Unresectable liver metastases originating from solid tumors present a therapeutic challenge to treatment providers.
Attempts at local control with non-radiation techniques, such as radiofrequency ablation, have not been wholly successful.
Several Phase I/II trials have been published investigating the use of conformal radiation therapy for liver metastases with a variety of dose and fractionation schemes.
The authors sought to evaluate the feasibility of high-dose stereotactic body radiation therapy (SBRT) in the treatment of unresectable liver metastases.
The authors conducted a single institution phase II trial of SBRT for liver metastases, and enrolled 61 patients with 1-3 liver metastases from a number of primary cancers between February 2010 and September 2011.
Inclusion criteria were liver metastases that were unresectable, patients medically unsuitable for surgery, good performance status of patients (KPS > 70), life expectancy greater than 6 months, and tumor size < 6 cm.
Patients were simulated in the supine position using 4D CT to measure diaphragmatic excursion from breathing, as well as upper abdominal block to minimize diaphragmatic motion. Tri-phasic contrast-enhanced CT images were obtained to ensure proper visualization of tumor and normal tissue structures.
The standard dose delivered was 3 fractions of 25 Gy each, for a total of 75 Gy to the clinical target volume.
Dose reductions of up to 30% were allowed in order to meet normal tissue constraints. Normal tissue constraints were developed using data from Quantitative Analysis of Normal Tissue Effects in the Clinic (QUANTEC).
SBRT was administered using RapidArc with photon beam energy of 10 MV.
Daily image guidance was used to ensure patient positioning prior to delivery of each fraction of treatment.
The primary endpoint was infield local control (evaluated by CT/MRI/PET), and secondary endpoints were progression-free survival and overall survival.
79 lesions were treated among the 63 patients enrolled in this Phase II study.
Median follow-up was 12 months.
Median age was 65 years, and most common primary cancers were colorectal and breast cancer.
The majority of patients (79%) had one lesion, and 86% of lesions were treated with full dose.
The majority of the cohort (57.4%) had been diagnosed with cancer < 12 months prior to treatment, and 21% had received prior therapy.
The majority of patients received full dose, 25 Gy x 3 fractions
Local control was 95%, however 30% of patients failed distantly.
Acute toxicity was mild with no grade 3-5 toxicity or radiation-induced liver disease. One patient developed grade 3 chest wall pain.
12 month overall survival was 83.5%, and 18 month overall survival was 60%
SBRT should be considered locally ablative for liver metastases if surgical resection is not feasible.
High dose radiation resulted in full ablation of larger lesions (> 3 cm) and radioresistant tumors.
A randomized controlled trial is needed to further evaluate the efficacy of SBRT for unresectable liver metastases.
Clinical and Scientific Implications
The liver is the most common site of metastatic disease after the lymph nodes, and a large number of primary cancers have a propensity to metastasize to the liver including colon, pancreas, breast, and lung.
Treatment options include surgery, ablation (chemoablation, radiofrequency ablation, alcohol ablation, etc.), and radiation therapy.
Radiation therapy has historically not been favored due to the low median tolerance of the liver, however advances in conformal therapy have made radiation therapy a more feasible option, particularly for patients with unresectable disease.
Several phase I/II studies have demonstrated the feasibility of SBRT for liver metastases. One notable and recent study was a multi-institutional phase I/II study describing 47 patients with lesions < 6 cm treated to maximum dose of 20 Gy x 3 fractions (total 60 Gy). The authors demonstrated excellent local control (Ruthoven, KR, JCO 2009)
Several other dose and fractionation schemes have been studied, and local control has been excellent with minimal toxicity.
The present study contributes to the literature by demonstrating the safety of further dose escalation, although the median follow-up was short and further follow-up is needed to ascertain the long-term effects of hypofractionation and high total doses.
The study also contributes by documenting the efficacy of SBRT in controlling larger lesions (> 3 cm in size).
Another interesting aspect of this study was the patterns-of-failure analysis. Although local control was excellent, 30% of patients failed in distant sites. This finding suggests that the addition of chemotherapy to SBRT may provide additional benefit. In fact, Brade et al are presenting the results of a phase I study of Sorafenib and SBRT for liver metastases elsewhere at the ASTRO 2012 Meeting (Presentation # 26).
The results presented in this study are encouraging. As primary treatment paradigms for colon, breast, and other cancers improve, management of metastatic disease becomes of critical importance. SBRT is a non-invasive way to safely and effectively treat liver metastases.
In spite of the strong points of this study, the results need to the validated in a Phase III clinical trial. As mentioned previously, there are numerous Phase I/II trials demonstrating the efficacy of SBRT in treating liver metastases, however limited randomized data exist comparing SBRT to other non-surgical approaches.
Jun 14, 2012 - A woman who was treated with stereotactic body-radiation therapy for two non-metastasized non-small-cell lung cancers died from fatal central-airway necrosis, according to a case report published in the June 14 issue of the New England Journal of Medicine.