Down-Staging of Hepatocellular Carcinoma via External-Beam Radiotherapy With Subsequent Liver Transplantation: A Case Report

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1 LIVER TRANSPLANTATION 19: , 2013 ORIGINAL ARTICLE Down-Staging of Hepatocellular Carcinoma via External-Beam Radiotherapy With Subsequent Liver Transplantation: A Case Report Alan Wigg, 1,2 Kenneth Hon, 1,2 Leigh Mosel, 3 Nicole Sladden, 4 and Kevin Palumbo 5 1 Hepatology and Liver Transplant Medicine Unit, 2 South Australian Liver Transplant Unit, 3 Department of Medical Imaging, and 4 Department of Anatomical Pathology, Flinders Medical Centre, Bedford Park, Australia, and 5 Adelaide Radiotherapy Centre, Adelaide, Australia Despite the widespread use of locoregional therapies [radiofrequency ablation and transarterial chemoembolization (TACE)], there is currently a lack of high-quality evidence supporting their use for hepatocellular carcinoma (HCC) in patients on the liver transplantation (LT) waiting list or requiring down-staging. Radiotherapy has rarely been used in this setting and has usually been in the form of more complex and less accessible techniques such as proton-beam and stereotactic body radiation therapy. Only 1 report describes the use of conventional 3-dimensional conformal external-beam radiotherapy (cebrt) techniques as neoadjuvant or down-staging therapy for patients who are LT candidates. This report describes the use of cebrt in a 52-year-old hepatitis C positive man with cirrhosis. A 40-mm right lobe HCC was treated initially with TACE while he was on the waiting list. The lesion progressed beyond transplant criteria (76 mm). Conventional external-beam radiotherapy (EBRT) was used (54 Gy in 27 fractions) to down-stage the lesion. EBRT was well tolerated and resulted in a complete radiological response with no arterial enhancement of the lesion for a total of 16 months. Subsequent LT and a review of the explant demonstrated complete histological necrosis of the lesion. This report provides the first description of complete histological necrosis of HCC through the use of cebrt techniques as down-staging/neoadjuvant therapy before LT. Because of its potential efficacy, accessibility, tolerability, noninvasive and outpatient nature, and ability to treat lesions adjacent to vessels and biliary structures, further trials examining the efficacy of cebrt versus other neoadjuvant techniques are urgently required. Liver Transpl 19: , VC 2013 AASLD. Received April 2, 2013; accepted July 8, Locoregional therapies (LRTs) for hepatocellular carcinoma (HCC) are commonly used in patients on the liver transplantation (LT) waiting list to prevent tumor progression and to down-stage tumors to meet transplant criteria. The most common modalities are transarterial chemoembolization (TACE) and percutaneous radiofrequency ablation (RFA). Despite the widespread use of these LRTs, their pretransplant efficacy and improved survival for treated patients versus untreated patients have not been established in either retrospective cohort studies 1 or randomized controlled trials. In addition, these treatments can be associated with significant morbidity and mortality. Because of this lack of high-quality evidence, an exploration of alternative therapies in this setting with potentially greater efficacy, fewer side effects, and lower costs is appropriate. Conventional 3-dimensional (3D) conformal external-beam radiotherapy (cebrt) Abbreviations: 3D, 3-dimensional; cebrt, conformal external-beam radiotherapy; CP, cirrhotic parenchyma; CT, computed tomography; CTV, clinical target volume; EBRT, external-beam radiotherapy; GTV, gross target volume; HCC, hepatocellular carcinoma; LRT, locoregional therapy; LT, liver transplantation; MRI, magnetic resonance imaging; NT, necrotic tissue; PTV, planning target volume; RFA, radiofrequency ablation; SBRT, stereotactic body radiation therapy; SR, sclerosis from radiotherapy; TACE, transarterial chemoembolization. The authors have no conflicts of interest or financial support to declare. The case report had the consent of the patient and followed guidelines of our local hospital ethics committee. Address reprint requests to Alan Wigg, M.D., Hepatology and Liver Transplant Medicine Unit, Flinders Medical Centre, Flinders Drive, Bedford Park, South Australia, Australia Telephone: ; FAX: ; alan.wigg@health.sa.gov.au DOI /lt View this article online at wileyonlinelibrary.com. LIVER TRANSPLANTATION.DOI /lt. Published on behalf of the American Association for the Study of Liver Diseases VC 2013 American Association for the Study of Liver Diseases.

2 1120 WIGG ET AL. LIVER TRANSPLANTATION, October 2013 has been neglected by researchers as LRT for HCC. This likely reflects a number of misconceptions concerning the radioresistance of HCC and radiationinduced liver injury. A recent review of HCC radiobiology suggests that HCC has a radiosensitivity within the range of non-hcc tumors commonly treated with radiotherapy and that there is a high probability of tumor control and sterilization of small tumors less than 5 cm in their maximum diameter. 2 Further modeling and clinical data have also demonstrated that with cebrt techniques, high radiation doses (>100 Gy with 1.5 Gy per fraction) can be used with little risk of radiation-induced liver disease in patients with Child- Pugh class A/B cirrhosis when the irradiated volume of the liver is less than 20%, 3-6 and cebrt is associated with promising radiological response rates for small HCCs. 7 The use of radiotherapy as LRT for preventing waitlist dropout or down-staging has not been extensively described. Most reports concerning radiotherapy as LRT for LT candidates have described the use of proton beams, 8 stereotactic body radiation therapy (SBRT), 9 and yttrium spheres. It is our view that more conventional external-beam fractionated radiotherapy treatment using standard multifield treatment techniques and modern 3D computer planning could achieve similar results with far greater accessibility for patients and potentially lower costs. To our knowledge, only 1 report has described the use of cebrt as LRT before LT. 10 In that report, 10 patients 6 with decompensated (Child B/C) liver disease and 8 outside the Milan criteria were treated with cebrt. Five of these patients had previously undergone unsuccessful treatments with TACE or RFA. Patients received relatively low radiation doses (mean dose 5 33 Gy) in 1 to 6 fractions. The treatment was well tolerated with no toxicities > grade 1 and with 100% local tumor control. Five patients subsequently underwent transplantation with no radiotherapy-related posttransplant complications. A microscopic examination of explants did not demonstrate complete tumor necrosis in any specimen, but tumor necrosis rates ranged from 40% to 90%. In this case report, we describe the first use of cebrt as LRT for HCC leading to complete histological tumor necrosis, and we subsequently discuss the significance of this finding for the LT community. CLINICAL CASE AND RADIOTHERAPY TREATMENT DETAILS The patient was a 52-year-old man with Child-Pugh class A cirrhosis secondary to chronic hepatitis C. Ultrasound surveillance, followed by a triple-phase computed tomography (CT) scan and then a magnetic resonance imaging (MRI) scan, showed a 40-mm hypervascular lesion in segment 5/6 of the right liver lobe that was suggestive of HCC (Fig. 1A). Subsequent CT-guided biopsy of the lesion confirmed HCC. The patient was listed for LT because of the size of the lesion and significant portal hypertension. Figure 1. (A) Contrast MRI showing hypervascular HCC in segment 5/6. (B) Contrast MRI showing a hypervascular segment 5/6 lesion with progression. (C) Contrast MRI showing nonenhancing HCC after EBRT. White arrow indicates HCC. The patient was treated on the waiting list with TACE as bridging LRT to prevent tumor progression. A superselective TACE procedure was performed with 50 mg of epirubicin mixed with lipiodol. TACE was complicated by severe right upper quadrant pain for 48 hours that required opiate analgesia and hospitalization for 36 hours after the procedure. A follow-up CT scan 6 weeks after TACE demonstrated tumor progression, with the maximum diameter of the lesion now measuring 76 mm (Fig. 1B). The patient was delisted. Between March 16 and April 23, 2010, the patient received cebrt for the lesion, which was peripherally located. Image-guided or gated radiotherapy was not available at that time. The gross target volume (GTV) described the tumor visible on imaging. Liver images

3 LIVER TRANSPLANTATION, Vol. 19, No. 10, 2013 WIGG ET AL Figure 2. Radiotherapy treatment plan (2A) and dose volume histogram (2B). from diagnostic MRI were fused with a planning CT scan to produce the composite GTV to minimize the risk of geographic miss. As the treatment plan shows (Fig. 2A), there was residual contrast in the lesion from the prior TACE procedure. The clinical target volume (CTV), which is the volume that may contain subclinical disease not evident radiologically, consisted of a 5-mm expansion of the GTV into the liver but not beyond the liver capsule. The planning target volume (PTV) is a volume expansion that allows for uncertainties in the tumor position, patient and respiratory movement, and setup errors. To determine the PTV, the CTV was expanded 1.5 cm superiorly and inferiorly (to allow for respiratory movement), 1 cm to the left and 1.2 cm to the right (the differential reduced the encroachment of beams on the right kidney and the normal liver), and 1.2 cm anteriorly and 1 cm posteriorly (for the same reasons). A 3-field conformal technique was used with beam arrangements to reduce the irradiated volume of the right kidney. With 3D conformal radiotherapy, the convention is to encompass the PTV within the 95% isodose line. A 3D plan and a dose-volume histogram were produced (Fig. 2B). The critical organ dose tolerances were as follows: a volume receiving 30 Gy < 50% and a volume receiving 50 Gy < 33% for the liver, a volume receiving 30 Gy < 50% for the kidneys, and no more than 20 Gy for an entire kidney. These doses

4 1122 WIGG ET AL. LIVER TRANSPLANTATION, October 2013 Figure 4. Costs of LRTs for HCC. ANALYSIS OF COSTS The costs of cebrt in this case and alternative LRTs (TACE and RFA) are shown in Fig. 4. The costs for TACE and RFA were calculated from the bottom up and from the perspective of costs to the public health system. The costs include both direct costs (salaries and wages and goods) and indirect costs (estimated at 35%). The costs for cebrt in this case were calculated with the Australian Commonwealth Medicare Benefits Schedule and the relevant schedule fees for specialist consultation, simulation, planning, and treatment with 27 fractions and a 3-field technique, and they also represent the costs to the public health system for the treatment of this patient. The analysis shows similar total costs for RFA, TACE, and cebrt, which were A$5145, A$5291, and A$6021, respectively. Figure 3. (A) Gross histology of the liver explant showing complete necrosis of HCC. (B) Microscopic histology of the liver explant showing complete necrosis of HCC. were for conventionally fractionated radiotherapy with 1.8 to 2.0 Gy per fraction. The dose prescribed and delivered was 54 Gy in 27 fractions (with the PTV receiving a minimum of 51.3 Gy). As can be seen in the dose-volume histogram in Fig. 2B, these criteria were met, and the patient tolerated the treatment well with no toxicity > grade 1 experienced. Serial MRI every 3 months after the completion of external-beam radiotherapy (EBRT) demonstrated a 5.2-cm nonenhancing, stable segment 5/6 lesion for 6 months (Fig. 1C). The patient was subsequently relisted for LT. The lesion remained stable in size and without enhancement for another 10 months after listing and before LT. The lesion remained stable in size and without enhancement for a total of 16 months after EBRT before LT. The liver explant showed complete necrosis of the tumor with no residual viable tumor cells (Fig. 3A,B). At the time of this writing, the patient was 18 months past LT with no evidence of tumor recurrence and with no complications attributable to pre-lt EBRT. DISCUSSION To our knowledge, this is the first report to describe complete histological necrosis after cebrt used as LRT for HCC in an LT candidate. The report, therefore, provides proof of the concept that cebrt techniques can be highly effective in this setting. The lack of complete necrosis in the only other report of cebrt as LRT 10 may be related to the fact that a lower radiotherapy dose was delivered and fewer fractions were used because of concerns about radiation-induced liver injury in patients with more advanced liver failure. Another important consideration may be the longer time interval between radiotherapy treatment and transplantation. This mean time interval was 157 days in Sandroussi et al. s study, days in O Connor et al. s SBRT study, 9 and 480 days in this report. This longer interval may have permitted the necessary time required for a complete histological response after radiotherapy. Nevertheless, it should be noted that local tumor control was the major clinical aim in both series, and it was achieved in 100% of cases. The relative efficacy of cebrt versus TACE, as suggested by this report, is not unexpected when the biological aspects of tumor cell kill are considered. For typical cancers, radiotherapy may achieve an approximately 10- to 12-log kill, whereas chemotherapy is

5 LIVER TRANSPLANTATION, Vol. 19, No. 10, 2013 WIGG ET AL associated with up to an approximately 6-log kill. 2 The relatively poor tumor sterilization of HCC with TACE is not unexpected because of the complex microvasculature of hepatic tumors, which restricts chemotherapy or ablation effects on many clonogens. However, we cannot exclude the idea that there was a synergistic interaction between TACE and cebrt because of the use of epirubicin, which is a known radiosensitizer. Indeed, the role of cebrt as adjuvant therapy after an initial treatment with another modality such as TACE or RFA has been suggested by other investigators, 11 and this is an area that requires further investigation. Tumor control probability modeling in this setting highlights the need for high radiation doses to sterilize HCC after other local therapies for HCC, which may leave residual subclinical disease. 2 The costs of cebrt appear similar to the costs of TACE and RFA in an Australian health context. However, cebrt may be less costly than other modalities when the frequent need for repeat TACE or RFA and the significant complication rates associated with TACE and RFA are considered. A further important consideration is the outpatient nature of cebrt, which frees valuable hospital beds for other activities. Finally, the costs of cebrt could be further reduced through the use of fewer, larger fractions. A further key message of this report is the fact that currently available cebrt treatment is likely to be sufficient for most cases. More sophisticated forms of radiotherapy such as intensity modulation, respiratory gating, SBRT, and proton beams are frequently discussed but may not provide more clinically meaningful benefits. Moreover, their use is significantly limited by their unavailability at many LT centers and increased costs, particularly in the case of protonbeam therapy. In contrast, cebrt techniques are already established cancer therapies and are widely accessible and routinely available. In addition to the efficacy, tolerability, cost competitiveness, and accessibility of cebrt, there are other compelling advantages of cebrt versus other currently available LRTs. The noninvasive nature of cebrt suggests significantly greater patient tolerability. TACE is associated with significant morbidity, including postembolization syndrome related pain (as occurred in this case), infection, precipitation of liver failure, and systemic chemotherapy side effects. The estimated frequency of RFA-related adverse events due to percutaneous puncture (pain, bleeding, and pneumothorax) is 10%, and there are also lower risks of mortality and tumor seeding. 12 A further attractive and practical advantage offered by cebrt versus percutaneous techniques is its ability to treat liver lesions at all sites. Its use is not contraindicated by the proximity of lesions to major vessels or bile ducts. These structures, if intact, are relatively tolerant of irradiation, and adjacent tumors can be irradiated without undue concern about subsequent vascular or biliary injury. The noninvasive nature of radiotherapy also removes the risk of tumor seeding associated with the percutaneous ablation of high-risk lesions. Although cebrt may provide greater flexibility for treating HCC in locations traditionally difficult for other LRT modalities, ideal lesions for cebrt are likely to be solitary, small, and peripherally located. All these factors limit the dose to the unaffected liver and optimize the dose-volume relationship. In this case, if the lesion had been located more centrally, the critical organ dose tolerance criteria may not have been met with this simple technique. In such situations, narrower margins, afforded by image-guided and respiratory-gated or stereotactic body radiotherapy techniques, may allow critical organ tolerances to be better achieved. In conclusion, this is the first report of an HCC that was successfully both down-staged and sterilized with standard and widely available EBRT techniques to facilitate LT. We believe that cebrt as LRT for HCC before LT is likely to be a cost-effective, well-tolerated, and accessible form of therapy. We encourage transplant clinicians to consider the use of cebrt and to participate in high-quality studies, which are urgently required to evaluate its efficacy in comparison with other forms of LRT in this setting. ACKNOWLEDGMENT The authors gratefully acknowledge the contribution of the late Associate Professor David Wigg, whose enthusiasm and skill in clinical radiobiology led directly to this work. 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