Clinical Investigation
Dose-Escalation Study of Single-Fraction Stereotactic Body Radiotherapy for Liver Malignancies

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Purpose

We performed a Phase I dose-escalation study to explore the feasibility and safety of treating primary and metastatic liver tumors with single-fraction stereotactic body radiotherapy (SBRT).

Methods and Materials

Between February 2004 and February 2008, 26 patients were treated for 40 identifiable lesions. Nineteen patients had hepatic metastases, 5 had intrahepatic cholangiocarcinomas, and 2 had recurrent hepatocellular carcinomas. The prescribed radiation dose was escalated from 18 to 30 Gy at 4-Gy increments with a planned maximum dose of 30 Gy. Cumulative incidence functions accounted for competing risks to estimate local failure (LF) incidence over time under the competing risk of death.

Results

All patients tolerated the single-fraction SBRT well without developing a dose-limiting toxicity. Nine acute Grade 1 toxicities, one acute Grade 2 toxicity, and two late Grade 2 gastrointestinal toxicities were observed. After a median of 17 months follow-up (range, 2–55 months), the cumulative risk of LF at 12 months was 23%. Fifteen patients have died: 11 treated for liver metastases and 4 with primary liver tumors died. The median survival was 28.6 months, and the 2-year actuarial overall survival was 50.4%.

Conclusions

It is feasible and safe to deliver single-fraction, high-dose SBRT to primary or metastatic liver malignancies measuring ≤5 cm. Moreover, single-fraction SBRT for liver lesions demonstrated promising local tumor control with minimal acute and long-term toxicity. Single-fraction SBRT appears to be a viable nonsurgical option, but further studies are warranted to evaluate both control rates and impact on quality of life.

Introduction

Malignant tumors of the liver, including hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinomas (IHCC), and metastatic lesions, are an important cause of morbidity and mortality. These tumors are primarily managed with surgery, which can be curative for primary liver tumors diagnosed early and for isolated colorectal metastases to the liver 1, 2. However, the majority of these tumors are unresectable, and alternative therapies provide only partial palliation of symptoms and slight prolongation of survival. Local ablative techniques such as radiofrequency ablation and cryoablation can be applied to unresectable tumors, but their use is limited by lesion location, underlying liver dysfunction, and a significant risk of local failure 3, 4, 5, 6.

Historically, radiotherapy for primary and metastatic liver lesions has been limited because of the low tolerance of the whole liver to irradiation. Conformal techniques and image guidance have allowed for the delivery of focal ablative doses of radiation. Dose-escalation studies with fractionated regimens have shown a clear dose response for HCC, IHCC, and liver metastases 7, 8. Stereotactic body radiotherapy (SBRT) techniques have been applied to the treatment of liver tumors, further refining our ability to target the tumor and minimize normal tissue toxicity 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19. The spatial precision of SBRT makes it feasible to administer a tumoricidal radiation dose in only a few outpatient treatments. By minimizing irradiation of surrounding healthy tissue, it may be possible to decrease complication rates, thereby allowing for dose escalation and ultimately better local tumor control.

We performed a Phase I dose-escalation study to explore the feasibility and safety of treating primary and metastatic liver tumors with stereotactic single-fraction radiation therapy. The single-fraction SBRT approach was developed based on our institutional experience with pancreatic tumors, which was developed in Phase I and Phase II studies 20, 21, 22. This Phase I study was designed to determine the feasibility and toxicity of single-fraction SBRT for liver lesions and to evaluate the clinical outcome for unresectable primary and metastatic liver tumors.

Section snippets

Patients and eligibility

All patients had primary or metastatic liver lesions that either were deemed unresectable by a hepatobiliary surgeon or for which the patient refused surgical resection and had an Eastern Cooperative Oncology Group (ECOG) performance status of ≤2. Study eligibility required patients to have histologically confirmed nonmetastatic HCC and IHCC or metastatic liver tumors from other primary sites. The number of liver lesions could not exceed five, and the maximum tumor diameter could not exceed 5

Patient and treatment characteristics

Between February 2004 and February 2008, 26 patients were treated on this institutional review board–approved dose escalation protocol. Thirty-two target volumes were treated encompassing a total of 40 treated lesions. Nineteen patients had hepatic metastases, five had IHCC, and two had recurrent HCC. Patient characteristics are described in Table 1. The 32 target volumes were treated at four prescribed dose levels (18 Gy, n = 3 targets; 22 Gy, n = 8 targets; 26 Gy, n = 12 targets; and 30 Gy, n

Discussion

Unresectable liver lesions remain a therapeutic challenge; however, new modalities of local therapy are emerging. In this Phase I study, we established that it is feasible and safe to deliver single-fraction, high-dose SBRT to primary or metastatic liver malignancies measuring up to 5 cm. Moreover, single-fraction SBRT for liver lesions demonstrated promising local tumor control with minimal toxicity. A tolerance dose was not reached in this dose escalation study.

The results of our study are

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    Conflict of interest: Dr. Goodman received an honorarium from Accuray in 2005–2006. Dr. Koong received honoraria from Accuray and Varian and received grant support from Varian in 2005–2006.

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