Clinical Investigation
Stereotactic Hypofractionated Radiation Therapy as a Bridge to Transplantation for Hepatocellular Carcinoma: Clinical Outcome and Pathologic Correlation

Presented at the 52nd Annual Meeting of the American Society for Radiation Oncology, San Diego, CA, Oct 31–Nov 4, 2010.
https://doi.org/10.1016/j.ijrobp.2011.08.032Get rights and content

Purpose

We sought to determine efficacy, safety, and outcome of stereotactic hypofractionated radiation therapy (SHORT) as a suitable bridging therapy for patients awaiting liver transplantation (LT) for hepatocellular carcinoma (HCC). We also examined histological response to radiation in the resected or explanted livers.

Methods and Materials

Between August 2007 and January 2009, 18 patients with 21 lesions received SHORT. A median total dose of 50 Gy was delivered in 10 fractions. Three patients underwent either chemoembolization (n = 1) or radiofrequency ablation (n = 2) prior to SHORT. Radiographic response was based on computed tomography evaluation at 3 months after SHORT. Histological response as a percentage of tumor necrosis was assessed by a quantitative morphometric method.

Results

Six of 18 patients were delisted because of progression (n = 3) or other causes (n = 3). Twelve patients successfully underwent major hepatic resection (n = 1) or LT (n = 11) at a median follow-up of 6.3 months (range, 0.6–11.6 months) after completion of SHORT. No patient developed gastrointestinal toxicity Grade ≥3 or radiation-induced liver disease. Ten patients with 11 lesions were evaluable for pathological response. Two lesions had 100% necrosis, three lesions had ≥50% necrosis, four lesions had ≤50% necrosis, and two lesions had no necrosis. All patients were alive after LT and/or major hepatic resection at a median follow-up of 19.6 months.

Conclusions

SHORT is an effective bridging therapy for patients awaiting LT for HCC. It provides excellent in-field control with minimal side effects, helps to downsize or stabilize tumors prior to LT, and achieves good pathological response.

Introduction

Hepatocellular carcinoma (HCC) is the third leading cause of cancer mortality worldwide (1). In the United States, the incidence rate of HCC has shown a marked increase over the past several decades, primarily due to a rise in the incidence of hepatitis C (2). According to the American Cancer Society, in 2010 there were 24,120 new cases of liver cancer and 18,910 resultant deaths in the United States (3).

Most HCC develops in the setting of cirrhosis. For selected patients, orthotopic liver transplantation offers the best results in terms of overall and disease-free survival (4). The most suitable patients for transplantation have a single tumor measuring ≤5 cm in diameter or up to three tumors, each of which does not exceed 3 cm, with no proven vascular invasion. In this setting, the 4-year survival rate is 85%, and the recurrence-free survival rate is 92% (5). However, many HCC patients awaiting transplantation are delisted due to tumor progression (6).

A bridge therapy is an important option for patients awaiting transplantation due to the scarcity of organ donors, particularly in regions of the country where waiting lists for transplantation are long. Bridge therapies are typically used to delay disease progression, although some centers use these therapies to downstage patients’ tumors to within Milan selection criteria limits (7). Therapies include radiofrequency ablation (RFA) (8), transcatheter arterial embolization (TACE) (9), and radioembolization with yttrium-90 microspheres (10). Tumor downstaging not only keeps patients within criteria during the waiting period but may have a beneficial effect on long-term outcome in terms of reduced recurrence and improved survival for patients who ultimately undergo transplantation (11).

Radiation therapy has had a historically limited role in the treatment of HCC, either as definitive treatment for inoperable HCC or as bridge therapy to liver transplantation. Early reports indicated that radiation tolerance of the whole liver was far lower than the effective therapeutic dose (12). However, the low therapeutic ratio of the hepatic parenchyma has been improved by a number of technological developments that allow for more conformal delivery of radiation to the tumor, with greater sparing of the normal liver parenchyma. Studies by Lawrence et al. (13) and Liang et al. (14) have shown that three-dimensional conformal radiation therapy is safe and effective for patients with HCC, whose mean liver dose is below tolerance levels. More advanced radiation therapy techniques such as stereotactic body radiation therapy (SBRT) have further enhanced the ability to successfully treat HCC with radiation (15).

At the University of Rochester Medical Center, we have a program for treating liver malignancies using stereotactic hypofractionated radiation therapy (SHORT). This technique enables delivery of high doses of radiation therapy precisely to the tumor while minimizing dose to critical surrounding structures and preserving maximal liver function. A review of the initial 69 patients treated for liver metastasis showed SHORT to be an effective and well-tolerated treatment, with no patient developing toxicity higher than Grade 3 (16).

In the present study, we report our experience using SHORT as a bridge therapy to liver transplantation (LT) for patients with primary HCC. For patients undergoing LT after SHORT, we evaluated explant pathology for the percentage of necrosis using a morphometric method.

Section snippets

Methods and Materials

All cases of patients with HCC at our institution are presented at a multidisciplinary tumor board. Potential transplantation candidates outside the Milan criteria are treated with the intent of shrinking tumors to within criteria, and patients who meet Milan criteria but do not have an available donor are treated with bridge therapy. SHORT is offered to patients whose conditions rendered them unsuited for other therapies or for whom other forms of locoregional therapies had failed, such as

Results

Eighteen patients underwent treatment as a bridge therapy to LT. Patient characteristics are shown in Table 1. HCC diagnosis was confirmed by biopsy sample analysis in 3 patients. Fifteen patients met AASLD criteria for HCC without requiring biopsy. Median age was 56.4 years (range, 44.9–71.9 years) with a male preponderance. Two patients were previously treated with TACE and one with RFA prior to SHORT. Most patients had a Karnofsky performance status of >60. Child-Pugh classes were A, B, C,

Discussion

Liver-directed therapies have been used as a bridge therapy to liver transplantation. Each therapy has limitations relative to the patient’s general health condition, the location, number, and size of the lesions, and underlying liver function. These techniques decrease the dropout rate from the transplant waiting list (19); however, data supporting a potential survival advantage is limited (20). Our dropout rate of 6/18 patients (33%) is consistent with that in the literature.

Radiation therapy

Conclusions

In conclusion, our study demonstrates that SHORT is a safe and effective bridge therapy for HCC patients awaiting liver transplantation. Further studies are warranted to define which patients are most likely to benefit from SHORT compared to other bridge therapies and to evaluate the role of combined modality therapy to improve down-staging and enable more patients to undergo transplantation.

Acknowledgment

The authors thank Laura Brumbaugh for editorial assistance and Umayal Sivagnanalingam for performing morphometric analyses.

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    Conflict of interest: none.

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