95% of the target volume. A superposition algorithm was used for dose calculations.
Before stereotactic ablative body radiotherapy, TACE was performed for some patients to obtain a synergistic local treatment effect, as well as to visualize the position of the target with unenhanced CT by the deposition of lipiodol. Tumors treated with TACE in this study had insufficient lipiodol accumulation and were partially left to be hypervascular; therefore, they showed tumor enhancement on dynamic CT before and after stereotactic ablative body radiotherapy.
Patient Follow-Up The patients were seen monthly. Laboratory tests were done to evaluate liver function and blood cell counts. Treatment responses and local recurrences were evaluated with dynamic CT at 1 month and every 3 months after treatment. The CT technique at follow-up was identical to that at diagnosis. Laboratory tests included aspartate aminotransferase, total bilirubin, platelet count, and albumin. Toxicity was evaluated by the Common Terminology Criteria for Adverse Events (version 4) occurring within 3 months after stereotactic ablative body radiotherapy.
Imaging Evaluation A CT examination was performed with a 16MDCT scanner (Bright Speed, GE Healthcare) with a reconstructed slice width of 5 mm and a slice interval of 5 mm for both unenhanced and enhanced phases. Scanning parameters were 120 kV, 440 mA, 5-mm section thickness, 22 helical pitch (1.375 beam pitch), and 0.5-second rotation speed.
Dynamic CT scans were done over the range of the diaphragmatic dome to the inferior edge of the liver. Images were obtained before contrast enhancement and at 25 seconds (early arterial phase), 40 seconds (late arterial phase), and 63 seconds (portal venous phase) after injection of 100 mL of nonionic contrast medium at a rate of 4 mL/s. Treatment response was first reported by a diagnostic radiologist who made diagnostic reports. Then, images were reviewed by two radiation oncologists for the current analysis. If there was a discrepancy between reports and review, the final response evaluation was made on the basis of a consensus decision between the radiologist and radiation oncologists. Unenhanced images were compared with enhanced images to measure the longest viable tumor diameter; enhancement on either early or late arterial phase dynamic CT as well as washout in delayed phase was observed on follow-up CT scans. Reactions of the normal liver tissue surrounding a tumor were defined as sharply demarcated regions fitting to a high-dose area. They often presented as enhanced lesions in the portal venous phases, began at a median of 3 months, and peaked at 6 months [12–14]. According to the modified RECIST [15], a complete response (CR) was defined as the disappearance of contrast enhancement in the tumor for the arterial phase. At least 30% volume reduction of an enhanced area in the arterial phase, taking as reference the baseline diameter of the tumor, was judged to be a partial response (PR). Tumors without any of these changes or an increase in volume were judged
TABLE 1: Patient and Tumor Characteristics Characteristic
Value
No. of lesions
42
No. of patients
38
Sex (no. of patients) Male Female
22 16
Patient age (y), median (range)
75 (52–86)
Tumor size (cm), median (range)
2.1 (1.0–3.8)
Child-Pugh class (no. of lesions) A
38
B
4
Type of chronic hepatitis (no. of lesions) Hepatitis B virus infection
32
Hepatitis C virus infection
5
Alcoholic
4
Nonalcoholic steatohepatitis
1
Total dose (no. of lesions) 35 Gy
9
40 Gy
33
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Sanuki et al. as stable disease. An increase of at least 20% of the diameter of a viable (enhancing) lesion, taking as reference the smallest diameter of the viable lesion, was judged as progressive disease (PD). In this study, PD was counted when it occurred before CR to distinguish it from local recurrence following CR. A local recurrence was defined as the new appearance of an enhanced lesion within the site of the PTV after CR. Conversely, a new appearance of a tumor outside the PTV was judged to be an intrahepatic recurrence. Local control and survival rates were calculated with the Kaplan-Meier method using SPSS software (version 20.0, IBM).
Results Eligible Patients Between March 2005 and July 2012, 277 HCC tumors in 232 patients underwent stereotactic ablative body radiotherapy. Among these, 38 patients with 42 tumors that enhanced on CT were eligible for this study. Baseline characteristics of the eligible patients are listed in Table 1. There were 22 men and 16 women with a median age of 75 years (range, 52–86 years). All patients had underlying liver cirrhosis with Child-Pugh class A or B. The median tumor size was 2.1 cm (range, 1.0–3.8 cm). The prescribed doses were 35 Gy in nine lesions and 40 Gy in 33 lesions, in five fractions. Twenty-five tumors (60%) underwent TACE before stereotactic ablative body radiotherapy. Among them, patterns of lipiodol deposit were partial (n = 3), inhomogeneous (n = 3), and no or slight accumulation (n = 19). For those treated with TACE, the median time between TACE and stereotactic ablative body radiotherapy was 1.1 months (range, 0.5–2.8 months). Treatment Outcomes and Objective Responses During the follow-up period (median, 23.3 months; range, 9–56 months), all lesions but two maintained CR. The two local relapses occurred 12.3 and 43.2 months after treatment. Both cases had achieved CR previously (6.2 and 21.1 months after treatment, respectively) and then presented with a new arterial enhancement and delayed washout lesion on dynamic CT. The local recurrence in the first case arose from the edge of the PTV (Fig. 1), whereas it emerged within the gross tumor volume in the second case. Intrahepatic recurrences outside the treated volumes developed in 22 (58%) patients during follow-up. Distant metastases were observed in three patients (all three had preceding intrahepatic recurrences). Thirteen patients (34%) died as a result of either progression of HCC (n = 6), liver failure with W814
hepatic decompensation (n = 4), or a nonhepatic cause (n = 3). The 2-year local control rate was 97%, and the 2-year overall survival rate was 81% for all patients (100% for previously untreated tumors and 67% for recurrent tumors) (Figs. 2A and 2B). CR increased over time; it was 10 (24%), 28 (67%), and 30 (71%) at 3, 6, and 12 months after stereotactic ablative body radiotherapy, respectively, with a maximum overall CR of 39 tumors (93%). However, there were three enhanced tumors that persisted for more than 2 years (24, 29, and 34 months, respectively). In contrast, there was no PD before CR. Figure 3 shows response rates by duration after treatment. To distinguish PD (before CR) from relapse (after CR), the two locally relapsed tumors were censored at the time of their CR and were included in CR group because both had achieved CR before relapse. In contrast, there was no PD. Four tumors showed continuous vascularity after 12 months, and CR was achieved at 15, 16, 21, and 43 months after treatment. Figure 4 shows the images of a tumor with persistent vascularity for 34 months after stereotactic ablative body radiotherapy. Overall, the median time to reach CR was 5.9 months (range, 1.2–34.2 months). Treatment-Related Toxicity All scheduled treatments were completed without manifestations of toxicity. There were five patients with grade 3 laboratory abnormalities in pretreatment data. All of these recovered from grade 3 to grades 1 and 2. Excluding the five patients, acute grade 3 or higher toxicities were observed in two patients. Among them, one persistent toxicity resulted in hepatic decompensation. Other laboratory toxicities were transient and resolved to baseline levels. Discussion Recently, high local control rates after stereotactic ablative body radiotherapy for HCC have been reported, although little evidence exists for the optimal evaluation of treatment response. In this study, we attempted to describe the long-term imaging appearance after stereotactic ablative body radiotherapy for HCC with enhancement on arterial phase CT. With regard to the optimal time for tumor response assessment, we evaluated objective response rates at 3, 6, and 12 months after treatment as well as at the maximum followup time, which varied significantly over time. Measurement of response rate in HCC is challenging, because HCC can be treated with
several modalities, including surgery, TACE, radiofrequency ablation, and radiotherapy. Guidelines for treatment evaluation are proposed as methods for measuring treatment response on the basis of tumor shrinkage; however, tumor response metrics are mainly useful for chemotherapy and can be misleading, particularly following local ablation or chemoembolization treatments [15–17]. Recently, groups of experts developed a guideline taking into account treatment-induced tumor necrosis and the concept of viable tumor showing uptake in the arterial phase of contrast-enhanced radiologic imaging [15]. Response rate can also be used in evaluating the effect of conventionally fractionated radiotherapy. However, with regard to the time of evaluation, reports on treatment response following conventional radiotherapy for HCC vary significantly. Park et al. [18] evaluated the maximum tumor size on serial CT scans 4–8 weeks after completion of radiotherapy and reported CR and PR in five (8%) and 34 (58%) patients, respectively. Kim et al. [19] evaluated the imaging change in contrast enhancement in 50 patients with HCC after local radiotherapy. According to their final response evaluation on 6–12 months after treatment, a CR was observed in 11 (22%) patients, and a PR was observed in 16 (32%) patients. Compared with nonresponsive patients on 1-month follow-up CT, responsive patients showed a significant decrease in tumor enhancement. Those authors concluded that the change in contrast enhancement of HCC seen on 1-month follow-up CT in patients after local radiotherapy may be used as an early predictor of final treatment response. Information on optimal response evaluation of stereotactic ablative body radiotherapy is also limited. Controversies in HCC response assessment exist because of variability in response rates among published HCC stereotactic ablative body radiotherapy studies [3–9, 20–22] (Table 2). Although the majority of the studies took more than 12 months to evaluate response, evaluation criteria, time of evaluation, and definition of local recurrence were different across studies. It seems that the longer the time to evaluation, the better the response, which means that the results can change significantly over time. Price et al. [22] evaluated radiologic response by RECIST [23] in 26 patients with HCC treated with stereotactic ablative body radiotherapy. Mean tumor dimension decreased by 35%, 37%, 48%, and 55% at 3, 6, 9, and 12 months, respectively, compared with pretreatment size. They also compared RECIST [23] and European AJR:201, December 2013
0 0 7 93 At 23 months
Note—CR = complete response, EASL = European Association for the Study of the Liver, PD = progressive disease, PR = partial response, PTV = planning target volume, RECIST = Response Evaluation Criteria in Solid Tumors, SD = stable disease.
0
0 0
0 71
29
67
At 12 months
43 Current study
35–40
5
Modified RECIST
2.1 cm(1.0–3.8 cm)
23 (9–56)
At 6 months
33
Not mentioned
New appearance of an enhanced lesion within the PTV 0
0 27
24 52
58 15
24 At 3 months
26 Price et al. [22] (2012)
24–48
3–5
RECIST
13 (3–42)
Maximum response
Progression of the targeted lesion 42 32 16 10 13 (0.5–54)
33.9 cm3 (2.0–95 cm3)
21 Ibarra et al. [21] (2012)
18–50
1–10
RECIST
4.1 cm3 (11–464 cm3)
Maximum response
Not mentioned 0 78 22 0 At 3 months 19 (1–39) 4 cm (1.2–6.5 cm) RECIST 10 50 18 (21 lesions) Katz et al. [20] (2012)
Not mentioned 7 56 7 30 At 3 months 22 (2–48) 2.0 cm (0.8 cm) Modified RECIST 2–4 39 Facciuto et al. [6] (2012)
24–36
Not mentioned 2 21 38 38 Best response within 6 months 17 (6–38) 2.9 cm (1.3–0.8 cm) Modified RECIST 3 47 Kang et al. [4] (2012)
42–60
Recurrence within the PTV
Recurrence within the PTV 5
2 39
25 40
37 22
30 Maximum response
Maximum response 14 (2–35)
27 (2–52) 3.2 cm
4.4 cm (1.1–12.3 cm) RECIST
RECIST 3–5
4–5 42
24–48 60 Andolino et al. [9] (2011)
Huang et al. [5] (2012)
25–48
Any progression of the target lesion within the irradiated field
Not mentioned 7
29 0
7 29
12 60
57 Maximum response
Maximum reduction within 12 months
13 (1–24)
29 (8–49)
4.5 cm (1.8–10 cm)
15.4 cm3 (3.0–81.8 cm3)
EASL criteria
Modified RECIST 3
3 45
Kwon et al. [8] (2010)
30–39
14
42
Louis et al. [7] (2010)
Recurrence within the high-dose region (> 80% isodose volume) 9 42 44 5 18 (11–39) RECIST 6 24–54 31
No. of Patients Study (Year)
Tse et al. [3] (2008)
No. of Fractions
Evaluation Criteria
173 cm3 (9–1913 cm3)
Maximum response
Definition of Local (or In-Field) Recurrence CR PR SD PD Time of Evaluation
Response (%)
Duration of Follow-Up (mos), Median (Range) Tumor Size, Median (Range or SD) Total Doses (Gy)
TABLE 2: Reports on Treatment Response After Stereotactic Ablative Body Radiotherapy for Hepatocellular Carcinoma
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CT of Hepatocellular Carcinoma Treated With Stereotactic Ablative Body Radiotherapy Association for the Study of the Liver criteria [16] and concluded that reduced vascularity or nonenhancement as tumor necrosis might be a more useful indicator than size reduction in evaluating HCC response to stereotactic ablative body radiotherapy in the first 6–12 months [22]. In the current study, the size reduction or disappearance of hypervascularity of the nodule also took considerable time in some cases, and treatment response varied depending on duration after treatment (Fig. 3). In fact, there were tumors that finally achieved CR but had presented long-lasting vascularity for more than 12 months after stereotactic ablative body radiotherapy. In the current study, two local recurrences were observed in spite of initial CR. However, there is substantial ambiguity in the definition of local recurrence (or in-field recurrence) across studies (Table 2). It is critical but difficult to define local recurrence or in-field recurrence clearly, because the mode of local recurrence can reflect the reason for treatment failure. If a recurrent tumor arises from the gross tumor volume, it implies an inadequate dose for control. On the other hand, if a recurrence is observed around the border of the high-dose region with a steep dose gradient, it may be due to insufficient subclinical margins around the tumor volume or excessive respiratory movements or uncertainties in patient positioning during therapy. It is known that HCC bears satellite lesions around a nodule, and it is possible that growth of a satellite lesion arises as a new tumor within the relatively high-dose area adjacent to the PTV. In the current study, the first local recurrence (Fig. 1) arose from the high-dose area peripheral to the PTV in the diaphragmatic dome 1 year after stereotactic ablative body radiotherapy. By our definition, local recurrence should have arisen within the PTV; however, the main location of the recurrent tumor was so close to the PTV that we could not eliminate it from an event as a local recurrence. In contrast, the second case recurred within the gross tumor volume 3.6 years later. Although the true reason for local recurrence could not be revealed, the first case may have suffered from insufficient subclinical margins or geometric uncertainties, and the second case may have been radioresistant. Reactions of the normal liver tissue surrounding a tumor after stereotactic ablative body radiotherapy present unique and distinctive pathophysiologic features, in both the normally functioning liver and the cirrhotic liver, and their imaging appearances on CT have
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Sanuki et al. been described elsewhere [12, 14]. These reactions typically present as areas that are sharply demarcated from the surrounding liver tissue and that presents, often enhanced, in the portal venous or late phases. Previously, we reported that radiation-induced focal liver reactions in the cirrhotic liver began at a median of 3 months, peaked at 6 months, and disappeared about 9 months later, and these appearances remained for more than 12 months in at least one third of the patients [12]. This reaction following stereotactic ablative body radiotherapy to the liver has to be recognized, and it should not be misinterpreted as local recurrence, because the duration with tumor viability after stereotactic ablative body radiotherapy overlaps with this time. Fortunately, this focal liver reaction with contrast enhancement can be distinguished from recurrence by noticing that the enhanced lesion corresponds to the highdose area with a certain threshold [13, 14] and is not washed out in the portal venous phase. Our study has several limitations. First, we studied only hypervascular HCCs. In addition, we did not provide a pathologic correlation in any of the cases. Moreover, the influence of preceding TACE on outcome is unclear because of the low incidence of local recurrence in this study. In contrast, the strength of our report is that it probed deeply into the issue of changes after stereotactic ablative body radiotherapy and provided an extensive literature review. In conclusion, the response rate to hypofractionated stereotactic ablative body radiotherapy in hypervascular HCC increased over time during a 2-year follow-up period. Despite a remarkably high local control rate, it took considerable time to show disappearance of tumor enhancement. Therefore, cautious and continuous observation until tumor regrowth is relevant to evaluate a true effect of this treatment. Further studies regarding the optimal evaluation of treatment outcome after use of this new treatment modality are warranted. References 1. El-Serag HB, Mason AC. Rising incidence of hepatocellular carcinoma in the United States. N Engl J Med 1999; 340:745–750 2. Dawson LA, McGinn CJ, Normolle D, et al. Esca-
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lated focal liver radiation and concurrent hepatic artery fluorodeoxyuridine for unresectable intrahepatic malignancies. J Clin Oncol 2000; 18: 2210–2218 3. Tse RV, Hawkins M, Lockwood G, et al. Phase I study of individualized stereotactic body radiotherapy for hepatocellular carcinoma and intrahepatic cholangiocarcinoma. J Clin Oncol 2008; 26:657–664 4. Kang JK, Kim MS, Cho CK, et al. Stereotactic body radiation therapy for inoperable hepatocellular carcinoma as a local salvage treatment after incomplete transarterial chemoembolization. Cancer 2012; 118:5424–5231 5. Huang WY, Jen YM, Lee MS, et al. Stereotactic body radiation therapy in recurrent hepatocellular carcinoma. Int J Radiat Oncol Biol Phys 2012; 84:355–361 6. Facciuto ME, Singh MK, Rochon C, et al. Stereotactic body radiation therapy in hepatocellular carcinoma and cirrhosis: evaluation of radiological and pathological response. J Surg Oncol 2012; 105:692–698 7. Louis C, Dewas S, Mirabel X, et al. Stereotactic radiotherapy of hepatocellular carcinoma: preliminary results. Technol Cancer Res Treat 2010; 9:479–487 8. Kwon JH, Bae SH, Kim JY, et al. Long-term effect of stereotactic body radiation therapy for primary hepatocellular carcinoma ineligible for local ablation therapy or surgical resection: stereotactic radiotherapy for liver cancer. BMC Cancer 2010; 10:475 9. Andolino DL, Johnson CS, Maluccio M, et al. Stereotactic body radiotherapy for primary hepatocellular carcinoma. Int J Radiat Oncol Biol Phys 2011; 81:e447–e453 10. Dewas S, Bibault JE, Mirabel X, et al. Prognostic factors affecting local control of hepatic tumors treated by stereotactic body radiation therapy. Radiat Oncol 2012; 7:166 11. European Association for the Study of the Liver; European Organisation for Research and Treatment of Cancer. EASL-EORTC clinical practice guidelines: management of hepatocellular carcinoma. J Hepatol 2012; 56:908–943 12. Sanuki-Fujimoto N, Takeda A, Ohashi T, et al. CT evaluations of focal liver reactions following stereotactic body radiotherapy for small hepatocellular carcinoma with cirrhosis: relationship between imaging appearance and baseline liver function. Br J Radiol 2010; 83:1063–1071
13. Takeda A, Oku Y, Sanuki N, et al. Dose volume histogram analysis of focal liver reaction in follow-up multiphasic CT following stereotactic body radiotherapy for small hepatocellular carcinoma. Radiother Oncol 2012; 104:374–378 14. Herfarth KK, Hof H, Bahner ML, et al. Assessment of focal liver reaction by multiphasic CT after stereotactic single-dose radiotherapy of liver tumors. Int J Radiat Oncol Biol Phys 2003; 57:444–451 15. Lencioni R, Llovet JM. Modified RECIST (mRECIST) assessment for hepatocellular carcinoma. Semin Liver Dis 2010; 30:52–60 16. Bruix J, Sherman M, Llovet JM, et al. Clinical management of hepatocellular carcinoma: conclusions of the Barcelona-2000 EASL conference. European Association for the Study of the Liver. J Hepatol 2001; 35:421–430 17. Therasse P, Arbuck SG, Eisenhauer EA, et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 2000; 92:205–216 18. Park W, Lim DH, Paik SW, et al. Local radiotherapy for patients with unresectable hepatocellular carcinoma. Int J Radiat Oncol Biol Phys 2005; 61:1143–1150 19. Kim EY, Choi D, Lim do H, Lee WJ, Yoo BC, Paik SW. Change in contrast enhancement of HCC on 1-month follow-up CT after local radiotherapy: an early predictor of final treatment response. Eur J Radiol 2009; 72:440–446 20. Katz AW, Chawla S, Qu Z, Kashyap R, Milano MT, Hezel AF. Stereotactic hypofractionated radiation therapy as a bridge to transplantation for hepatocellular carcinoma: clinical outcome and pathologic correlation. Int J Radiat Oncol Biol Phys 2012; 83:895–900 21. Ibarra RA, Rojas D, Snyder L, et al. Multicenter results of stereotactic body radiotherapy (SBRT) for non-resectable primary liver tumors. Acta Oncol 2012; 51:575–583 22. Price TR, Perkins SM, Sandrasegaran K, et al. Evaluation of response after stereotactic body radiotherapy for hepatocellular carcinoma. Cancer 2012; 118:3191–3198 23. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 2009; 45:228–247 (Figures appear on next page)
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CT of Hepatocellular Carcinoma Treated With Stereotactic Ablative Body Radiotherapy
A
B
D
C
E
Fig. 1—83-year-old man with local recurrence of hepatocellular carcinoma after stereotactic ablative body radiation therapy. A, Dose distribution. Bold lines from center to outer curve are 80%, 60%, 40%, and 20% isodose lines, respectively. B–E Tumor enhancement (arrow, B–D), shown before treatment (B) and 1 month (C) and 3 months (D) after treatment, gradually shrank and disappeared 6 months after stereotactic ablative body radiotherapy (E). In contrast, focal liver reaction in surrounding normal liver (arrowheads, C–E) appeared after 1 month and remained after disappearance of tumor enhancement. (Fig. 1 continues on next page)
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F
G
H
Fig. 1 (continued)—83-year-old man with local recurrence of hepatocellular carcinoma after stereotactic ablative body radiation therapy. F, Dose distribution. Bold lines from center to outer curve are 80%, 60%, 40%, and 20% isodose lines, respectively. G and H, Local recurrence arose from high-dose area. Twelve months after treatment, enhanced nodule (arrow, G) appeared at edge of focal liver reaction cranial to first tumor volume, suggesting local recurrence. Three months later (H), follow-up CT scan revealed increased tumor enhancement.
100
100
90
90
Overall Survival Rate (%)
Local Control Rate (%)
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Sanuki et al.
80 70 60 50 40 30 20 10 0
0
10
20
30
40 Months After Treatment
50
80 70 60 50 40 30 20 10 0
60
0
10
20 30 40 Months After Treatment
A
50
60
B
Fig. 2—Control and survival rates. A and B, Graphs show local control (A) and overall survival (B) rates. Vertical hash marks indicate where data were censored.
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CT of Hepatocellular Carcinoma Treated With Stereotactic Ablative Body Radiotherapy Fig. 3—Response rates by duration after treatment. To distinguish progressive disease (PD) (before complete response [CR]) from relapse (after CR), two locally relapsed tumors were censored at time of their CR and were included in CR group because both had achieved CR before relapse. SD = stable disease.
100 Percentage of Patients
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90 80 70
SD
60
PR
50
CR
40 30 20 10 0
3 Months
6 Months
12 Months
A
D
Maximum
B
E
C
Fig. 4—68-year-old man with gradually decreased but persistent tumor enhancement of hepatocellular carcinoma after stereotactic ablative body radiation therapy. A, Dose distribution. Bold lines from center to outer curve are 80%, 60%, 40%, and 20% isodose lines, respectively. B–E, Pretreatment images at unenhanced with slight lipiodol deposit (B), early arterial (at 25 seconds) (C), late arterial (at 40 seconds) (D), and portal venous (at 63 seconds) (E) phases show that tumor enhancement peaked in late arterial phase and was washed out in portal venous phase. (Fig. 4 continues on next page)
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Sanuki et al.
F
I
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G
J
H
Fig. 4 (continued)—68-year-old man with gradually decreased but persistent tumor enhancement of hepatocellular carcinoma after stereotactic ablative body radiation therapy. F–J, Size of tumor enhancement (arrow, F–I) in segment 4 gradually decreased at 1 (F), 6 (G), 12 (H), and 24 (I) months; however, vascularity remained for more than 2 years and disappeared 35 months after treatment (J). This patient had new intrahepatic recurrence in segment 4/8 at 31 months after first stereotactic ablative body radiotherapy, and recurrence was treated with second stereotactic ablative body radiotherapy.
AJR:201, December 2013
