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Long-term outcomes of stereotactic body radiation therapy in the treatment of hepatocellular cancer as a bridge to transplantation
Article first published online: 24 JUL 2012
Copyright © 2012 American Association for the Study of Liver Diseases
Volume 18, Issue 8, pages 949–954, August 2012
How to Cite
O'Connor, J. K., Trotter, J., Davis, G. L., Dempster, J., Klintmalm, G. B. and Goldstein, R. M. (2012), Long-term outcomes of stereotactic body radiation therapy in the treatment of hepatocellular cancer as a bridge to transplantation. Liver Transpl, 18: 949–954. doi: 10.1002/lt.23439
- Issue published online: 24 JUL 2012
- Article first published online: 24 JUL 2012
- Accepted manuscript online: 29 MAR 2012 06:12AM EST
- Manuscript Accepted: 16 MAR 2012
- Manuscript Received: 14 JAN 2012
Hepatocellular carcinoma (HCC) is potentially curable with hepatic resection or transplantation. Few patients are eligible for resection, and many face a long wait for donor organ availability for liver transplantation. Here we report the safety and efficacy of stereotactic body radiation therapy (SBRT), the explant pathology findings and survival of patients treated with SBRT as a bridge to transplantation for HCC. From April 2005 to August 2010, 10 patients with 11 HCCs were treated with SBRT as a bridge to transplantation. All patients were evaluated by a liver transplant surgeon before radiosurgery. SBRT was delivered with the CyberKnife robotic radiosurgery system. After SBRT, all patients underwent orthotopic liver transplantation. The tumor response was determined by explant pathology. The median follow-up was 62 months from the time of SBRT. The mean time on the liver transplant wait list was 163 days. The median tumor size was 3.4 cm (range = 2.5-5.5 cm). The median SBRT dose was 51 Gy (range = 33-54 Gy) in 3 fractions. The median time from SBRT to liver transplantation was 113 days (range = 8-794 days). At 5 years, the overall survival rate and the disease-free survival rate were both 100%. Overall, 4 of the 10 patients (40%) experienced acute toxicity. Most toxicities were grade 1, and they included nausea, fatigue, and abdominal discomfort. One patient had grade 2 nausea/vomiting. Explant pathology revealed no viable tumor in 3 of the 11 tumors for a complete response rate of 27%. The remaining 8 tumors decreased or remained stable in size. In conclusion, with a median follow-up over 5 years, we have found that SBRT as a bridge to liver transplantation for HCC is feasible and well tolerated. SBRT for HCC may enable patients to remain on the list for frequently curative transplantation during the wait for organ availability. Liver Transpl, 2012. © 2012 AASLD.
The use of hepatic transplantation for hepatocellular carcinoma (HCC) is limited by the shortage of donor organs. Many patients face a long wait on the transplant list and may drop out because of tumor progression.1-3 Local HCC treatment as a bridge therapy in patients awaiting liver transplantation is performed at many institutions. The rationale for local treatment during the wait for a donor organ includes preventing tumor progression, reducing the dropout rate, and decreasing posttransplant HCC recurrence. Successful tumor down-staging of HCC can be achieved in select patients and make them eligible for transplantation.4 Transarterial chemoembolization (TACE), radiofrequency ablation (RFA), and ethanol injection have been used in patients with HCC while they are awaiting transplantation.5 Chemoembolization and RFA are local therapies with the potential to enhance tumor control and survival for select patients with HCC undergoing liver transplantation.6, 7
Historically, radiotherapy for primary liver malignancies has been limited because of concerns related to efficacy and the risk of radiation-induced liver disease (RILD). Recently, because of better imaging, techniques that can account for respiratory tumor motion, and hypofractionation, stereotactic body radiation therapy (SBRT) has been used in patients with unresectable intra-abdominal malignancies, including HCC. SBRT provides a noninvasive treatment alternative for malignant liver lesions when established curative treatment modalities cannot be applied.8-10 SBRT has also been colloquially called radiosurgery because of the high doses of radiation per fraction and the use of stereotactic localization techniques similar to those used in intracranial radiosurgery.
Here we report our experience with using SBRT for patients with HCC as a bridge to liver transplantation. We evaluate the toxicity, local control, disease-free survival, overall survival, and explant pathology.
PATIENTS AND METHODS
From April 2005 to August 2010, 10 patients with 11 HCCs were treated with SBRT as a bridge to transplantation at the Baylor Radiosurgery Center (Baylor University Medical Center, Dallas, TX). Institutional review board approval was granted before the initiation of this retrospective study. Patient characteristics at the time of SBRT are listed in Table 1. All patients were evaluated by a liver transplant surgeon (R.M.G.) before radiosurgery. Patients were listed for liver transplantation at the Annette C. and Harold C. Simmons Transplant Institute and underwent orthotopic liver transplantation at the Baylor University Medical Center. The Annette C. and Harold C. Simmons Transplant Institute uses the criteria for region 4 (Oklahoma and Texas) for liver transplantation and allows transplantation for patients with 1 lesion <6 cm in diameter or with ≤3 lesions when none are >5 cm in diameter and the total diameter is <9 cm. This study included all patients treated with SBRT as a bridge to transplantation. SBRT was delivered with the CyberKnife robotic radiosurgery system (Accuray, Inc., Sunnyvale, CA), and respiratory tumor tracking was used for all patients. The tumor response was determined by explant pathology examination. Patients were followed at 3-month intervals until liver transplantation. Follow-up data were collected through February 2012. The median follow-up was 62 months (range = 17-74 months) from the time of SBRT.
|Sex [n (%)]|
|Age (years)*||59 (43-68)|
|Tumor size (cm)*||3.4 (2.5-5.5)|
|Tumor location [n (%)]|
|Right lobe||9 (90)|
|Left lobe||1 (10)|
|Cirrhosis [n (%)]|
|Hepatitis [n (%)]|
|Model for End-Stage Liver Disease score [n (%)]|
|Child-Pugh classification [n (%)]|
|Previous treatment [n (%)]|
|No previous therapy||6 (60)|
|TACE × 1||2 (20)|
|TACE × 2||2 (20)|
SBRT Planning and Treatment
Before SBRT, all patients had 3 to 5 peritumoral fiducials placed percutaneously by interventional radiology for respiratory tracking of the tumor during treatment. Fiducials were placed in the tumor or within 5 cm of the tumor, and each fiducial was spaced apart from other fiducials by 2 cm. Five to 10 days after fiducial placement, patients underwent contrast-enhanced, dual-phase computed tomography (CT) with a 1.25-mm slice thickness at expiration for SBRT planning. Diagnostic magnetic resonance imaging (MRI) was also used to determine the extent of disease. The gross tumor volume (GTV) was defined as the enhancing tumor seen with CT and MRI. The GTV was contoured by both the radiation oncologist and the liver transplant surgeon in all cases. A 10-mm margin was placed around the GTV to create the clinical target volume.11 A planning target volume (PTV) was created by the addition of another margin of 0 to 3 mm, which was based on the tumor's size and its proximity to normal tissues. The PTV was reduced if the tumor was in close proximity to critical normal tissues. Normal tissues were contoured, and the dose constraints for 3 fractions on 3 consecutive days were as follows: <35% of the liver (minus the PTV) received >15 Gy, and >700 cc received <15 Gy. The liver dose constraints were the same for all patients regardless of the liver function status. For the esophagus, stomach, duodenum, and bowel, the maximum dose was limited to 24 Gy (8 Gy per fraction). For a single kidney, >67% received <15 Gy, and for both kidneys, <35% received >15 Gy. The maximum dose for the heart was limited to <30 Gy, the maximum dose for the skin was limited to <27 Gy, and the maximum dose for the spinal cord was limited to <18 Gy. Patients were treated in the supine position with respiratory tracking of the tumor via the peritumoral fiducials.
The patients were assessed during SBRT on the first and last days of treatment. After the completion of treatment, the patients were followed at 3-month intervals until orthotopic liver transplantation.
Actuarial survival was evaluated with the Kaplan-Meier method. Survival was measured from the time of SBRT. Statistical analysis was performed with GraphPad Prism software (GraphPad Software, San Diego, CA). The tumor response was determined by explant pathology. Toxicity was graded according to Common Terminology Criteria for Adverse Events 3.0.
The median age of all patients was 59 years (range = 43-68 years; Table 1). All patients had a good performance status with an Eastern Cooperative Oncology Group status of 0/1. The severity of liver disease before liver transplantation, as measured with the Model for End-Stage Liver Disease score, was 20 for 1 patient (10%), 22 for 7 patients (70%), 25 for 1 patient (10%), and 36 for 1 patient (10%). The Child-Pugh classification for the severity of liver disease was A for 7 patients (70%), B for 2 patients (20%), and C for 1 patient (10%). The majority of the patients had hepatitis C (70%). One patient (10%) had hepatitis B. Two patients (20%) did not have hepatitis. All patients had evidence of cirrhosis. Tumors were located in the right lobe in 9 patients and in the left lobe in 1 patient. The median time from initial tumor imaging to SBRT was 4 months (range = 1-9 months).
Patients selected for SBRT were no longer eligible for more conventional therapies. Four patients (40%) had undergone previous treatment in the form of TACE. Two patients underwent TACE twice. Two patients underwent TACE once. In all 4 patients, SBRT was administered because of evidence of progressive disease on MRI. Surgical resection or RFA was not performed because of the anatomic position of the tumor, its proximity to major vessels, or its size. Six patients (60%) were not treated for HCC before SBRT because of their ineligibility for other therapies. Laparoscopic RFA was attempted for 3 patients. RFA was not performed because of the tumor's location in 3 patients: ablation would have been difficult and could have damaged retroperitoneal structures in 1 patient, and the tumor's adjacency to the bifurcation of the portal vein or other major vessels was problematic in the other 2 patients. Two other patients did not undergo RFA: one because of the tumor size (5.5 cm) and the other because of its location in the liver dome near the diaphragm. Two patients were not considered candidates for TACE. One patient was not a candidate because angiography revealed a splenic artery aneurysm, massive mesenteric varices, and a kink in the hepatic artery, and TACE was not performed because of concerns about shunt diversion. The other patient was not a TACE candidate because of neutropenia. One patient in this series underwent SBRT for 2 HCCs as a bridge to transplantation. In this patient, the second lesion was not apparent until the planning CT scan for SBRT, and upon its discovery, it was decided to treat both lesions with SBRT.
SBRT as a Bridge to Hepatic Transplantation
Ten patients with 11 HCCs underwent SBRT as a bridge to orthotopic liver transplantation. The median tumor size was 3.4 cm (range = 2.5-5.5 cm). The median radiosurgery dose was 51 Gy (range = 33-54 Gy) in 3 fractions given on 3 consecutive days (Table 2). The median biologically equivalent dose in 2-Gy fractions was 115 Gy (range = 58-126 Gy) with an α/β ratio of 10 for many tumors and acutely reacting normal tissues. The median prescription isodose line was 61% (range = 50%-66%).
|Patient||Pre-SBRT Treatment||Tumor Diameter (cm)||SBRT Dose (Gy)*||Time From SBRT to Liver Transplantation (Days)||Explant Pathology/ Tumor Size||Follow-Up After SBRT (Months)||Disease Status|
|1||None||5.5||33||8||Residual HCC/5 cm||60||NED|
|2||None||3.4||39||48||Residual HCC/3.4 cm||74||NED|
|4||TACE × 1||2.5||42||794||Residual HCC/millimetric||64||NED|
|5||None||4.3||51||209||Residual HCC/4.3 cm||63||NED|
|6||TACE × 1||3.8||51||330||Residual HCC/3.0 cm||64||NED|
|7||None||3.0||54||38||No viable tumor||57||NED|
|8a||None||4.5||54||67||No viable tumor||50||NED|
|8b||None||2.5||54||67||No viable tumor||50||NED|
|9||TACE × 2||2.9||54||185||Residual HCC/1.2 cm||57||NED|
|10||TACE × 2||2.8||54||112||Residual HCC/millimetric||17||NED|
All 10 patients underwent orthotopic liver transplantation. No patients who were treated with SBRT with the intent of undergoing transplantation dropped off the wait list because of progression. The mean time on the liver transplant wait list was 163 days (range = 9-984 days). The mean time from SBRT to orthotopic liver transplantation was 113 days (range = 8-794 days). The radiographic tumor response, which was measured with CT or MRI at 3 months, revealed stable disease in 5 patients and a partial response in 1 patient. Four patients underwent orthotopic liver transplantation within 3 months of SBRT. No patients had evidence of progressive tumors from the time of SBRT until the time of orthotopic liver transplantation.
Explant Pathology and Clinicopathological Correlations
After SBRT and liver transplantation, explant pathology revealed that in 3 of the 11 tumors, there was no evidence of a viable tumor for a complete pathological response rate of 27%. Residual HCC was seen in the other 8 tumors (Table 2). In 3 of these patients, only small, millimetric foci of viable HCC with otherwise extensive necrosis were present after SBRT. These patients received 42, 42, and 54 Gy for 3.0-, 2.5-, and 2.8-cm tumors, respectively.
For the 8 tumors with viable HCC according to explant pathology, the maximum tumor diameter on imaging before radiosurgery was compared to the maximum tumor diameter according to the gross pathology examination. Six of the 8 tumors (75%) decreased in size after radiosurgery, and 2 tumors (25%) were stable in size. The diameters of these tumors decreased by an average of 59% (range = 10%-95%).
The median survival of all patients was not determined: the 5-year overall survival and disease-free survival rates were both 100%. All patients were alive and free of disease at the last follow-up. No patients experienced HCC recurrence during the follow-up period.
Overall, SBRT was well tolerated. After SBRT, 4 of the 10 patients (40%) experienced acute toxicity (Table 3). Most toxicities were grade 1 and included nausea/vomiting, fatigue, and abdominal discomfort. One patient had grade 2 nausea/vomiting. No toxicity was grade 3 to 5. No cases of RILD were observed. Overall, 6 of the 10 patients (60%) had no acute toxicity after SBRT for HCC while they were awaiting liver transplantation. There were no episodes of biliary obstruction or pulmonary toxicity. There were no late toxicities. We observed no differences in operative morbidities or hospitalization in patients whose transplantation was preceded by SBRT versus institutional controls. Intraoperatively, there was no evidence of damage to the hepatic artery, and there were no issues with postoperative healing.
|Grade 1||Grade 2||Grades 3-5|
|Nausea/vomiting [n/N (%)]||1/10 (10)||1/10 (10)||—|
|Fatigue [n/N (%)]||1/10 (10)||—||—|
|Abdominal pain [n/N (%)]||1/10 (10)||—||—|
Historically, radiotherapy has been used sparingly in the treatment of liver tumors because of concerns about efficacy and toxicity—particularly RILD. RILD is a clinical syndrome of anicteric hepatomegaly, ascites, and elevated liver enzymes (particularly serum alkaline phosphatase) occurring typically 2 weeks to 4 months after hepatic radiation.12 However, over the past several years, because of better radiographic imaging of tumors and normal tissues, techniques that can account for tumor motion with respiration, and dose escalation with hypofractionation via stereotactic techniques, SBRT has been increasingly used for the treatment of malignancies throughout the body, including primary and secondary liver malignancies.13 No radiation therapy technology can completely eliminate the radiation exposure of normal tissue immediately adjacent to a tumor. However, through the targeting of tumors with numerous small beams of radiation and through the tracking of tumor movement with respiration, inoperable liver tumors can receive high doses of radiation. Delivering high doses of radiation to tumors while minimizing the exposure of surrounding critical structures to radiation, SBRT has been shown to have the potential for a high local control rate with low morbidity rates when it is used to treat primary and metastatic liver malignancies.9, 10
Dewas et al.14 reported their experience with SBRT for primary and secondary liver malignancies. Forty-two patients were treated for HCC. The SBRT dose was 40 to 45 Gy in 3 to 4 fractions over a period of 12 days, and the overall local control and survival rates at 2 years were 72.5% and 58%, respectively. Price et al.15 reported 26 patients with HCC who were treated with SBRT in 3 or 5 fractions with a median dose of 42 Gy. No patients in that series underwent transplantation, and according to the Response Evaluation Criteria in Solid Tumors, the radiographic complete and partial response rates were 15% and 58%, respectively. Facciuto et al.16 reported a 14% complete response rate for 17 patients after transplantation. With a median post-SBRT follow-up of 22 months, the actuarial 2-year survival was 82%. The SBRT dose was 24 to 36 Gy in 2 or 4 fractions. In comparison with these series, we treated HCC patients with a higher median SBRT dose of 51 Gy (instead of 24-45 Gy). Additionally, the patients in our series were all treated on 3 consecutive days, whereas other studies have reported the administration of SBRT on nonconsecutive days or over several weeks. The higher SBRT dose may have contributed to the higher pathological complete response rate in comparison with Facciuto et al.: 27% versus 14%. Although the overall number of patients is low, the current series with its >5-year median follow-up after SBRT has demonstrated long-term safety and efficacy.
HCC is generally considered to be a hypervascular tumor, and TACE is currently one of the more common bridge therapies for HCC. TACE can result in extensive tumor necrosis (50%-77%).17 However, after TACE, doxorubicin impregnation is seen only several millimeters beyond the hypervascular tumor.18 Additionally, tumor cells surviving TACE show up-regulation of angiogenic and growth factors.19-21 HCC recurrence after TACE tends to occur at the periphery of the tumor.22 In patients with tumors for whom TACE has failed, SBRT may be an option. SBRT may also be beneficial because of the treatment of a larger margin around the tumor (1 cm in this series). Kelsey et al.11 performed a clinicopathological correlation between the radiographic size and the true gross pathological size for subjects with primary HCC.11 They concluded that radiation therapy with a 0.5- or 1.0-cm margin around the radiographic tumor would have encompassed the gross pathological tumor in 93% and 100% of cases, respectively. According to evaluations of the costs of TACE and SBRT, TACE had a median cost of $13,400 per procedure, whereas a course of SBRT had a medicare cost of approximately $11,000.23, 24
This series illustrates that SBRT could be advantageous for patients with HCC tumors for whom TACE has failed or for patients who are unable to undergo TACE. SBRT may also be used for patients with tumors who are unable to undergo RFA because of the tumors' proximity to major vessels. Because large blood vessels can generally tolerate high doses of radiation, SBRT can be delivered safely to tumors adjacent to major vessels, including the portal vein and the vena cava. The most suitable HCC lesions for SBRT would not touch the stomach or the small or large bowel because of the relative radiosensitivity of these organs. Although there is no strict tumor size cutoff for liver SBRT, the treatment of larger tumors does make it more difficult to meet normal liver radiation dose constraints. For the same reason, when multiple tumors are being treated in the liver, it may be difficult to deliver SBRT and meet the liver's radiation dose tolerance.
We have reported a series of patients with HCC who underwent radiosurgery as a bridge to liver transplantation. SBRT was very well tolerated and conferred no increased risk of operative complications for orthotopic liver transplantation. Additionally, according to explant pathology, 27% of the patients had complete tumor necrosis. According to a comparison of the tumor sizes before radiosurgery and after transplantation, the overall local control rate was 100%. At the last follow-up visit, all the patients were alive and disease-free. No patients dropped off the liver transplant wait list, and there were no posttransplant recurrences. Because of the good local control, SBRT may enable patients to remain on the transplant wait list longer by preventing tumor progression and the ensuing dropout. With limited donor organ availability, SBRT could play an important role in select patients by bridging the gap between the diagnosis of HCC and curative liver transplantation. Although the number of patients was small, clinicians may want to consider SBRT as a treatment option for patients with HCC.
- 15Evaluation of response after stereotactic body radiotherapy for hepatocellular carcinoma. Cancer; doi:10.1002/cncr.26404., , , , , , et al.
- 16Stereotactic body radiation therapy in hepatocellular carcinoma and cirrhosis: evaluation of radiological and pathological response. J Surg Oncol; doi:10.1002/jso.22104., , , , , , et al.
- 20Transcatheter arterial chemoembolization (TACE) in hepatocellular carcinoma (HCC): the role of angiogenesis and invasiveness. Am J Gastroenterol 2008; 103: 914-921., , , , , , et al.Direct Link: