High-dose radiotherapy with intensity-modulated radiation therapy for advanced hepatocellular carcinoma

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1 Tu mo ri, 97: , 2011 High-dose radiotherapy with intensity-modulated radiation therapy for advanced hepatocellular carcinoma Min Kyu Kang 1, Myung Se Kim 1, Sung Kyu Kim 1, Gi Won Ye 1, Heon Ju Lee 2, Tae Nyeun Kim 2, and Jong Ryul Eun 2 Departments of 1 Radiation Oncology, and 2 Internal Medicine, Yeungnam University College of Medicine, Daegu, Republic of Korea ABSTRACT Aims and background. We report the results of intensity-modulated radiotherapy for patients with advanced hepatocellular carcinoma who were not candidate for local ablative therapies, transarterial chemoembolization or hepatic arterial infusion chemotherapy. Methods and study design. Between 2003 and 2008, 27 patients were treated with high-dose radiotherapy (median dose, 50.4 Gy). The equivalent sphere size of tumors was 11.4 ± 2.6 cm. Nineteen and 8 patients were Child-Pugh class A and B, respectively. Eighteen patients had thromboses in large veins. Six patients were treated with radiotherapy as the initial treatment modality, and 21 patients received other treatments before radiotherapy. Results. The overall response rate was 44.4% (1 pathologic complete response and 11 partial responses). The primary failure pattern was intrahepatic disease progression. Until the last follow-up, the primary liver masses and vein thromboses did not progress in 63.6% and 60.0% of the patients, respectively. The median progressionfree survival and overall survival after radiotherapy rate were 3 and 5 months, respectively. Based on univariate analyses, response, Child-Pugh classification, and vein thrombosis were significant factors for overall survival, and tumor response, tumor size, vein thrombosis, and multiplicity were significant factors for progression-free survival. Tumor response was the only significant prognostic factor for overall survival and progression-free survival based on multivariate analyses. Conclusions. Radiotherapy with intensity-modulated radiotherapy achieved a good response rate in patients with advanced hepatocellular carcinoma, and patients who had a good response lived longer than patients who did not have a good response. Introduction Unresectable hepatocellular carcinoma (HCC) is usually treated with transarterial chemoembolization (TACE), which has been shown to increase the survival of HCC patients 1,2. However, the prognosis of patients who are not candidates for TACE due to co-existing conditions, including portal vein thrombosis (PVT), is dismal. Thus, other effective treatments are needed. In the past, radiotherapy had a very limited role in HCC because normal liver was thought to be radiosensitive and HCC had been believed to be radioresistant. Now, HCC has been shown to be radiosensitive, and with advances in the radiotherapy technique, including 3-dimensional conformal radiotherapy (3D-CRT), the use of radiotherapy has extended from small HCC to large HCC with PVT 3-6. Although it has been reported in several studies 6-9 that a radiation dose >45-50 Gy is related to increased survival of patients with HCC, there is little room for increasing dose in patients with a large HCC, even if 3D-CRT is used. Accordingly, in patients Key words: hepatocellular carcinoma, intensity-modulated radiotherapy, radiotherapy. Acknowledgments: The study was supported by Yeungnam University research grants in Financial disclosure and conflict of interest: the authors declare that they have no competing interests. Correspondence to: Min Kyu Kang, MD, Department of Radiation Oncology, Yeungnam University College of Medicine, 317-1, Daemyeong-dong, Nam-gu, Daegu, , Republic of Korea. Tel ; fax ; mkkang@ynu.ac.kr Received February 17, 2011; accepted May 13, 2011.

2 IMRT FOR ADVANCED HCC 725 with tumors occupying a large proportion of the liver, many clinicians have reduced the total dose in an attempt to prevent radiation-induced liver disease (RILD) 5. For these tumors, intensity-modulated radiotherapy (IMRT) has the potential to escalate the radiation dose without increasing hepatic toxicity 10,11. Nevertheless, IMRT has not been widely used for HCC due to the uncertainty of the dose distribution in the moving target. We have applied fractionated high-dose radiotherapy delivered by IMRT to patients with advanced HCC and analyzed the treatment outcomes retrospectively, including tumor response, survival, and hepatic toxicity. Material and methods Patients Between 2003 and 2008, high-dose radiotherapy with IMRT was attempted in 35 patients who had advanced HCC without distant metastasis at the Yeungnam University Medical Center. All of the patients were referred for radiotherapy since they were not candidate for local ablative therapies, transarterial chemoembolization or hepatic arterial infusion chemotherapy at the time of diagnosis or after repeated treatments with aforementioned modalities. Eight patients did not complete the scheduled treatment (treated dose range, Gy) due to the following causes: self-withdrawal of treatment in 3 patients, poor general condition in 2 patients, deterioration of liver function in 1 patient, variceal bleeding in 1 patient, and neutropenia in 1 patient. Thus, 27 patients who received high-dose radiotherapy ( 45 Gy) were enrolled in the study to analyze the effect of IMRT on tumor response, survival, and hepatic toxicity. Treatment Twenty-one patients had received other treatments before the radiotherapy. Sixteen patients were treated 1-3 times with TACE and 5 patients were treated with percutaneous ethanol injection, intra-arterial chemotherapy, or transarterial embolization. When these treatments were ineffective or failed, patients were referred for radiotherapy. The interval from diagnosis to radiotherapy ranged from 2 weeks to 9 months. The remaining 6 patients received radiotherapy immediately after diagnosis because TACE was contraindicated due to PVT. Twenty-seven patients received a median dose of 50.4 Gy (range, ) with 1.8 Gy daily, and 16 patients received 50.4 Gy. Four patients received Gy and 7 patients received Gy. During the course of the radiotherapy, 3 patients underwent TACE and 3 patients received intra-arterial chemotherapy. After radiotherapy, other possible treatment modalities were utilized. Thirteen patients were treated with TACE, intra-arterial chemotherapy, transarterial embolization, or resection. Two patients underwent surgery (one patient after achieving a partial response [PR] and the other patient when local recurrence occurred after a PR). Radiotherapy planning and treatment Patient immobilization was aided by posterior vacuum-lock body fixation. To reduce movement of the liver by respiration, we used thermoplast anteriorly and trained patients to breathe shallowly in order to reduce the amplitude of tumor motion within 5 mm. Computed tomography (CT) simulation with intravenous contrast media was done during free breathing. Gross tumor volume including primary mass and venous thrombus was delineated in CT data sets while referring to the diagnostic 3-phase CT images. Planning target volume (PTV) was made by adding a 1 cm radial margin and a 1.5 cm craniocaudal margin to the gross tumor volume. Then, inverse treatment planning using a dynamic multileaf collimator was performed using the Corvus (Nomos Corp., Cranberry Township, PA, USA) or the Eclipse treatment planning system (Varian, Palo Alto, CA, USA). We did not use an equidistant beam angle, but 5-9 beams with a separation entering the body near the tumor to reduce the entering beam path in the normal liver. Figure 1 shows the treatment plan and dose-volume histogram of the patient who underwent surgery 2 months later and achieved a pathologic complete response (pcr). Radiation therapy was delivered with a 6- or 10-MV linear accelerator (21EX or 21EX-S, Varian). During treatments, interfractional setup error was weekly assessed from the orthogonal portal images with portal films or electronic portal images. Response and toxicity The best response to radiotherapy was evaluated with the Response Evaluation to Criteria in Solid Tumors (RECIST) guidelines 12. The radiologic disappearance of all target lesions was defined as a complete response. A PR was defined as a 30% decrease in the sum of the longest diameter of the target lesions. Progressive disease was defined as a 20% increase in the sum of the longest diameter of the target lesions or the appearance of new lesions. Stable disease was defined as the status of the tumors that did not meet the three response criteria. Objective response reflected the sum of complete and partial responses. Radiation-induced liver disease was graded in 14 patients in whom the elevation of liver enzymes was not related to progressive disease. Increases in transaminase and alkalaine phosphatase levels within 4 months of completing radiotherapy were scored using the Common Terminology Criteria for Adverse Events (version 3.0) 13. For the analysis of hepatic toxicity, we divided patients into two groups according to the interval between radiotherapy and other treatments. The combined modality treatment group consisted of patients who re-

3 726 MK KANG, MS KIM, SK KIM ET AL ceived other treatments within 1 month before or after radiotherapy (n = 14). Thirteen other patients were allocated to the radiotherapy alone group. Statistical analysis We analyzed the response rate, failure patterns, and survival rates. Survival rates were calculated from the start of radiotherapy to the date of the event using the Kaplan-Meier method. Factors affecting the response to radiotherapy were analyzed with the chi-square test or Fisher s exact test. Log-rank tests and the Cox proportional hazard model were used for analysis of the factors affecting survival rates, and factors with P <0.1 in univariate analysis were analyzed with multivariate analysis. We used PASW18.0 software (SPSS Inc., Chicago, IL, USA) for statistical analysis. P <0.05 was considered significant. Results Patient and tumor characteristics The median age of the patients was 47 years (range, 30-70), and the ratio of males-to-females was 23:4. Patient and tumor characteristics are shown in Table 1. Nineteen (70.4%) and 8 patients (29.4%) were Child- Pugh class A and class B, respectively. Sixteen patients had a single liver mass, 10 had daughter nodules near the largest mass, and 1 had 2 tumors in the right and left lobes. Thromboses in large veins were present in 18 patients (66.7%) (the right or left portal vein in 6 patients, the main portal vein in 11 patients, and the hepatic vein to inferior vena cava in 1 patient). The volume and equivalent sphere diameter of the tumors was 908 ± 703 cc (range, ) and 11.4 ± 2.6 cm (range, ). Most patients had T3 or T4 tumors, and 5 had abdominal lymph node metastases. The mean value of serum alpha-fetoprotein (AFP) was 11,833 ng/ml (range, 2-94,619), respectively. Twenty-six of 27 patients were diagnosed serologically with hepatitis virus infection (type B in 25 patients and type C in 1 patient). Response to radiotherapy The median follow-up period was 5 months (range, 2-82). Evaluation of the tumor response to radiotherapy was possible in 25 patients. The overall response rate was 44.4% (1 pcr and 11 PR). In 6 patients (22.2%), the tumors progressed during or immediately after radiotherapy. Of several factors including age, tumor size, vein thrombosis, T stage, N stage, and Child-Pugh classification, vein thrombosis and Child-Pugh classification were significantly related to the tumor response to radiotherapy (Table 2). The level of AFP decreased in 16 patients; normalization was achieved in 6 patients; a 50% decrease occurred in 6 patients; a <50% decrease occurred in 4 patients; and an increase occurred in 6 patients. Of the patients in whom the AFP level was normalized, the radiologic response rates included PR in 4 patients (1 pcr), stable disease in 1 patient, and progressive disease in 1 patient (progression of PVT). Patterns of failure The primary pattern of initial failure was intrahepatic disease progression in 22 assessable patients (in-field in 6 patients, out-field in 8 patients, and both in 5 patients). Until the last follow-up, the primary liver mass treated with radiotherapy did not progress in 63.6% of the patients (14/22) and vein thrombosis did not progress in 60.0% of the patients (9/15), resulting in an Table 1 - Patient and tumor characteristics No. of patients Percentage (%) Age (yr) > Gender M F Child-Pugh classification A B Multiplicity Single Multiple Tumor size (cm) < Vein thrombosis Absent Present T stage N stage Table 2 - Factors affecting tumor response to radiotherapy Non- Responder Response P responder (pcr/pr) rate (%) (SD/PD) Age (yr) > Tumor size (cm) < Vein thrombosis Absent Present T stage / Child-Pugh A classification B Treatment RT alone CMT SD, stable disease; PD, progressive disease; pcr, pathologic complete response; PR, partial response; RT, radiotherapy; CMT, combined modality treatment.

4 IMRT FOR ADVANCED HCC 727 overall in-field control rate of 45.5% (10/22). Four patients developed lung metastases, 3 of them with simultaneous intrahepatic disease progression. Pre-existing abdominal lymph nodes progressed in 1 patient without evidence of intrahepatic progression or distant metastasis. There were 5 patients in whom the pattern of failure was not determined: 3 patients were lost to follow-up and 2 patients died At the last follow-up, 2 patients were alive without disease. One patient, who underwent surgical resection 2 months after radiotherapy, achieved pcr and was disease-free for 33 months (Figure 1). Another patient who achieved a PR (tumor size reduction from 13.2 cm 10 cm to 7.2 cm 5.0 cm 3 months after radiotherapy) developed a local recurrence 5 months after radiotherapy and underwent salvage partial hepatectomy. He underwent additional surgery due to lung metastasis at 31 months and adrenal gland metastasis at 43 months and was alive 82 months after the radiotherapy. Table 3 - Prognostic factors related to overall survival rates A Normal liver PTV CTV Dose (cgy) No. of Survival P patients (1 yr) Univariate Multivariate Age (yr) > Size (cm) < Vein thrombosis Absent Present Multiplicity Single Multiple Child-Pugh A classification B 8 0 Response SD/PD 13 0 < pcr/pr Treatment RT alone CMT SD, stable disease; PD, progressive disease; pcr, pathologic complete response; PR, partial response; RT, radiotherapy; CMT, combined modality treatment. B Table 4 - Prognostic factors related to progression-free survival rates No. of Survival P patients (1 yr) Univariate Multivariate C Figure 1 - Representative case of IMRT for patients with advanced HCC. The patient received 50.4 Gy in 28 fractions with a 7-field IMRT (15 separation from 270 to 360 ). The tumor size was reduced from 11 cm to 7.5 cm 2 months after the completion of radiotherapy. Then, he underwent surgery and the surgical specimen showed complete necrosis. A) Dose-volume histogram of CTV, PTV, and normal liver. B) Dose distribution, and C) follow-up image 2 months after radiotherapy, which showed a reduction in tumor size and radiation change in the normal liver surrounding the tumor. Age (yr) > Size (cm) < Vein thrombosis Absent Present 18 0 Multiplicity Single Multiple 11 0 Child-Pugh A classification B 8 0 Response SD/PD pcr/pr Treatment RT alone CMT SD, stable disease; PD, progressive disease; pcr, pathologic complete response; PR, partial response; RT, radiotherapy; CMT, combined modality treatment.

5 728 MK KANG, MS KIM, SK KIM ET AL Survival rates and prognostic factors For all patients, the median progression-free and overall survival time after radiotherapy was 3 and 5 months, respectively. The factors affecting survival rates are shown in Tables 3 and 4. Tumor response, Child- Pugh classification, and vein thrombosis were significant factors for overall survival. Patients without vein thromboses survived longer than patients with vein thromboses (1-year overall survival, 44.4% vs 11.1%, P = 0.011). The 1-year overall survival rate of responders and non-responders was 50.0% (median, 9 months) and 0% (median, 3 months), respectively (P <0.001). Patients with good liver function survived longer (Child-Pugh A [31.6%] vs Child-Pugh B [0%] at 1-year, P = 0.020). For progression-free survival, tumor size, vein thrombosis, multiplicity, and tumor response were significant prognostic factors. The 1-year progression-free survival rate Overall survival Progression-free survival Non-responders (P <0.001) Responders All patients Months Non-responders (P <0.001) Responders All patients Months Figure 2 - Overall and progression-free survival rates according to tumor response to IMRT. of responders and non-responders was 20.4% (median, 8 months) and 0% (median, 2 months), respectively (P = 0.001). Tumor response was the only significant factor for overall and progression-free survival based on multivariate analyses (Figure 2). Hepatic toxicities Table 5 shows the details of hepatic toxicity: grade 0-1 RILD developed in 6 patients and grade 2-3 in 6 patients. Fatal hepatic toxicity occurred only in patients who received the combined modality treatment: 1 patient started radiotherapy 10 days after TACE and another patient received intra-arterial chemotherapy during radiotherapy. We evaluated the dose-volume parameters in only 17 patients due to malfunction of the Corvus system. The mean normal liver dose was 25.0 ± 6.4 Gy (range, Gy). Of the patients in whom hepatic toxicity was evaluated, dose-volume parameters were available for 7 patients, all of whom were treated with a combined modality. The mean normal liver dose of these 7 patients was 22.5 ± 6.8 Gy (range, ). Two patients with a mean normal liver dose >28 Gy (29.9 and 30.6 Gy) experienced grade 3 RILD; however, both patients were treated with TACE or intra-arterial chemotherapy before the elevation of transaminases occurred. For patients with a mean normal liver dose <28 Gy, grade 0-2 RILD developed in 4 patients and grade 5 RILD developed in 1 patient, who died 1.5 months after radiotherapy combined with concurrent intra-arterial chemotherapy. Hepatitis B virus reactivation developed in 1 patient one month after radiotherapy and concurrent intra-arterial chemotherapy. Discussion In the present study, we achieved a response rate of 44.4% and an in-field control rate of 47.6% without a high rate of hepatic toxicity by applying IMRT to advanced HCC not suitable for or progressed after local ablative therapy, transarterial chemoembolization, or hepatic arterial infusion chemotherapy. With the introduction of 3D-CRT, many trials of highdose radiotherapy for partial liver have been reported. The response rates after radiotherapy with or without other local modalities were 40-76% in advanced HCC 6- Table 5 - Radiation-induced hepatic toxicity related to treatment according to Common Terminology Criteria for Adverse Events (v3.0) in 14 patients Grade Radiation alone Combined modality treatment

6 IMRT FOR ADVANCED HCC 729 8,14. The response rates of PVT and/or inferior vena cava thrombosis have been reported to be approximately 46% after radiotherapy 15,16. Similar to these results, the objective response to IMRT was approximately 45% in patients with HCC with or without PVT in the current and another study 17. Although this objective response seems relatively low, it is not a low value when considering that most of the patient population in both studies had advanced HCC. Furthermore, this response rate after IMRT suggests that we could use IMRT for a moving target or HCC with or without PVT. Of several prognostic factors related to radiotherapy, the dose of radiation has been shown to be the most important factor in several studies 6-9, A higher radiation dose (>50 Gy or 50 Gy 10 ) achieved a higher response rate 18,19. A higher total dose (>45-60 Gy) showed a higher survival rate 6,8,9,20. In addition, when comparing the results from radiotherapy alone or radiotherapy combined with TACE, combined treatment achieved a better tumor response 21. The current study also showed that combined treatment was related to a better response with a difference of 20%, although the difference was not statistically significant (Table 2). In addition, meta-analysis of 1,476 patients from 5 randomized and 12 non-randomized trials, comparing TACE combined with radiotherapy with TACE alone, revealed that combined treatment achieved a better survival and tumor response 22. Based on the above results regarding radiation dose and treatment modalities, high-dose radiotherapy combined with other treatments might have the potential to achieve the best tumor control. However, the ever-present problem is hepatic toxicity. Hepatic toxicity has been reported to increase as the irradiated dose of the normal liver increases. Since the mean normal liver dose was significantly higher in patients with RILD in several studies, it has been recommended that the mean normal liver dose should be <28 Gy in 2-Gy fractions for primary liver cancer 23. In addition to the radiation dose, radiotherapy combined with TACE or non-selective hepatic arterial chemotherapy give a higher rate of hepatic toxicity than radiotherapy alone Hence, the highly conformal radiotherapy technique is needed for treatment of advanced HCC to reduce the radiation dose to normal liver while guaranteeing a high tumor dose. Some studies have reported the dosimetric advantages of IMRT over 3D-CRT. Eccles et al. 27 compared IMRT with 3D-CRT for hypofractionated isotoxicity liver radiotherapy and explored dose escalation using IMRT for the same or improved nominal risk of liver toxicity in a treatment-planning study. Dose escalation was feasible in 35% of the patients, and other clinical gains were seen in another 58% of the patients, in whom improved target coverage, a reduction in the doses to the non-liver organs at risk, and/or a reduction in the effective liver volume irradiated were noted for the same prescription dose. Cheng et al. 10 compared the difference in the dose-volume data between IMRT and 3D-CRT for patients with HCC who had developed RILD after 3D- CRT, in which IMRT significantly reduced normal tissue complication probability (23.7% vs 36.6%, P = 0.009) but significantly increased the mean normal liver dose (29.2 Gy vs 25.0 Gy, P = 0.009). Although the increase in mean liver dose by IMRT is a problem, it appears to be a function of the IMRT planning technique. The former authors used the same beam arrangements as the original conformal plans, which were selected to have minimal path lengths through the normal liver; however, the latter authors used standard coplanar 5 fields with equidistance whereas the 3D-CRT field angles were individually optimized by using coplanar and non-coplanar beam entry angles. In addition, Hsieh et al. 28 compared three IMRT techniques, including coplanar and non-coplanar IMRT and helical tomotherapy, and gained a mean normal liver dose <20 Gy in patients with unresectable HCC with PVT, which is less than the recommended liver dose. We have created IMRT plans by using 5-9 empirically selected beams with an angular distance of 15-20, and we are going to compare these plans with a standard beam configuration with equidistance. However, clinical data on hepatic toxicity after IMRT are very limited. Fuss et al. 11 treated 10 HCC patients with a total dose of Gy using conventionally fractionated IMRT, and no case of RILD was observed with a mean liver dose of 29.8 Gy (range, ). McIntosh et al. 29 prescribed 50 Gy in 20 fractions to 20 HCC patients, whose mean tumor size was 9 cm, with helical tomotherapy-based IMRT; the average normal liver volume receiving 30 Gy was 27.2% (range, 12-43%) and the mean normal liver dose was 22.6 Gy (range, 8-52 Gy), and no severe RILD was observed. Jang et al. 17 irradiated intra- and extra-hepatic lesions simultaneously with tomotherapy but did not report detailed RILD data. In the current study, 4 of 5 patients with a mean normal liver dose <28 Gy (range, ) had no or mild RILD (grades 0-2). Although 2 patients with a mean normal liver dose >28 Gy (29.9 Gy and 30.6 Gy) experienced grade 3 RILD, their liver enzyme activities increased after TACE or intra-arterial chemotherapy and recovered. In the patient who died after radiotherapy concurrent with intra-arterial chemotherapy, the mean normal liver dose was 18.1 Gy. Based on these data, the normal liver dose could be reduced by IMRT in patients with advanced HCC and the incidence of RILD after IMRT would be low. However, special attention needs to be given to other treatments given during or immediately after IMRT. In order to reduce the dose to normal liver, we tried to reduce the amplitude of respiratory motion and added a relatively small margin to create the PTV due to the small proportion of normal liver, in contrast to other 3D-CRT studies that usually used larger margins for the PTV than in our study. Since most tumors had microscopic extension of less than 2-5 mm beyond the tumor margin shown in CT images, a CTV margin of 5 mm seems to be adequate 30,31. Since the PTV margin is de-

7 730 MK KANG, MS KIM, SK KIM ET AL termined by the extent of setup error and tumor motion, image-guided radiotherapy techniques or devices which can reduce tumor motion may be useful to reduce the PTV margin. Although IMRT for tumors in moving organs has not been widely challenged due to the concerns about dose uncertainty, there is increasing evidence that the uncertainty is not too great to prevent its use. Two studies investigated the effect of motion on the fluences generated from IMRT plans or the point dose near the tumor center with a motor-driven moving phatom 32,33. Both reported that a single dose of irradiation could cause a large dose variation but, after repeating irradiation 25 or 30 times, the error was reduced to less than 1-2% when the amplitude of tumor motion was below 0.5 cm. Higher dose rate (500 vs 300 MU min -1 ) and larger amplitude of tumor motion were related to a larger dose variation, whereas the dose variation was insensitive to the multileaf collimator delivery mode (sliding window versus step-and-shoot). Flampouri et al. 34 investigated the difference between the planned dose in free-breathing helical CT images and the delivered dose, which were estimated from all the tumor positions during respiration in a 4D-CT data set. They reported that conventional IMRT planning with a free-breathing 3D-CT set was sufficient for patients with tumor motion less than 12 mm when the free-breathing helical CT images had small or no artifacts. In summary, we could give high-dose radiation to advanced HCC with the help of IMRT while giving lowdose radiation to normal liver. Tumor response to IMRT was similar to the previously reported responses to 3D- CRT, and the patients in whom the tumors responded to radiotherapy showed a better survival. 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